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Immune-mediated disease genetics: The shared basis of pathogenesis
Abstract
Recent genetic studies in multiple autoimmune and inflammatory diseases have identified hundreds of genomic loci harboring risk variants. These variants are shared between diseases at unexpectedly high rates, providing a molecular basis for the shared pathogenesis of immune-mediated disease. If properly used, these results could allow us to identify specific pathways underlying disease; explain disease heterogeneity by grouping patients by molecular causes rather than overall symptomatology; and develop more rational approaches to diagnosis and therapy targeting these molecular defects. Here we review the current state of play in the genetics of immune-mediated disease, evidence for this sharing and how this new knowledge can lead to medically actionable discoveries of pathobiology.
... Previous investigations on the shared genetic effect of autoimmune diseases have identified numerous pleiotropic loci 29 . To identify the underlying causal pleiotropic variants and molecular pathways modulating autoimmune comorbidity, we systematically curated genome-wide studies (including cross-phenotype meta-analysis and pleiotropy analysis based on different statistical models) to identify the potential pleiotropic or shared genetic loci associated with at least two autoimmune diseases. ...
... Using pleiotropic variant-target gene relationships on each autoimmune disease, we constructed a bipartite network and visualized the genetic architecture among the investigated autoimmune diseases by compressing all pleiotropic variants from the same autoimmune disease into one node (Fig. 1e). The seronegative immune-driven diseases (including CD, UC, AS, PS, and primary sclerosing cholangitis [PSC]) and inflammatory systemic disorders (e.g., systemic lupus erythematosus [SLE] and systemic sclerosis [SSC]) were separately clustered and pushed away from other autoimmune diseases with different genetic sharing profiles in the collapsed network, which is highly consistent with previous findings 29 . We also found that rheumatoid arthritis (RA) was clustered with celiac disease (CeD), type 1 diabetes (T1D), and multiple sclerosis (MS) with respective distinct shared genes (Fig. 1e). ...
Genetic sharing is extensively observed for autoimmune diseases, but the causal variants and their underlying molecular mechanisms remain largely unknown. Through systematic investigation of autoimmune disease pleiotropic loci, we found most of these shared genetic effects are transmitted from regulatory code. We used an evidence-based strategy to functionally prioritize causal pleiotropic variants and identify their target genes. A top-ranked pleiotropic variant, rs4728142, yielded many lines of evidence as being causal. Mechanistically, the rs4728142-containing region interacts with the IRF5 alternative promoter in an allele-specific manner and orchestrates its upstream enhancer to regulate IRF5 alternative promoter usage through chromatin looping. A putative structural regulator, ZBTB3, mediates the allele-specific loop to promote IRF5-short transcript expression at the rs4728142 risk allele, resulting in IRF5 overactivation and M1 macrophage polarization. Together, our findings establish a causal mechanism between the regulatory variant and fine-scale molecular phenotype underlying the dysfunction of pleiotropic genes in human autoimmunity. Here the authors used an evidence-based strategy to prioritize causal pleiotropic variants of autoimmune diseases, and revealed that rs4728142 modulates aberrant IRF5 alternative promoter usage by ZBTB3-mediated chromatin looping.
... The collected summary data of genome-wide association studies (GWAS) represent, in a compressed form, assays of thousands of phenotypes across millions of common genetic variants. Analysed individually, GWAS have elucidated the polygenic component of common human diseases [1], and comparative studies of summary GWAS results have highlighted a shared genetic aetiology across different diseases [2]. Evidence for such sharing can highlight opportunities for therapeutic repurposing [3]. ...
... In a transfer learning paradigm, we can project independent datasets into this space, allowing us to study the distinct and shared genetic contributions to related diseases, and use standard statistical techniques to test for genetic association of rare diseases or genetic differences between disease subtypes. We use immunemediated diseases (IMD) as an example of a set of traits with established aetiological overlap [2] to highlight the potential uses of this method. ...
Background
Genome-wide association studies (GWAS) have identified pervasive sharing of genetic architectures across multiple immune-mediated diseases (IMD). By learning the genetic basis of IMD risk from common diseases, this sharing can be exploited to enable analysis of less frequent IMD where, due to limited sample size, traditional GWAS techniques are challenging.
Methods
Exploiting ideas from Bayesian genetic fine-mapping, we developed a disease-focused shrinkage approach to allow us to distill genetic risk components from GWAS summary statistics for a set of related diseases. We applied this technique to 13 larger GWAS of common IMD, deriving a reduced dimension “basis” that summarised the multidimensional components of genetic risk. We used independent datasets including the UK Biobank to assess the performance of the basis and characterise individual axes. Finally, we projected summary GWAS data for smaller IMD studies, with less than 1000 cases, to assess whether the approach was able to provide additional insights into genetic architecture of less common IMD or IMD subtypes, where cohort collection is challenging.
Results
We identified 13 IMD genetic risk components. The projection of independent UK Biobank data demonstrated the IMD specificity and accuracy of the basis even for traits with very limited case-size (e.g. vitiligo, 150 cases). Projection of additional IMD-relevant studies allowed us to add biological interpretation to specific components, e.g. related to raised eosinophil counts in blood and serum concentration of the chemokine CXCL10 (IP-10). On application to 22 rare IMD and IMD subtypes, we were able to not only highlight subtype-discriminating axes (e.g. for juvenile idiopathic arthritis) but also suggest eight novel genetic associations.
Conclusions
Requiring only summary-level data, our unsupervised approach allows the genetic architectures across any range of clinically related traits to be characterised in fewer dimensions. This facilitates the analysis of studies with modest sample size by matching shared axes of both genetic and biological risk across a wider disease domain, and provides an evidence base for possible therapeutic repurposing opportunities.
... In addition, extensive clinical and epidemiologic observations have shown that autoimmune/autoinflammatory diseases are characterized by familial clustering of multiple diseases, epidemiological co-occurrence, overlapped autoantibody level, and the efficacy of therapies across diseases. These observations provide evidence that different autoimmune/autoinflammatory diseases share a substantial portion of their pathobiology and genetic predisposition underlies disease susceptibility (4)(5)(6). ...
... Systematic and comprehensive searches for pleiotropic genes and their effects are essential for an understanding of the mechanisms underlying the development of autoimmune/autoinflammatory diseases (4). Compared to the univariate GWAS analysis based on a cross-sectional population, our study was cost-effective and reliable, not only due to the increased sample size achieved by integrating the summary statistics of seven large GWAS. ...
Although genome-wide association studies (GWAS) have a dramatic impact on susceptibility locus discovery, this univariate approach has limitations in detecting complex genotype-phenotype correlations. Multivariate analysis is essential to identify shared genetic risk factors acting through common biological mechanisms of autoimmune/autoinflammatory diseases. In this study, GWAS summary statistics, including 41,274 single nucleotide polymorphisms (SNPs) located in 11,516 gene regions, were analyzed to identify shared variants of seven autoimmune/autoinflammatory diseases using the metaCCA method. Gene-based association analysis was used to refine the pleiotropic genes. In addition, GO term enrichment analysis and protein-protein interaction network analysis were applied to explore the potential biological functions of the identified genes. A total of 4,962 SNPs (P < 1.21 × 10⁻⁶) and 1,044 pleotropic genes (P < 4.34 × 10⁻⁶) were identified by metaCCA analysis. By screening the results of gene-based P-values, we identified the existence of 27 confirmed pleiotropic genes and highlighted 40 novel pleiotropic genes that achieved statistical significance in the metaCCA analysis and were also associated with at least one autoimmune/autoinflammatory in the VEGAS2 analysis. Using the metaCCA method, we identified novel variants associated with complex diseases incorporating different GWAS datasets. Our analysis may provide insights for the development of common therapeutic approaches for autoimmune/autoinflammatory diseases based on the pleiotropic genes and common mechanisms identified.
... The development of co-occurring IMIDs may be attributed to a number of factors. These include genetic factors (9)(10)(11) and shared environmental factors such as smoking, lack of vitamin D, and the use of antibiotics (12)(13)(14). Considering the overlapping pathophysiology of IMIDs, it has been hypothesized that the gut microbiome of IMIDs might be similar (15) or, alternatively, may offer etiological clues to other diseases. ...
... Consistent with findings of gut microbiome studies in MS (26) and IBD (42), a reduction of Faecalibacterium and an increase in Actinobacteria have been reported in RA relative to healthy controls (9,43). Interestingly, contradictory findings for ...
There is a growing appreciation for the role of the gut microbiome in human health and disease. Aided by advances in sequencing technologies and analytical methods, recent research has shown the healthy gut microbiome to possess considerable diversity and functional capacity. Dysbiosis of the gut microbiota is believed to be involved in the pathogenesis of not only diseases that primarily affect the gastrointestinal tract but also other less obvious diseases, including neurologic, rheumatologic, metabolic, hepatic, and other illnesses. Chronic immune-mediated inflammatory diseases (IMIDs) represent a group of diseases that share many underlying etiological factors including genetics, aberrant immunological responses, and environmental factors. Gut dysbiosis has been reported to be common to IMIDs as a whole, and much effort is currently being directed toward elucidating microbiome-mediated disease mechanisms and their implications for causality. In this review, we discuss gut microbiome studies in several IMIDs and show how these studies can inform our understanding of the role of the gut microbiome in inflammatory bowel disease.
... However, any WGCNA network in the category of immune diseases can be added on, regardless of the given disease, if it passes a selection procedure. This is designated because genetic sharing is well-known to underlie the pathophysiology of immune or inflammatory diseases (Cotsapas and Hafler, 2013). In addition, by using PPI as the backbone network, we can expect some more (plausible) genes among those that interact with the known disease genes (a WGCNA network cannot be regarded as containing all genes related to an immune disease). ...
... Immune and inflammatory diseases have a strong genetic component with Mendelian patterns of inheritance (Gregersen and Olsson, 2009). Additionally, a major concept of the underlying pathophysiology of autoimmune diseases has been evaluated in genome-wide association scans, which have identified a degree of genetic sharing among autoimmune diseases such as rheumatoid arthritis and multiple sclerosis, among others (Cotsapas and Hafler, 2013). Although the common features of these diseases remain unclear, they are generally grouped in the immune category (Mariani, 2004). ...
Motivation:
Immune diseases have a strong genetic component with Mendelian patterns of inheritance. While the tight association has been a major understanding in the underlying pathophysiology for the category of immune diseases, the common features of these diseases remain unclear. Based on the potential commonality among immune genes, we design Gene Ranker for key gene identification.
Methods:
Gene Ranker is a network-based gene scoring algorithm that initially constructs a backbone network based on protein interactions. Patient gene expression networks are added into the network. An add-on process screens the networks of weighted gene co-expression network analysis (WGCNA) on the samples of immune patients. Gene Ranker is disease-specific; however, any WGCNA network that passes the screening procedure can be added on. With the constructed network, it employs the semi-supervised learning for gene scoring.
Results:
The proposed method was applied to immune diseases. Based on the resulting scores, Gene Ranker identified potential key genes in immune diseases. In scoring validation, an average area under the receiver operating characteristic curve of 0.82 was achieved, which is a significant increase from the reference average of 0.76. Highly ranked genes were verified through retrieval and review of 27 million PubMed literatures. As a typical case, 20 potential key genes in rheumatoid arthritis were identified: 10 were de facto genes and the remaining were novel.
Supplementary information:
Supplementary data are available at Bioinformatics online.
... 68 As these results emerged, it became obvious that many loci were associated with multiple diseases and that the genes encoded in those loci fall into distinct immune pathways. 69,70 These results suggest that perturbations to key immune processes mediate risk to multiple diseases. For example, loci encoding the core components of the IL-23-mediated signalling pathway mediate risk for MS, psoriasis and Crohn's disease and those involved in IL-2-mediated signalling with rheumatoid arthritis and type I diabetes. ...
... However, those associations unique to MS may identify disease-specific biology, including CNS-relevant mechanisms. 69 ...
Large-scale genetic studies of multiple sclerosis have identified over 230 risk effects across the human genome, making it a prototypical common disease with complex genetic architecture. Here, after a brief historical background on the discovery and definition of the disease, we summarise the last fifteen years of genetic discoveries and map out the challenges that remain to translate these findings into an aetiological framework and actionable clinical understanding. © 2018 The Authors. Clinical & Translational Immunology published by John Wiley & Sons Australia, Ltd on behalf of Australasian Society for Immunology Inc.
... As such, there remains significant space for development in SNP identification tools, precision, sensibility, and effectiveness. Autoimmune disease-associated genes Immune-related diseases, including celiac disease, inflammatory bowel disease, heart disease, arthritis, diabetes, and multiple sclerosis, are a variety of biologically complex disorders that result from autoimmune malfunction and share basic pathogenic processes that remain unclear, although it is commonly believed to develop as a result of an imbalance interaction of environmental as well as genetic variables [33,34]. It exhibits abnormalities of several significant regulatory processes, and methods such as GWAS along with NGS have greatly enhanced our awareness of biological factors [35]. ...
The etiology and clinical manifestations of immune-mediated diseases are known to be attributed to a variety of hereditary and environmental variables. In the instance of the genetic factor, genetic variations have been identified in a range of autoimmune disorders. Genome-wide association studies (GWAS) are a viable approach for determining the inherited basis of disease-causing genes. We can investigate mutation or polymorphisms correlated to identify the diseases and predict outcomes by fully understanding these results. Autoimmune diseases are distinguished by a lack of self-tolerance, which results in immune-mediated tissue damage and chronic inflammation. Although studies indicate associations between single nucleotide polymorphism (SNPs) in the human genome and autoimmune disorders, the findings are still ambiguous. A literature review was explored to identify the relationship between polymorphisms and autoimmune disease. In this study, we will discuss the significant outcomes of GWAS in common autoimmune conditions such as multiple sclerosis, diabetes, migraine, Parkinson's disease, and Alzheimer's disease. We further explore the prospective role of these innovations in terms of disease forecasting, basic biology, and the development of possible therapies. Continuous developments in technology and analytic methods have boosted the effectiveness and efficiency of genetic mapping approaches.
... Pleiotropic effects on human diseases are very common. For example, several studies have reported shared genetic markers among immune-mediated diseases (7,8), such as asthma, allergy, rheumatoid and psoriatic arthritis, and Crohn's disease. While some of these shared associations make immediate, intuitive sense (like diabetes-hypothyroidism (9)), others are more subtle. ...
Background: Case-control studies are efficient designs for investigating gene-disease associations. A discovery of genome-wide association studies (GWAS) is that many genetic variants are associated with multiple health outcomes and diseases, a phenomenon known as pleiotropy. We aimed to discuss about pleiotropic bias in genetic association studies. Methods: The opinions of the researchers on the basis of the literature were presented as a critical review. Results: Pleiotropic effect can bias the results of gene-disease association studies if they use individuals with pre-existing diseases as the control group, while the disease in cases and controls have shared genetic markers. The idea supports the conclusion that when the exposure of interest in a case-control study is a genetic marker, the use of controls from diseased cases that share similar genetic markers may increase the risk of pleiotropic effect. However, not manifesting the disease symptoms among controls at the time of recruitment does not guarantee that the individual will not develop the disease of interest in the future. Age-matched disease-free controls may be a better solution in similar situations. Different analytical techniques are also available that can be used to identify pleiotropic effects. Known pleiotropic effects can be searched from various online databases. Conclusion: Pleiotropic effects may result in bias in genetic association studies. Suggestions consist of selecting healthy yet age-matched controls and considering diseases with independent genetic architecture. Checking the related databases is recommended before designing a study.
... 3.4 SIgAD has significant genetic correlation with a range of immune-mediated diseases is well-attested [126][127][128] and five of the nine loci we report to be associated with SIgAD in Table 1 are also associated with other IMDs (Supplementary Table 6). ...
Selective IgA deficiency (SIgAD) is the most common inborn error of immunity (IEI). Unlike many IEIs, evidence of a role for highly penetrant rare variants in SIgAD is lacking. Known SIgAD-associated variants are common in the general population, but previous studies have had limited power to identify common-variant associations due to their small sample size. We sought to overcome this problem first through meta-analysis of two existing GWAS. This identified four novel common-variant associations and we found also that SIgAD-associated variants were enriched in genes known to harbour variants causal for Mendelian IEIs. SIgAD showed evidence of shared genetic architecture with serum IgA and a number of immune-mediated diseases. To further enhance power, we leveraged this pleiotropy through the conditional false discovery rate procedure, conditioning our SIgAD meta-analysis on large GWAS of asthma and rheumatoid arthritis, and our own meta-analysis of serum IgA. This identified an additional 17 variants associated with SIgAD. Our results increase the number of known SIgAD-associated variants outside the MHC to 26 and strengthen the evidence for a polygenic, common-variant aetiology for SIgAD, highlighting both T- and B-cell biology in the development of this disease. Our approach to genetic variant discovery is relevant to the study of other rare diseases and we hypothesise genes newly associated with SIgAD might be explored for as-yet elusive rare-variant associations with SIgAD or IEIs more generally.
... The existence of pleiotropic loci manifesting cross-phenotype effects across many immunemediated diseases is well-attested [6,39,[47][48][49][50]. We surveyed UKBB disease traits to identify groups of immune-and non-immune-related diseases, including phenotypes with small, medium, and large numbers of cases (Table 2). ...
Assessment of the genetic similarity between two phenotypes can provide insight into a common genetic aetiology and inform the use of pleiotropy-informed, cross-phenotype analytical methods to identify novel genetic associations. The genetic correlation is a well-known means of quantifying and testing for genetic similarity between traits, but its estimates are subject to comparatively large sampling error. This makes it unsuitable for use in a small-sample context. We discuss the use of a previously published nonparametric test of genetic similarity for application to GWAS summary statistics. We establish that the null distribution of the test statistic is modelled better by an extreme value distribution than a transformation of the standard exponential distribution. We show with simulation studies and real data from GWAS of 18 phenotypes from the UK Biobank that the test is to be preferred for use with small sample sizes, particularly when genetic effects are few and large, outperforming the genetic correlation and another nonparametric statistical test of independence. We find the test suitable for the detection of genetic similarity in the rare disease context.
... Cross-trait 37 linkage disequilibrium score regression (LDSC) allows the fast estimation of each trait's 38 heritability and the genetic covariance of trait pairs using GWAS summary statistics 39 instead 15,16 . LDSC correlation estimates for a large number of phenotype pairs are now 40 publicly available online [17][18][19] . The more recently published SumHer program, part of 41 the LDAK software package, offers similar functionality to LDSC 21 . ...
Assessment of the genetic similarity between two phenotypes can provide insight into a common genetic aetiology and inform the use of pleiotropy-informed, cross-phenotype analytical methods to identify novel genetic associations. The genetic correlation is a well-known means of quantifying and testing for genetic similarity between traits, but its estimates are subject to comparatively large sampling error. This makes it unsuitable for use in a small-sample context. We discuss the use of a nonparametric test of genetic similarity first introduced by Li et al. for application to GWAS summary statistics. We establish that the null distribution of the test statistic is modelled better by an extreme value distribution than a transformation of the standard exponential distribution as originally recommended by Li and colleagues. We show with simulation studies and real data from GWAS of 18 phenotypes from the UK Biobank that the test is to be preferred for use with small sample sizes, particularly when genetic effects are few and large, outperforming the genetic correlation and another nonparametric statistical test of independence. We find the test suitable for the detection of genetic similarity in the rare disease context.
Author summary
The genome-wide association study (GWAS) is a method used to identify genetic variants which contribute to the risk of developing disease. These genetic variants are frequently shared between conditions, such that the study of the genetic basis of one disease can be informed by knowledge of another, similar disease. This approach can be productive where the disease in question is rare such that a GWAS has less power to associate variants with the disease, but there exist larger GWAS of similar diseases. Existing methods do not measure genetic similarity precisely when patients are few. Here we assess a previously published method of testing for genetic similarity between pairs of diseases using GWAS data, the ‘GPS’ test, against three other methods with the use of real and simulated data. We present a new computational procedure for carrying out the test and show that the GPS test is superior to its comparators in identifying genetic similarity when the sample size is small and when the genetic similarity signal is less strong. Use of the test will enable accurate detection of genetic similarity and the study of rarer conditions using data from better-characterised diseases.
... Although future validation will be required before it can be implemented in the clinic, the test could eliminate the requirement for biopsies in the rural or indigent areas (12). An autoimmune disease called rheumatoid arthritis (RA) affects joints leading to chronic inflammation (13). In individuals complaining from (RA) a specific type of antibodies detected, and called anti-cyclic citrullinated peptides (anti-ccp) (14) (15). ...
All the patients diagnosed as having autoimmune disease by the clinical examiner and confirmed the diagnosis by laboratory results. Serum samples obtained from patient’s blood and tested for the presence of specific autoantibodies using commercial ELISA kits. Out of 342 patients, 240(70.2%) were diagnosed with celiac disease, 94(27.5%) with Rheumatoid arthritis and 8(2.3%) with Systemic lupus erythematosus (SLE). Results of ELISA test indicated statistically significant increased level of antibodies specific to anti-gliadin (IgA and IgG) and anti-tTg (IgA and IgG) antibodies in patients with celiac disease (p-value< 0.001). Results indicated statistically significant level of (ANA) and (Anti-ccp) in individuals suffering from rheumatoid arthritis. Regarding to (anti-dsDNA), (anti-cardiolipin) and (anti-phospholipids), a statistically significant increased levels detected in individuals with SLE.
... Immune-mediated inflammatory diseases (IMIDs) represent a diverse group of chronic inflammatory and autoimmune disorders that share common inflammatory pathways [1][2][3]. The etiology of these complex diseases is multifactorial, including environmental, microbial, immune and genetic factors, resulting in immune dysregulation and excessive inflammation in the affected organs. ...
Immune-mediated inflammatory diseases (IMIDs) represent a diverse group of diseases and challenges remain for the current medications. Herein, we present an activatable and targeted nanosystem for detecting and imaging IMIDs foci and treating them through blocking NF-κB/NLRP3 pathways. A ROS-activatable prodrug BH-EGCG is synthesized by coupling a near-infrared chromophore with the NF-κB/NLRP3 inhibitor epigallocatechin-3-gallate (EGCG) through boronate bond which serves as both the fluorescence quencher and ROS-responsive moiety. BH-EGCG molecules readily form stable nanoparticles in aqueous medium, which are then coated with macrophage membrane to ensure the actively-targeting capability toward inflammation sites. Additionally, an antioxidant precursor N-acetylcysteine is co-encapsulated into the coated nanoparticles to afford the nanosystem BH-EGCG&[email protected] to further improve the anti-inflammatory efficacy. Benefiting from the inflammation-homing effect of the macrophage membrane, the nanosystem delivers payloads (diagnostic probe and therapeutic drugs) to inflammatory lesions more efficiently and releases a chromophore and two drugs upon being triggered by the overexpressed in-situ ROS, thus exhibiting better theranostic performance in the autoimmune hepatitis and hind paw edema mouse models, including more salient imaging signals and better therapeutic efficacy via inhibiting NF-κB pathway and suppressing NLRP3 inflammasome activation. This work may provide perceptions for designing other actively-targeting theranostic nanosystems for various inflammatory diseases.
... Many immune-mediated diseases share many risk loci with the same directional effect, exhibiting high genetic correlations [112][113][114][115]. A recent study by Peyrot et al. devised a new method called case-case GWAS (CC-GWAS) to test differences in allele frequencies and measure a genetic distance between similar diseases using summary statistics [116]. ...
Systemic lupus erythematosus (SLE) is a polygenic chronic autoimmune disease leading to multiple organ damage. A large heritability of up to 66% is estimated in SLE, with roughly 180 reported susceptibility loci that have been identified mostly by genome-wide association studies (GWASs) and account for approximately 30% of genetic heritability. A vast majority of risk variants reside in non-coding regions, which makes it quite challenging to interpret their functional implications in the SLE-affected immune system, suggesting the importance of understanding cell type-specific epigenetic regulation around SLE GWAS variants. The latest genetic studies have been highly fruitful as several dozens of SLE loci were newly discovered in the last few years and many loci have come to be understood in systemic approaches integrating GWAS signals with other biological resources. In this review, we summarize SLE-associated genetic variants in both the major histocompatibility complex (MHC) and non-MHC loci, examining polygenetic risk scores for SLE and their associations with clinical features. Finally, variant-driven pathogenetic functions underlying genetic associations are described, coupled with discussion about challenges and future directions in genetic studies on SLE.
... 2 , 3 Common examples of IMDs include inflammatory bowel disease (IBD), systemic lupus erythematosus (SLE), multiple sclerosis (MS), rheumatoid arthritis (RA), psoriasis, and scleroderma. 4 Despite the diversity of organ systems affected, most IMDs result from the interplay of genetic and environmental factors and include alternating periods of disease flares and remission. 4 , 5 Although no curative therapies exist for IMDs, achieving disease remission is a realistic therapeutic goal for several IMDs (eg, IBD and RA). ...
Purpose
This study assessed the association between thromboembolic events (TEs) and immune-mediated diseases (IMDs) and characterized the risk profile of TEs among patients with IMDs.
Methods
An administrative claims database (2014–2018) was used to identify adults with ≥2 diagnoses on different dates for ≥1 IMD (IMD cohort; ankylosing spondylitis, atopic dermatitis, inflammatory bowel disease, multiple sclerosis, psoriasis, psoriatic arthritis, rheumatoid arthritis, and systemic lupus erythematosus); patients without an IMD diagnosis were assigned to the non-IMD cohort. Patients in the IMD cohort were matched 1:1 to patients in the non-IMD cohort on age, sex, and index date. Incremental risk of TE (ie, deep vein thrombosis [DVT], pulmonary embolism [PE], myocardial infarction [MI], and ischemic stroke [IS]) was assessed using adjusted incidence rate ratios (aIRRs) to control for covariates in both cohorts. Risk factors for TEs were assessed in the IMD cohort and included age, female sex, comorbidities, baseline TEs, non-IMD treatments, and IMD treatments.
Findings
A total of 182,431 patients were included in each cohort (mean age, [51.3] years; 64.3% female). A higher proportion of patients in the IMD cohort versus the non-IMD cohort had ≥1 baseline TE (4.1% vs 2.7%; P < 0.0001). The IMD cohort had a 1.80 (95% CI, 1.68–1.92; P < 0.0001) times higher rate of TEs versus patients in the non-IMD cohort. After adjustments, patients in the IMD cohort had a 1.49 (95% CI, 1.40–1.59; P < 0.0001) times higher rate of TEs versus patients in the non-IMD cohort. Similar results were observed across individual TEs (DVT: aIRR = 1.78; PE: aIRR = 1.66; MI: aIRR = 1.17; IS: aIRR = 1.35; all P < 0.05). Risk factor profiles varied by TE. The greatest risk factor was respective TE during baseline (eg, patients with baseline DVT had 41.1 times the rate of DVT during the study period vs patients without baseline DVT; P < 0.001). Comorbidities, such as cardiovascular diseases, type 2 diabetes, and peripheral vascular disease, were associated with increased rates of MI (IRR = 2.60, 1.30, and 1.54, respectively; all P < 0.05) and IS (IRR = 1.53, 1.54, and 1.24, respectively; all P < 0.05). Janus kinase inhibitors were associated with an increased rate of PE (IRR = 2.52; P < 0.05) and nonsignificant, numerically higher rates of DVT (IRR = 1.23; P = NS) and IS (IRR = 1.82; P = NS). Sphingosine 1-phosphate receptor modulators were associated with decreased rates of TEs (DVT: IRR = 0.61, P = NS; PE: IRR = 0.30, P = NS; MI: IRR = 0.54, P = NS; IS: IRR = 0.33, P < 0.05).
Implications
The risk of TEs was higher among patients with IMD versus patients without IMD; several factors may affect this risk.
... The comorbidity problem is by no means unique to psychiatry. Similar sets of results with respect to familial clustering, cross-disorder treatment effects, and high levels of pleiotropy are observed across autoimmune disorders including Crohn's disease, rheumatoid arthritis, and type 1 diabetes (for review see Cotsapas & Hafler, 2013). This has resulted in analogous conversations surrounding revision of autoimmune nosology and highlights an important point: Type 1 diabetes and arthritis certainly appear quite different, but despite our observation the biology points towards a conglomeration of both cross-cutting and distinct pathways. ...
Psychiatric disorders overlap substantially at the genetic level, with family-based methods long pointing toward transdiagnostic risk pathways. Psychiatric genomics has progressed rapidly in the last decade, shedding light on the biological makeup of cross-disorder risk at multiple levels of analysis. Over a hundred genetic variants have been identified that affect multiple disorders, with many more to be uncovered as sample sizes continue to grow. Cross-disorder mechanistic studies build on these findings to cluster transdiagnostic variants into meaningful categories, including in what tissues or when in development these variants are expressed. At the upper-most level, methods have been developed to estimate the overall shared genetic signal across pairs of traits (i.e. single-nucleotide polymorphism-based genetic correlations) and subsequently model these relationships to identify overarching, genomic risk factors. These factors can subsequently be associated with external traits (e.g. functional imaging phenotypes) to begin to understand the makeup of these transdiagnostic risk factors. As psychiatric genomic efforts continue to expand, we can begin to gain even greater insight by including more fine-grained phenotypes (i.e. symptom-level data) and explicitly considering the environment. The culmination of these efforts will help to inform bottom-up revisions of our current nosology.
... As complex diseases often share biological pathways, VTE GWAS findings might bring a new understanding of the genetic architecture that influences OC initiation and progression and the acquisition of cellular chemoresistant behaviour, which could help to personalise the treatment approaches aiming a better clinical outcome [85]. In this context, the present study is the first to analyse the impact of VTE-associated SNPs reported by GWAS on the clinical outcome of OC patients. ...
Ovarian cancer (OC) represents the most lethal gynaecological neoplasia. Conversely, venous thromboembolism (VTE) and OC are intricately connected, with many haemostatic components favouring OC progression. In light of this bilateral relationship, genome-wide association studies (GWAS) have reported several single-nucleotide polymorphisms (SNPs) associated with VTE risk that could be used as predictors of OC clinical outcome for better therapeutic management strategies. Thus, the present study aimed to analyse the impact of VTE GWAS-identified SNPs on the clinical outcome of 336 epithelial ovarian cancer (EOC) patients. Polymorphism genotyping was performed using the TaqMan® Allelic Discrimination methodology. Carriers with the ZFPM2 rs4734879 G allele presented a significantly higher 5-year OS, 10-year OS and disease-free survival (DFS) compared to AA genotype patients with FIGO I/II stages (P = 0.009, P = 0.001 and P = 0.003, respectively). Regarding SLC19A2 rs2038024 polymorphism, carriers with the CC genotype presented a significantly lower 5-year OS, 10-year OS and DFS compared to A allele carriers in the same FIGO subgroup (P < 0.001, P = 0.004 and P = 0.005, respectively). As for CNTN6 rs6764623 polymorphism, carriers with the CC genotype presented a significantly lower 5-year OS compared to A allele carriers with FIGO I/II stages (P = 0.015). As for OTUD7A rs7164569, F11 rs4253417 and PROCR rs10747514, no significant impact on EOC patients’ survival was observed. However, future studies are required to validate these results and uncover the biological mechanisms underlying our results.
... Genetic factors may play a major role [9], whereas other studies have indicated a correlation between pathogenic infections and the development of the disease [10]. Several genetic variations are shared within different autoimmune diseases suggesting several common pathogeneses [11]. Currently, the most widely accepted hypothesis is that MS is an autoimmune disease that affects genetically predisposed individuals afflicted with an environmental pathogen [12]. ...
... Multiple sclerosis (MS) commonly occurs as a progressive central nervous system (CNS) disease, characterized by inflammation, demyelination, and axonal loss in the brain and spinal cord [1]. T cell-mediated inflammatory pathology and genetic factors are closely involved in the development of MS, causing damage to myelin sheaths surrounding neuronal axons and accumulation of neurological deficits [2][3][4]. Environmental factors also play a driving role in the pathogenesis of MS, such as geographical latitude, vitamin D3 deficiency, early life obesity, passive smoking, Epstein-Barr virus infection, dietary habits (especially high salt and fat diet), stress, and gut microbiota (GM) [5]. Study has shown that transplanting the intestinal microbiota of autism spectrum disorder patients into germ-free mice and that colonization of the microbiota induced typical autism spectrum disorder behaviors [6]. ...
Given the growing evidence of a link between gut microbiota (GM) dysbiosis and multiple sclerosis (MS), fecal microbiota transplantation (FMT), aimed at rebuilding GM, has been proposed as a new therapeutic approach to MS treatment. To evaluate the viability of FMT for MS treatment and its impact on MS pathology, we tested FMT in mice with experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. We provide evidence that FMT can rectify altered GM to some extent with a therapeutic effect on EAE. We also found that FMT led to reduced activation of microglia and astrocytes and conferred protection on the blood-brain barrier (BBB), myelin, and axons in EAE. Taken together, our data suggest that FMT, as a GM-based therapy, has the potential to be an effective treatment for MS.
... Over 50% of genome-wide significant autoimmune disease associations are shared by at least two distinct autoimmune diseases [60,61]. Several studies have combined data from multiple diseases in order to increase power to detect novel loci. ...
Purpose of Review
To provide an updated summary of discoveries made to date resulting from genome-wide association study (GWAS) and sequencing studies, and to discuss the latest loci added to the growing repertoire of genetic signals predisposing to type 1 diabetes (T1D).
Recent Findings
Genetic studies have identified over 60 loci associated with T1D susceptibility. GWAS alone does not specifically inform on underlying mechanisms, but in combination with other sequencing and omics-data, advances are being made in our understanding of T1D genetic etiology and pathogenesis. Current knowledge indicates that genetic variation operating in both pancreatic β cells and in immune cells is central in mediating T1D risk.
Summary
One of the main challenges is to determine how these recently discovered GWAS-implicated variants affect the expression and function of gene products. Once we understand the mechanism of action for disease-causing variants, we will be well placed to apply targeted genomic approaches to impede the premature activation of the immune system in an effort to ultimately prevent the onset of T1D.
... 16 Many genetic variants are shared across several autoimmune diseases suggesting some common pathogenesis. 17 Although most of the genetic work in MS has been conducted in populations with European ancestry, recent studies in African Americans have shown a significant overlap with MS variants reported in Whites. 18 Environmental factors (see also Table 1) ...
Recent findings have provided a molecular basis for the combined contributions of multifaceted risk factors for the onset of multiple sclerosis (MS). MS appears to start as a chronic dysregulation of immune homeostasis resulting from complex interactions between genetic predispositions, infectious exposures, and factors that lead to pro‐inflammatory states, including smoking, obesity, and low sun exposure. This is supported by the discovery of gene–environment (GxE) interactions and epigenetic alterations triggered by environmental exposures in individuals with particular genetic make‐ups. It is notable that several of these pro‐inflammatory factors have not emerged as strong prognostic indicators. Biological processes at play during the relapsing phase of the disease may result from initial inflammatory‐mediated injury, while risk factors for the later phase of MS, which is weighted toward neurodegeneration, are not yet well defined. This integrated review of current evidence guides recommendations for clinical practice and highlights research gaps.
... Aunque cada una de estas enfermedades tiene características clínicas diferentes, su rasgo común es un desequilibrio de las citocinas inflamatorias, común igualmente en su patogénesis (1,2,3,4) . Tanto el factor genético como el ambiental parecen jugar un papel importante en el desarrollo de estos trastornos (5,6) . ...
Objective:
Immune-mediated inflammatory diseases (IMID) are chronic and highly disabling diseases that share inflammatory sequences and immunological dysregulations. Considered as a disease in itself, the prevalence of IMID is virtually unknown. The aim of this study was to assess the prevalence of 10 selected UDI, including rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, ulcerative colitis, Crohn's disease, systemic lupus erythematosus, hidradenitis suppurativa, sarcoidosis and uveitis in Spain.
Methods:
cross-sectional epidemiological study of point prevalence was made. This study was carried out through a series of computerized interviews in households chosen at random in 17 autonomous communities in Spain. A structured questionnaire was used to determine the frequency of diagnosis and the concurrence of 10 IMID in the respondents and other individuals belonging to the same family nucleus. The point prevalence estimates were used and compared with the objective of determining the frequency of IMID by age, sex and communities. The data were processed using Excel 2016 (Microsoft, Redmond, WA, USA) and the SPSS V.019 system (IBM Corp. Armonk, NY, USA) for statistical analysis using the usual statistical tests in this type of studies.
Results:
Of the 7,980 respondents, 510 were diagnosed with an IMID, representing a cross-sectional study of 6.39% (95% CI: 6.02-6.76). One, two, three or more members of the family were affected in 87.2%, 7.8% and 5% of positive relatives in IMID, respectively. The most recurrent diseases were psoriasis (2.69% [95% CI: 2.32-3.06]) and rheumatic arthritis (1.07% [95% CI: 0.70-1.44]). There were differences in prevalence due to sex (p = 0.004) and age (p = 0.000). No significant differences were identified related to geographic location (p = 0.819). Attendance of at least 2 IMID was reported in 8.9% of respondents.
Conclusions:
The overall prevalence was of the IMID studied was 6.39%, psoriasis being the most frequent with 2.69%. This study constitutes an initial step to consider IMID as an independent disease within the health system..
... Immune mediated disorders, such as celiac disease (CeD), inflammatory bowel diseases (IBD), atherosclerosis, rheumatoid arthritis (RA), type 1 diabetes (T1D) or multiple sclerosis (MS) among others, are a group of clinically heterogeneous diseases caused by dysfunction of the immune system. These disorders, share underlying pathogenic mechanisms that are not totally understood, although the general belief is that they develop due to an imbalance in the interaction between genetic and environmental factors (1,2). ...
Immune-mediated diseases, such as celiac disease, type 1 diabetes or multiple sclerosis, are a clinically heterogeneous group of diseases that share many key genetic triggers. Although the pathogenic mechanisms responsible for the development of immune mediated disorders is not totally understood, high-throughput genomic studies, such as GWAS and Immunochip, performed in the past few years have provided intriguing hints about underlying mechanisms and pathways that lead to disease. More than a hundred gene variants associated with disease susceptibility have been identified through such studies, but the progress toward understanding the underlying mechanisms has been slow. The majority of the identified risk variants are located in non-coding regions of the genome making it difficult to assign a molecular function to the SNPs. However, recent studies have revealed that many of the non-coding regions bearing disease-associated SNPs generate long non-coding RNAs (lncRNAs). LncRNAs have been implicated in several inflammatory diseases, and many of them have been shown to function as regulators of gene expression. Many of the disease associated SNPs located in lncRNAs modify their secondary structure, or influence expression levels, thereby affecting their regulatory function, hence contributing to the development of disease.
... It is also possible that each individual variant can have a large molecular effect in the pathway of immune function but only account for a small fraction of disease susceptibility as a whole. 16 In fact, we have demonstrated that RA biological genes, which were identified by a transethnic meta-analysis of GWAS and subsequently predicted in silico, are the targets of approved therapies for RA, and thus further suggested that drugs approved for other indications may be repurposed for the treatment of RA. 14 Acosta-Herrera et al also discuss the possible drug repositioning to SLE, SSc and dermatomyositis as described above. Further, as GWAS predicted that psoriasis, IBD and AS could be the leading disease indications for anti-IL-17 and anti-IL-23 treatments, several of these treatments have been in fact approved and some are now in the midst of ongoing clinical studies. ...
... While it is still unknown what causes the disease, several environmental risk factors could be identified. An increased risk to develop MS is associated with environmental factors such as infection with Epstein-Barr virus, cigarette smoking, high-salt intake, vitamin D deficiency, and genetic factors, mostly associated with immune function [2]. Here, variations within the major histocompatibility complex exert the greatest risk [3]. ...
Multiple sclerosis treatment faces tremendous changes as a result of the approval of new medications. The new medications have differing safety considerations and risks after long-term treatment, which are important for treating physicians to optimize and individualize multiple sclerosis care. Since the approval of the first multiple sclerosis capsule, fingolimod, the armamentarium of multiple sclerosis therapy has grown with the orally available medications dimethyl fumarate and teriflunomide. Fingolimod is mainly associated with cardiac side effects, dimethyl fumarate with bowel symptoms. Several reports about progressive multifocal leukoencephalopathy as a result of dimethyl fumarate or fingolimod therapy raised the awareness of fatal opportunistic infections. Alemtuzumab, a CD52-depleting antibody, is highly effective in reducing relapses but leads to secondary immunity with mainly thyroid disorders in about 30% of patients. Development of secondary B-cell-mediated disease might also be a risk of this antibody. The follow-up drug of the B-cell-depleting antibody rituximab, ocrelizumab, is mainly associated with infusion-related reactions; long-term data are scarce. The medication daclizumab high yield process, acting via the activation of CD56brightnatural killer cells, can induce the elevation of liver function enzymes, but also fulminant liver failure has been reported. Therefore, daclizumab has been retracted from the market. Long-term data on the purine nucleoside cladribine in MS therapy, recently authorized in the European Union, have been acquired during the long-term follow-up of the cladribine studies. The small molecule laquinimod is currently under development. We review data of clinical trials and their extensions regarding long-term efficacy and side effects, which might be associated with long-term treatment.
... Mutations in the encoding gene CTLA4 have recently been discovered in families with Mendelian multi-organ autoimmune disease syndromes [9]. These rare mutations (including missense, nonsense, and splice variants) cause severe disease in heterozygous patients. ...
Disorders in immune system cause auto immune diseases in human and it affects almost 10% of population. Mendelian syndromes of auto immunity have an impact on monogenic mutations and it results in lack of tolerance in central and peripheral system. Most of the auto immune disorders arise from the complex interaction between polygenic risk component and an environmental component. Risk factor can contribute to individual changes in nucleotides. Genome wide association studies (GWAS) can provide the list of biological pathways that drives the auto immune diseases in humans. Interpretation of GWAS requires the integration of multiple datasets in genomics. Improvised level of understanding in auto immunity with respect to genetics will lead to the development of novel diagnostics and targeted therapies
... Some of these loci are also being shared across these diseases 4 and are involved in the certain biological pathways. 38 Studies have shown that several genetic loci can have opposite effects in different AIDs. 39 For studies like our study, it is thus very essential to look at what kind of AIDs are studied in relation to MS, because some AIDs will and some will not cluster with each other. ...
Objectives:
Autoimmune diseases (AIDs) cluster in families; however, to what extent AIDs co-occur in MS multiplex families with two or more affected individuals is still controversial. The study aimed to evaluate coexisting AIDs in this type of families from the Netherlands.
Materials and methods:
A total of 155 MS multiplex families (155 MS probands, 959 first-degree relatives and 212 spouses) were characterized for a history of 11 AIDs by means of a self-administered questionnaire.
Results:
In 43.2% of MS multiplex families, at least one AID was present in the first-degree relatives. Overall, the frequency of AIDs was not significantly different between patients with MS (11%), their first-degree family members (11%) and controls (5.2%). After correction for age at inclusion and gender, the odds ratios (OR) for AIDs were not significant for patients with MS (OR = 1.8 [0.77-4.34], P = .17) and first-degree family members (OR = 2.0 [0.98-4.10], P = .06) when both compared to spouses. The frequency of AIDs in mothers did not differ from that in fathers after correction for sex bias (19% vs 8%, P = .51). A presence of AID was more often reported in maternal than paternal second-degree relatives (23% vs 10%, P = .0020).
Conclusion:
Although nearly half of the Dutch MS multiplex families reported an AID, no excess of AIDs was present in patients with MS from multiplex families or their first-degree family members compared to the spouses.
... Only for a few association signals has the causal gene been identified, and for even fewer have the causal variant and underlying mechanism been defined. While some of the susceptibility loci outside the MHC appear to be disease-or phenotype-specific, many others are shared across IMDs and implicate similar susceptibility pathways in multiple diseases [12,13,[19][20][21][22]. For particular IMDs 70 or more non-HLA risk loci were identified. ...
Chronic immune-mediated disorders (IMDs) constitute a major health burden. Understanding IMD pathogenesis is facing two major constraints: Missing heritability explaining familial clustering, and missing autoantigens. Pinpointing IMD risk genes and autoimmune targets, however, is of fundamental importance for developing novel causal therapies. The strongest association of all IMDs is seen with human leukocyte antigen (HLA) alleles. Using psoriasis as an IMD model this article reviews the pathogenic role HLA molecules may have within the polygenic predisposition of IMDs. It concludes that disease-associated HLA alleles account for both missing heritability and autoimmune mechanisms by facilitating tissue-specific autoimmune responses through autoantigen presentation.
In this first chapter of the “autoimmunity” part, some basic principles in the development of autoimmune diseases are reviewed, focusing on conceptual mechanisms of central and peripheral T cell and B cell tolerance induction to self/self antigens. The centerpiece of this overview is the presentation of the danger/injury model of tolerance induction, which states that it is the responsibility of the peripheral bodily tissue, rather than the innate or adaptive immune system, to take control over immunity: The tissue decides whether protective peripheral tolerance or dangerous immune responses to self are ultimately induced. The tenor of the model here is: Antigenic stimulus (signal 1) presented by “healthy” tissue cells in the absence of damage-associated molecular patterns (DAMPs) establishes immune tolerance; and antigenic stimulus presented by “unhealthy” tissue cells in the presence of stress/injury-induced DAMPs, that is, along with the provision of DAMP-induced costimulation (signal 2), promotes destructive adaptive autoimmune responses. Hereinafter, some typical examples of autoimmunity to native self and altered-self antigens (neoantigens) are discussed as seen in the light of the danger/injury model. Following a change of the topic, autoimmune mechanisms of tissue destruction as sources of DAMPs emission are discussed, including the emerging role of autoantigen/autoantibody immune complexes and cytotoxic T lymphocytes in triggering subroutines of regulated cell death that serve as prolific sources of DAMPs. As a wrap-up to this chapter, the critical role of the environment and genetics in the etiopathogenesis of autoimmune diseases are discussed by highlighting the role of epigenetics as the link between the environmental factors that operate as exogenous DAMPs or induce endogenous DAMPs in the host and genetical factors, which determine the susceptibility of patients to autoimmune diseases.
The activation of the immune system is critical for cancer immunotherapy and treatments of inflammatory diseases. Non-invasive visualization of immunoactivation is designed to monitor the dynamic nature of the immune response and facilitate the assessment of therapeutic outcomes, which, however, remains challenging. Conventional imaging modalities, such as positron emission tomography, computed tomography, etc., were utilized for imaging immune-related biomarkers. To explore the dynamic immune monitoring, probes with signals correlated to biomarkers of immune activation or prognosis are urgently needed. These emerging molecular probes, which turn on the signal only in the presence of the intended biomarker, can improve the detection specificity. These probes with "turn on" signals enable non-invasive, dynamic, and real-time imaging with high sensitivity and efficiency, showing significance for multifunctionality/multimodality imaging. As a result, more and more innovative engineered nanoprobes combined with diverse imaging modalities were developed to assess the activation of the immune system. In this work, we comprehensively review the recent and emerging advances in engineered nanoprobes for monitoring immune activation in cancer or other immune-mediated inflammatory diseases and discuss the potential in predicting the efficacy following treatments. Research on real-time in vivo immunoimaging is still under exploration, and this review can provide guidance and facilitate the development and application of next-generation imaging technologies.
Autoimmune diseases are a heterogeneous group of diseases with an unclear aetiology. Genome-wide association studies (GWAS) and meta-analysis are inefficient in identifying shared variants. This study aims to identify shared genetic susceptibility for seven autoimmune diseases using sum of powered score (SPU) tests. GWAS summary statistics datasets of seven autoimmune diseases were downloaded from Open Targets Genetics, Dryad and International Multiple Sclerosis Genetics Consortium (IMSGC). The MTaSPUs was applied to confirm common single-nucleotide polymorphisms (SNP), MTaSPUsSet and aSPUs were performed to identify potential shared genes, and MTaSPUsPath was conducted to explore biological functions based on Kyoto encyclopedia of genes and genomes (KEGG) biological pathways. The MTaSPUs test found 104 pleiotropic SNPs (P < 1.19 × 10⁻⁶) in our study. The 38 of these SNPs were associated with at least one trait in the original GWAS study. A total of 56 genes associated with at least one trait (P<4.98×10⁻⁶) were recognized by aSPUs test. The 45 potential pleiotropic genes (P < 4.98 × 10⁻⁶) were significant in MTaSPUsSet test. By aggregating results of aSPUs test and MTaSPUsSet test, we ascertained 38 pleiotropic genes. The 10 of these 38 pleiotropic genes have been reported in previous studies, while the remaining 28 genes were newly discovered. These 38 genes were matched in 14 significant KEGG pathways. We found new variants linked with complicated illnesses derived from several GWAS datasets using the SPU testing technique. The discovery of pleiotropic genes and shared pathways may aid in the development of common treatment approaches for autoimmune disorders.
How mis-regulated chromatin directly impacts human immune disorders is poorly understood. Speckled Protein 140 (SP140) is an immune-restricted PHD and bromodomain-containing epigenetic “reader,” and SP140 loss-of-function mutations associate with Crohn’s disease (CD), multiple sclerosis (MS), and chronic lymphocytic leukemia (CLL). However, the relevance of these mutations and mechanisms underlying SP140-driven pathogenicity remains unexplored. Using a global proteomic strategy, we identified SP140 as a repressor of topoisomerases (TOPs) that maintains heterochromatin and macrophage fate. In humans and mice, SP140 loss resulted in unleashed TOP activity, de-repression of developmentally silenced genes, and ultimately defective microbe-inducible macrophage transcriptional programs and bacterial killing that drive intestinal pathology. Pharmacological inhibition of TOP1/2 rescued these defects. Furthermore, exacerbated colitis was restored with TOP1/2 inhibitors in Sp140−/− mice, but not wild-type mice, in vivo. Collectively, we identify SP140 as a TOP repressor and reveal repurposing of TOP inhibition to reverse immune diseases driven by SP140 loss.
Autoimmune Addison disease is an endocrinopathy that is fatal if not diagnosed and treated in a timely manner. Its rarity has hampered unbiased studies of the predisposing genetic factors. A 2021 genome-wide association study, explaining up to 40% of the genetic susceptibility, has revealed new disease loci and reproduced some of the previously reported associations, while failing to reproduce others. Credible risk loci from both candidate gene and genome-wide studies indicate that, like one of its most common comorbidities, type 1 diabetes mellitus, Addison disease is primarily caused by aberrant T cell behaviour. Here, we review the current understanding of the genetics of autoimmune Addison disease and its position in the wider field of autoimmune disorders. The mechanisms that could underlie the effects on the adrenal cortex are also discussed. This article discusses the current understanding of the genetics of autoimmune Addison disease and outlines the autoimmune mechanisms that could underlie the effects on the adrenal cortex. Autoimmune Addison disease (AAD) is an oligogenic complex disease.Genetic risk loci for AAD largely overlap with known autoimmune comorbidities.In particular, HLA and autoimmune regulator (AIRE) variants predispose to AAD.Probable functional elements of genetic risk variants highlight a T cell aetiology for AAD. Autoimmune Addison disease (AAD) is an oligogenic complex disease. Genetic risk loci for AAD largely overlap with known autoimmune comorbidities. In particular, HLA and autoimmune regulator (AIRE) variants predispose to AAD. Probable functional elements of genetic risk variants highlight a T cell aetiology for AAD.
Genome wide association studies (GWAS) have identified many loci contributing to genetic variation of complex traits. Immune mediated disorders are complex diseases for which hundreds of risk alleles have been identified by GWAS. However, the intergenic location of most of the signals has make it difficult to decipher their implication in disease pathogenesis. A significant number of immune disease-associated SNPs are located within long noncoding RNAs (lncRNAs). LncRNAs have gained importance due to their involvement in the regulation of a wide range of biological processes, including immune responses. GWAS SNPs located within lncRNAs can affect their regulatory capacity by modifying their secondary structure, altering their expression levels or regulating the transcription of different isoforms. In this review we discuss the functional implications of immune-related lncRNAs harboring disease associated SNPs on various disease conditions.
Autoreactive T cells pose a constant risk for the emergence of autoimmune skin diseases in genetically predisposed individuals carrying certain HLA risk alleles. Immune tolerance mechanisms are opposed by broad HLA-presented self-immunopeptidomes, a predefined repertoire of polyspecific TCRs, the continuous generation of new antibody specificities by somatic recombination of Ig genes in B cells, and heightened proinflammatory reactivity. Increased autoantigen presentation by HLA molecules, cross-activation of pathogen-induced T cells against autologous structures, altered metabolism of self-proteins, and excessive production of proinflammatory signals may all contribute to the breakdown of immune tolerance and the development of autoimmune skin diseases.
How mis-regulated chromatin directly impacts human immunological disease is poorly understood. Speckled Protein 140 (SP140) is an immune-restricted PHD and bromodomain-containing chromatin reader whose loss-of-function associates with Crohns disease (CD), multiple sclerosis (MS) and chronic lymphocytic leukemia (CLL). However, mechanisms underlying SP140-driven pathogenicity and therapeutic approaches that rescue SP140 remain unexplored. Using a global proteomic strategy, we identified SP140 as a repressor of topoisomerases (TOP) that maintains heterochromatin and immune cell fate. In humans and mice, SP140 loss resulted in unleashed TOP activity, genome instability, severely compromised lineage-defining and microbe-inducible innate transcriptional programs and defective bacterial killing. Pharmacological inhibition of TOP1 or TOP2 rescued these defects. Furthermore, exacerbated colitis was restored with TOP1 or TOP2 inhibitors in Sp140-/- mice, but not wild-type mice, in vivo. Collectively, we identify SP140 as a repressor of topoisomerases and reveal repurposing of TOP inhibition as a precision strategy for reversing SP140-driven immune disease.
Pernicious anemia is a rare condition characterized by vitamin B12 deficiency anemia due to lack of intrinsic factor, often caused by autoimmune gastritis. Patients with pernicious anemia have a higher incidence of other autoimmune disorders, such as type 1 diabetes, vitiligo, and autoimmune thyroid issues. Therefore, the disease has a clear autoimmune basis, although the genetic susceptibility factors have thus far remained poorly studied. We conduct a genome-wide association study meta-analysis in 2166 cases and 659,516 European controls from population-based biobanks and identify genome-wide significant signals in or near the PTPN22 (rs6679677, p = 1.91 × 10−24, OR = 1.63), PNPT1 (rs12616502, p = 3.14 × 10−8, OR = 1.70), HLA-DQB1 (rs28414666, p = 1.40 × 10−16, OR = 1.38), IL2RA (rs2476491, p = 1.90 × 10−8, OR = 1.22) and AIRE (rs74203920, p = 2.33 × 10−9, OR = 1.83) genes, thus providing robust associations between pernicious anemia and genetic risk factors. Pernicious anemia shows co-incidence with autoimmune disorders, yet the genetic basis for this condition is understudied. Here, the authors perform a genome-wide association study meta-analysis on pernicious anemia, identifying five susceptibility loci that map to genes with known roles in autoimmune disease.
LINKED CONTENT
This article is linked to Lo et al paper. To view these articles, visit https://doi.org/10.1111/apt.16210
The identification and measurement of human body biomarkers is a major goal in clinical diagnosis and disease monitoring. This chapter elaborates on the most popular physical, physiological, biological, and behavioural symptoms; abnormalities; and diseases which mostly can be measured and quantified by means of multiple body sensors. Genetic disorders are caused by point mutation or gene damage due to insertion or deletion of a gene bond, deletion of a gene or genes, missing chromosomes, or trinucleotide repeat disorder. Human development, often referred to as developmental psychology, explains the changes in human cognitive, emotional, and behavioural capabilities and functioning over the entire life. On the other hand, the availability of monoclonal antibodies, routine production of genetically altered animals, and new understanding of the genetic code have contributed to the exploration of how genetics interacts with development and early experiences to influence both vulnerability to disease and resistance to age‐related decline.
Non-alcoholic fatty liver disease (NAFLD) is a global health issue that afflicts approximately a quarter of the population and increases the risk of both liver complications, as well as cardiovascular disease and diabetes. The histological spectrum of NAFLD includes steatosis with or without steatohepatitis, and extends right through to fibrosis, cirrhosis and hepatocellular carcinoma. A cardinal feature of the phenotype is marked heterogeneity and inter-individual variation in both disease susceptibility and progression. This is at least partially attributed to genetic and epigenetic variation. Recent years have witnessed an exponential growth in knowledge of the genetic architecture of NAFLD that has been fuelled to a large extent by genome-wide association and large candidate gene studies. In this review, we provide an overview of current knowledge pertaining to the genetic and epigenetic basis of NAFLD, the potential translational implications of this knowledge, current challenges and perspectives on the future of advances in this field for precision medicine.
Genome-wide association studies (GWAS) have uncovered pervasive genetic overlap between common clinically related immune-mediated diseases (IMD). To distinguish axes of IMD risk, and extend genetic knowledge of rare IMDs and subtypes, we developed a Bayesian shrinkage approach to perform a disease-focused decomposition of IMD GWAS summary statistics. We derive 13 components which summarise the multidimensional patterns of IMD genetic risk including those related to raised eosinophil count and serum IP-10. Projection of UK Biobank data demonstrated the IMD-specificity and accuracy of our reduced dimension basis in independent datasets. By projecting 22 rare IMD or IMD subtypes onto the basis we were able to identify disease-discriminating components and suggest novel associations. Requiring only summary level data, our approach allows the genetic architectures across any range of clinically-related traits to be characterised in fewer dimensions, facilitating the analysis of studies with modest sample size, where classical GWAS approaches are challenging.
Multiple sclerosis (MS) is an inflammatory demyelinating and neurodegenerative disease of the central nervous system (CNS). Studies in rodent models demonstrated an association of CNS-infiltrating monocyte-derived macrophages with disease severity. However, little is known about humans. Here, we performed an exploratory analysis of peripheral blood mononuclear cells (PBMCs) isolated from healthy controls and drug-naïve patients with early MS using multiplexed single-cell mass cytometry and algorithm-based data analysis. Two antibody panels comprising a total of 64 antibodies were designed to comprehensively analyse diverse immune cell populations, with particular emphasis on monocytes. PBMC composition and marker expression were overall similar between the groups. However, an increased abundance of CCR7+ and IL-6+ T cells was detected in early MS-PBMCs, whereas NFAT1hiT-bethiCD4+ T cells were decreased. Similarly, we detected changes in the subset composition of the CCR7+ and MIPβhi HLA-DR+ lymphocyte compartment. Only mild alterations were detected in monocytes/myeloid cells of patients with early MS, namely a decreased abundance of CD141hiIRF8hiCXCR3+CD68− dendritic cells. Unlike in Crohn’s disease, no significant differences were found in the monocyte fraction of patients with early MS compared to healthy controls. This study provides a valuable resource for future studies designed to characterise and target diverse PBMC subsets in MS.
Nonalcoholic fatty liver disease (NAFLD) affects around a quarter of the global population, paralleling worldwide increases in obesity and metabolic syndrome. NAFLD arises in the context of systemic metabolic dysfunction that concomitantly amplifies the risk of cardiovascular disease and diabetes. These interrelated conditions have long been recognized to have a heritable component, and advances using unbiased association studies followed by functional characterization have created a paradigm for unravelling the genetic architecture of these conditions. A novel perspective is to characterize the shared genetic basis of NAFLD and other related disorders. This information on shared genetic risks and their biological overlap should in future enable the development of precision medicine approaches through better patient stratification, and enable the identification of preventive and therapeutic strategies. In this Review, we discuss current knowledge of the genetic basis of NAFLD and of possible pleiotropy between NAFLD and other liver diseases as well as other related metabolic disorders. We also discuss evidence of causality in NAFLD and other related diseases and the translational significance of such evidence, and future challenges from the study of genetic pleiotropy.
DNA methylation is a decisive regulator of gene expression. Differentially methylated promoters were described in rheumatoid arthritis (RA), but we do not know how these epimutations can trigger a proinflammatory cytokine milieu. B cell-focused DNA methylome studies identified a group of genes that had undergone disease-associated changes in a murine model of RA. An arthritis-specific epimutation (hypomethylation) was detected in the promoter region of the Zbtb38 gene, which encodes a transcriptional repressor. Gene expression studies revealed that hypomethylation of the Zbtb38 promoter was accompanied by disease-specific repressor expression, and two anti-inflammatory factors interleukin 1 receptor 2 gene (IL1r2) and interleukin-1 receptor antagonist (IL1rn) were among the downregulated genes. We hypothesized that Zbtb38 repressor could induce downregulated expression of these anti-inflammatory genes and that this could significantly contribute to arthritis pathogenesis. Our studies demonstrate that Zbtb38 forms a molecular bridge between an arthritis-associated epimutation (DNA hypomethylation in Zbtb38 promoter) and transcriptional silencing of the IL1r2 gene in B cells. In this way, disease-associated DNA hypomethylation can support autoimmune arthritis by interfering with an anti-inflammatory pathway.
An important aspect of public health is disease prediction and health promotion through better targeting of preventive strategies. Well-targeted preventive strategies will eventually decrease burden of diseases and thus precise prediction plays a crucial role in public health. Many investigators put efforts into finding models that improve prediction using known risk factors of diseases. Recently with the overwhelming load of genetic loci discovered for complex diseases through genome-wide association studies (GWAS), much of attention has been focused on the role of these genetic loci to improve prediction models. Genetic loci in solo explain little variance of diseases. It is thus necessary to create new genetic parameters that combine the effect of as many genetic loci as possible. Such new parameters aim to better distinguish individuals who will develop a disease from those who will not. In this chapter, various polygenic methods that use multiple genetic loci to directly or indirectly improve precision of genetic prediction are discussed.
The oral cavity is a part of the body. The health of the oral cavity affects the health of the entire body. This relationship is reciprocal, as the overall health of an individual will also affect the health of that individual's oral cavity. Periodontal disease is a common, chronic inflammatory disease affecting the supporting structures of the teeth. It has been proposed that periodontal disease is a risk factor for systemic diseases such as diabetes.
Schizophrenia is a severe mental disorder with a lifetime risk of about 1%, characterized by hallucinations, delusions and cognitive deficits, with heritability estimated at up to 80%(1,2). We performed a genome-wide association study of 3,322 European individuals with schizophrenia and 3,587 controls. Here we show, using two analytic approaches, the extent to which common genetic variation underlies the risk of schizophrenia. First, we implicate the major histocompatibility complex. Second, we provide molecular genetic evidence for a substantial polygenic component to the risk of schizophrenia involving thousands of common alleles of very small effect. We show that this component also contributes to the risk of bipolar disorder, but not to several non-psychiatric diseases.
Autism spectrum disorders (ASD) are believed to have genetic and environmental origins, yet in only a modest fraction of individuals can specific causes be identified. To identify further genetic risk factors, here we assess the role of de novo mutations in ASD by sequencing the exomes of ASD cases and their parents (n = 175 trios). Fewer than half of the cases (46.3%) carry a missense or nonsense de novo variant, and the overall rate of mutation is only modestly higher than the expected rate. In contrast, the proteins encoded by genes that harboured de novo missense or nonsense mutations showed a higher degree of connectivity among themselves and to previous ASD genes as indexed by protein-protein interaction screens. The small increase in the rate of de novo events, when taken together with the protein interaction results, are consistent with an important but limited role for de novo point mutations in ASD, similar to that documented for de novo copy number variants. Genetic models incorporating these data indicate that most of the observed de novo events are unconnected to ASD; those that do confer risk are distributed across many genes and are incompletely penetrant (that is, not necessarily sufficient for disease). Our results support polygenic models in which spontaneous coding mutations in any of a large number of genes increases risk by 5- to 20-fold. Despite the challenge posed by such models, results from de novo events and a large parallel case-control study provide strong evidence in favour of CHD8 and KATNAL2 as genuine autism risk factors.
The genetic architectures of common, complex diseases are largely uncharacterized. We modeled the genetic architecture underlying genome-wide association study (GWAS) data for rheumatoid arthritis and developed a new method using polygenic risk-score analyses to infer the total liability-scale variance explained by associated GWAS SNPs. Using this method, we estimated that, together, thousands of SNPs from rheumatoid arthritis GWAS explain an additional 20% of disease risk (excluding known associated loci). We further tested this method on datasets for three additional diseases and obtained comparable estimates for celiac disease (43% excluding the major histocompatibility complex), myocardial infarction and coronary artery disease (48%) and type 2 diabetes (49%). Our results are consistent with simulated genetic models in which hundreds of associated loci harbor common causal variants and a smaller number of loci harbor multiple rare causal variants. These analyses suggest that GWAS will continue to be highly productive for the discovery of additional susceptibility loci for common diseases.
The mammalian alimentary tract harbors hundreds of species of commensal microorganisms (microbiota) that intimately interact with the host and provide it with genetic, metabolic, and immunological attributes. Recent reports have indicated that the microbiota composition and its collective genomes (microbiome) are major factors in predetermining the type and robustness of mucosal immune responses. In this review, we discuss the recent advances in our understanding of host-microbiota interactions and their effect on the health and disease susceptibility of the host.
We performed a two-stage genome-wide association study of IgA nephropathy (IgAN) in Han Chinese, with 1,434 affected individuals (cases) and 4,270 controls in the discovery phase and follow-up of the top 61 SNPs in an additional 2,703 cases and 3,464 controls. We identified associations at 17p13 (rs3803800, P = 9.40 × 10(-11), OR = 1.21; rs4227, P = 4.31 × 10(-10), OR = 1.23) and 8p23 (rs2738048, P = 3.18 × 10(-14), OR = 0.79) that implicated the genes encoding tumor necrosis factor (TNFSF13) and α-defensin (DEFA) as susceptibility genes. In addition, we found multiple associations in the major histocompatibility complex (MHC) region (rs660895, P = 4.13 × 10(-20), OR = 1.34; rs1794275, P = 3.43 × 10(-13), OR = 1.30; rs2523946, P = 1.74 × 10(-11), OR = 1.21) and confirmed a previously reported association at 22q12 (rs12537, P = 1.17 × 10(-11), OR = 0.78). We also found that rs660895 was associated with clinical subtypes of IgAN (P = 0.003), proteinuria (P = 0.025) and IgA levels (P = 0.047). Our findings show that IgAN is associated with variants near genes involved in innate immunity and inflammation.
To identify susceptibility loci for ankylosing spondylitis, we performed a two-stage genome-wide association study in Han Chinese. In the discovery stage, we analyzed 1,356,350 autosomal SNPs in 1,837 individuals with ankylosing spondylitis and 4,231 controls; in the validation stage, we analyzed 30 suggestive SNPs in an additional 2,100 affected individuals and 3,496 controls. We identified two new susceptibility loci between EDIL3 and HAPLN1 at 5q14.3 (rs4552569; P = 8.77 × 10(-10)) and within ANO6 at 12q12 (rs17095830; P = 1.63 × 10(-8)). We also confirmed previously reported associations in Europeans within the major histocompatibility complex (MHC) region (top SNP, rs13202464; P < 5 × 10(-324)) and at 2p15 (rs10865331; P = 1.98 × 10(-8)). We show that rs13202464 within the MHC region mainly represents the risk effect of HLA-B*27 variants (including HLA-B*2704, HLA-B*2705 and HLA-B*2715) in Chinese. The two newly discovered loci implicate genes related to bone formation and cartilage development, suggesting their potential involvement in the etiology of ankylosing spondylitis.
Using variants from the 1000 Genomes Project pilot European CEU dataset and data from additional resequencing studies, we densely genotyped 183 non-HLA risk loci previously associated with immune-mediated diseases in 12,041 individuals with celiac disease (cases) and 12,228 controls. We identified 13 new celiac disease risk loci reaching genome-wide significance, bringing the number of known loci (including the HLA locus) to 40. We found multiple independent association signals at over one-third of these loci, a finding that is attributable to a combination of common, low-frequency and rare genetic variants. Compared to previously available data such as those from HapMap3, our dense genotyping in a large sample collection provided a higher resolution of the pattern of linkage disequilibrium and suggested localization of many signals to finer scale regions. In particular, 29 of the 54 fine-mapped signals seemed to be localized to single genes and, in some instances, to gene regulatory elements. Altogether, we define the complex genetic architecture of the risk regions of and refine the risk signals for celiac disease, providing the next step toward uncovering the causal mechanisms of the disease.
FUT2 encodes the α(1,2) fucosyltransferase that determines blood group secretor status. Homozygotes (A/A) for the common nonsense mutation rs601338A>G (W143X) are nonsecretors and are unable to express histo-blood group antigens in secretions and on mucosal surfaces. This mutation has been reported to provide resistance to Norovirus and susceptibility to Crohn's disease, and hence we aimed to determine if it also affects risk of type 1 diabetes.
rs601338A>G was genotyped in 8,344 patients with type 1 diabetes, 10,008 control subjects, and 3,360 type 1 diabetic families. Logistic regression models were used to analyze the case-control collection, and conditional logistic regression was used to analyze the family collection. RESULTS The nonsecretor A/A genotype of rs601338A>G was found to confer susceptibility to type 1 diabetes in both the case-control and family collections (odds ratio for AA 1.29 [95% CI 1.20-1.37] and relative risk for AA 1.22 [95% CI = 1.12-1.32]; combined P = 4.3 × 10(-18)), based on a recessive effects model.
Our findings linking FUT2 and type 1 diabetes highlight the intriguing relationship between host resistance to infections and susceptibility to autoimmune disease.
More than 1,000 susceptibility loci have been identified through genome-wide association studies (GWAS) of common variants; however, the specific genes and full allelic spectrum of causal variants underlying these findings have not yet been defined. Here we used pooled next-generation sequencing to study 56 genes from regions associated with Crohn's disease in 350 cases and 350 controls. Through follow-up genotyping of 70 rare and low-frequency protein-altering variants in nine independent case-control series (16,054 Crohn's disease cases, 12,153 ulcerative colitis cases and 17,575 healthy controls), we identified four additional independent risk factors in NOD2, two additional protective variants in IL23R, a highly significant association with a protective splice variant in CARD9 (P < 1 × 10(-16), odds ratio ≈ 0.29) and additional associations with coding variants in IL18RAP, CUL2, C1orf106, PTPN22 and MUC19. We extend the results of successful GWAS by identifying new, rare and probably functional variants that could aid functional experiments and predictive models.
Genome-wide association (GWA) studies have identified numerous, replicable, genetic associations between common single nucleotide polymorphisms (SNPs) and risk of common autoimmune and inflammatory (immune-mediated) diseases, some of which are shared between two diseases. Along with epidemiological and clinical evidence, this suggests that some genetic risk factors may be shared across diseases-as is the case with alleles in the Major Histocompatibility Locus. In this work we evaluate the extent of this sharing for 107 immune disease-risk SNPs in seven diseases: celiac disease, Crohn's disease, multiple sclerosis, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, and type 1 diabetes. We have developed a novel statistic for Cross Phenotype Meta-Analysis (CPMA) which detects association of a SNP to multiple, but not necessarily all, phenotypes. With it, we find evidence that 47/107 (44%) immune-mediated disease risk SNPs are associated to multiple-but not all-immune-mediated diseases (SNP-wise P(CPMA)<0.01). We also show that distinct groups of interacting proteins are encoded near SNPs which predispose to the same subsets of diseases; we propose these as the mechanistic basis of shared disease risk. We are thus able to leverage genetic data across diseases to construct biological hypotheses about the underlying mechanism of pathogenesis.
Genome-wide association studies have revealed a large number of genetic associations with autoimmune diseases. Despite this progress, the mechanisms underlying the contribution of allelic variants to the onset of immune-related diseases remain mostly unknown. Our recent meta-analysis of genome-wide association studies of multiple sclerosis (MS) identified a new susceptibility locus tagged by a single nucleotide polymorphism, rs17824933 (p = 3.8 × 10(-9)), that is found in a block of linkage disequilibrium containing the CD6 gene. Because CD6 plays an important role in maintenance of T cell activation and proliferation, we examined the biologic phenotypes of the risk-associated allele. In this article, we report that the MS susceptibility allele in CD6 is associated with decreased expression of full-length CD6 in CD4(+) and CD8(+) T cells. As a consequence, proliferation is diminished during long-term activation of CD4(+) T cells from subjects with the risk allele. Selective knockdown of full-length CD6 using exon 5-specific small interfering RNA induces a similar proliferation defect of CD4(+) T cells from subjects homozygous for the protective allele. Exon 5 encodes for the extracellular binding site of the CD6 ligand ALCAM, which is required for CD6 stimulation. In CD4(+) T cells from subjects with the risk allele, exon 5 is consistently underexpressed, thereby providing a mechanism by which the allele affects proliferation of CD4(+) T cells. These findings indicate that the MS risk allele in the CD6 locus is associated with altered proliferation of CD4(+) T cells and demonstrate the influence of a disease-related allelic variant on important immunological characteristics.
Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.
Atopic dermatitis is a chronic, relapsing form of inflammatory skin disorder that is affected by genetic and environmental factors. We performed a genome-wide association study of atopic dermatitis in a Chinese Han population using 1,012 affected individuals (cases) and 1,362 controls followed by a replication study in an additional 3,624 cases and 12,197 controls of Chinese Han ethnicity, as well as 1,806 cases and 3,256 controls from Germany. We identified previously undescribed susceptibility loci at 5q22.1 (TMEM232 and SLC25A46, rs7701890, P(combined) = 3.15 × 10(-9), odds ratio (OR) = 1.24) and 20q13.33 (TNFRSF6B and ZGPAT, rs6010620, P(combined) = 3.0 × 10(-8), OR = 1.17) and replicated another previously reported locus at 1q21.3 (FLG, rs3126085, P(combined) = 5.90 × 10(-12), OR = 0.82) in the Chinese sample. The 20q13.33 locus also showed evidence for association in the German sample (rs6010620, P = 2.87 × 10(-5), OR = 1.25). Our study identifies new genetic susceptibility factors and suggests previously unidentified biological pathways in atopic dermatitis.
Epidemiology and candidate gene studies indicate a shared genetic basis for celiac disease (CD) and rheumatoid arthritis (RA), but the extent of this sharing has not been systematically explored. Previous studies demonstrate that 6 of the established non-HLA CD and RA risk loci (out of 26 loci for each disease) are shared between both diseases. We hypothesized that there are additional shared risk alleles and that combining genome-wide association study (GWAS) data from each disease would increase power to identify these shared risk alleles. We performed a meta-analysis of two published GWAS on CD (4,533 cases and 10,750 controls) and RA (5,539 cases and 17,231 controls). After genotyping the top associated SNPs in 2,169 CD cases and 2,255 controls, and 2,845 RA cases and 4,944 controls, 8 additional SNPs demonstrated P<5 × 10(-8) in a combined analysis of all 50,266 samples, including four SNPs that have not been previously confirmed in either disease: rs10892279 near the DDX6 gene (P(combined) = 1.2 × 10(-12)), rs864537 near CD247 (P(combined) = 2.2 × 10(-11)), rs2298428 near UBE2L3 (P(combined) = 2.5 × 10(-10)), and rs11203203 near UBASH3A (P(combined) = 1.1 × 10(-8)). We also confirmed that 4 gene loci previously established in either CD or RA are associated with the other autoimmune disease at combined P<5 × 10(-8) (SH2B3, 8q24, STAT4, and TRAF1-C5). From the 14 shared gene loci, 7 SNPs showed a genome-wide significant effect on expression of one or more transcripts in the linkage disequilibrium (LD) block around the SNP. These associations implicate antigen presentation and T-cell activation as a shared mechanism of disease pathogenesis and underscore the utility of cross-disease meta-analysis for identification of genetic risk factors with pleiotropic effects between two clinically distinct diseases.
Crohn's disease (CD) and celiac disease (CelD) are chronic intestinal inflammatory diseases, involving genetic and environmental factors in their pathogenesis. The two diseases can co-occur within families, and studies suggest that CelD patients have a higher risk to develop CD than the general population. These observations suggest that CD and CelD may share common genetic risk loci. Two such shared loci, IL18RAP and PTPN2, have already been identified independently in these two diseases. The aim of our study was to explicitly identify shared risk loci for these diseases by combining results from genome-wide association study (GWAS) datasets of CD and CelD. Specifically, GWAS results from CelD (768 cases, 1,422 controls) and CD (3,230 cases, 4,829 controls) were combined in a meta-analysis. Nine independent regions had nominal association p-value <1.0 x 10⁻⁵ in this meta-analysis and showed evidence of association to the individual diseases in the original scans (p-value < 1 x 10⁻² in CelD and < 1 x 10⁻³ in CD). These include the two previously reported shared loci, IL18RAP and PTPN2, with p-values of 3.37 x 10⁻⁸ and 6.39 x 10⁻⁹, respectively, in the meta-analysis. The other seven had not been reported as shared loci and thus were tested in additional CelD (3,149 cases and 4,714 controls) and CD (1,835 cases and 1,669 controls) cohorts. Two of these loci, TAGAP and PUS10, showed significant evidence of replication (Bonferroni corrected p-values <0.0071) in the combined CelD and CD replication cohorts and were firmly established as shared risk loci of genome-wide significance, with overall combined p-values of 1.55 x 10⁻¹⁰ and 1.38 x 10⁻¹¹ respectively. Through a meta-analysis of GWAS data from CD and CelD, we have identified four shared risk loci: PTPN2, IL18RAP, TAGAP, and PUS10. The combined analysis of the two datasets provided the power, lacking in the individual GWAS for single diseases, to detect shared loci with a relatively small effect.
Genome-wide association studies and candidate gene studies in ulcerative colitis have identified 18 susceptibility loci. We conducted a meta-analysis of six ulcerative colitis genome-wide association study datasets, comprising 6,687 cases and 19,718 controls, and followed up the top association signals in 9,628 cases and 12,917 controls. We identified 29 additional risk loci (P < 5 × 10(-8)), increasing the number of ulcerative colitis-associated loci to 47. After annotating associated regions using GRAIL, expression quantitative trait loci data and correlations with non-synonymous SNPs, we identified many candidate genes that provide potentially important insights into disease pathogenesis, including IL1R2, IL8RA-IL8RB, IL7R, IL12B, DAP, PRDM1, JAK2, IRF5, GNA12 and LSP1. The total number of confirmed inflammatory bowel disease risk loci is now 99, including a minimum of 28 shared association signals between Crohn's disease and ulcerative colitis.
Synthetic associations have been posited as a possible explanation for missing heritability in complex disease. We show several lines of evidence which suggest that, while possible, these synthetic associations are not common.
Genome-wide association studies have uncovered hundreds of DNA changes associated with complex disease. The ultimate promise of these studies is the understanding of disease biology; this goal, however, is not easily achieved because each disease has yielded numerous associations, each one pointing to a region of the genome, rather than a specific causal mutation. Presumably, the causal variants affect components of common molecular processes, and a first step in understanding the disease biology perturbed in patients is to identify connections among regions associated to disease. Since it has been reported in numerous Mendelian diseases that protein products of causal genes tend to physically bind each other, we chose to approach this problem using known protein–protein interactions to test whether any of the products of genes in five complex trait-associated loci bind each other. We applied several permutation methods and find robustly significant connectivity within four of the traits. In Crohn's disease and rheumatoid arthritis, we are able to show that these genes are co-expressed and that other proteins emerging in the network are enriched for association to disease. These findings suggest that, for the complex traits studied here, associated loci contain variants that affect common molecular processes, rather than distinct mechanisms specific to each association.
We undertook a meta-analysis of six Crohn's disease genome-wide association studies (GWAS) comprising 6,333 affected individuals (cases) and 15,056 controls and followed up the top association signals in 15,694 cases, 14,026 controls and 414 parent-offspring trios. We identified 30 new susceptibility loci meeting genome-wide significance (P < 5 × 10⁻⁸). A series of in silico analyses highlighted particular genes within these loci and, together with manual curation, implicated functionally interesting candidate genes including SMAD3, ERAP2, IL10, IL2RA, TYK2, FUT2, DNMT3A, DENND1B, BACH2 and TAGAP. Combined with previously confirmed loci, these results identify 71 distinct loci with genome-wide significant evidence for association with Crohn's disease.
Mitochondrial dysfunction has been observed in skeletal muscle of people with diabetes and insulin-resistant individuals. Furthermore, inherited mutations in mitochondrial DNA can cause a rare form of diabetes. However, it is unclear whether mitochondrial dysfunction is a primary cause of the common form of diabetes. To date, common genetic variants robustly associated with type 2 diabetes (T2D) are not known to affect mitochondrial function. One possibility is that multiple mitochondrial genes contain modest genetic effects that collectively influence T2D risk. To test this hypothesis we developed a method named Meta-Analysis Gene-set Enrichment of variaNT Associations (MAGENTA; http://www.broadinstitute.org/mpg/magenta). MAGENTA, in analogy to Gene Set Enrichment Analysis, tests whether sets of functionally related genes are enriched for associations with a polygenic disease or trait. MAGENTA was specifically designed to exploit the statistical power of large genome-wide association (GWA) study meta-analyses whose individual genotypes are not available. This is achieved by combining variant association p-values into gene scores and then correcting for confounders, such as gene size, variant number, and linkage disequilibrium properties. Using simulations, we determined the range of parameters for which MAGENTA can detect associations likely missed by single-marker analysis. We verified MAGENTA's performance on empirical data by identifying known relevant pathways in lipid and lipoprotein GWA meta-analyses. We then tested our mitochondrial hypothesis by applying MAGENTA to three gene sets: nuclear regulators of mitochondrial genes, oxidative phosphorylation genes, and approximately 1,000 nuclear-encoded mitochondrial genes. The analysis was performed using the most recent T2D GWA meta-analysis of 47,117 people and meta-analyses of seven diabetes-related glycemic traits (up to 46,186 non-diabetic individuals). This well-powered analysis found no significant enrichment of associations to T2D or any of the glycemic traits in any of the gene sets tested. These results suggest that common variants affecting nuclear-encoded mitochondrial genes have at most a small genetic contribution to T2D susceptibility.
We report a set of tools to estimate the number of susceptibility loci and the distribution of their effect sizes for a trait on the basis of discoveries from existing genome-wide association studies (GWASs). We propose statistical power calculations for future GWASs using estimated distributions of effect sizes. Using reported GWAS findings for height, Crohn's disease and breast, prostate and colorectal (BPC) cancers, we determine that each of these traits is likely to harbor additional loci within the spectrum of low-penetrance common variants. These loci, which can be identified from sufficiently powerful GWASs, together could explain at least 15-20% of the known heritability of these traits. However, for BPC cancers, which have modest familial aggregation, our analysis suggests that risk models based on common variants alone will have modest discriminatory power (63.5% area under curve), even with new discoveries.
With multiple genome-wide association studies (GWAS) performed across autoimmune diseases, there is a great opportunity to study the homogeneity of genetic architectures across autoimmune disease. Previous approaches have been limited in the scope of their analysis and have failed to properly incorporate the direction of allele-specific disease associations for SNPs. In this work, we refine the notion of a genetic variation profile for a given disease to capture strength of association with multiple SNPs in an allele-specific fashion. We apply this method to compare genetic variation profiles of six autoimmune diseases: multiple sclerosis (MS), ankylosing spondylitis (AS), autoimmune thyroid disease (ATD), rheumatoid arthritis (RA), Crohn's disease (CD), and type 1 diabetes (T1D), as well as five non-autoimmune diseases. We quantify pair-wise relationships between these diseases and find two broad clusters of autoimmune disease where SNPs that make an individual susceptible to one class of autoimmune disease also protect from diseases in the other autoimmune class. We find that RA and AS form one such class, and MS and ATD another. We identify specific SNPs and genes with opposite risk profiles for these two classes. We furthermore explore individual SNPs that play an important role in defining similarities and differences between disease pairs. We present a novel, systematic, cross-platform approach to identify allele-specific relationships between disease pairs based on genetic variation as well as the individual SNPs which drive the relationships. While recognizing similarities between diseases might lead to identifying novel treatment options, detecting differences between diseases previously thought to be similar may point to key novel disease-specific genes and pathways.
We performed a genome-wide association study (GWAS) of systemic lupus erythematosus (SLE) in a Chinese Han population by genotyping 1,047 cases and 1,205 controls using Illumina Human610-Quad BeadChips and replicating 78 SNPs in two additional cohorts (3,152 cases and 7,050 controls). We identified nine new susceptibility loci (ETS1, IKZF1, RASGRP3, SLC15A4, TNIP1, 7q11.23, 10q11.22, 11q23.3 and 16p11.2; 1.77 x 10(-25) < or = P(combined) < or = 2.77 x 10(-8)) and confirmed seven previously reported loci (BLK, IRF5, STAT4, TNFAIP3, TNFSF4, 6q21 and 22q11.21; 5.17 x 10(-42) < or = P(combined) < or = 5.18 x 10(-12)). Comparison with previous GWAS findings highlighted the genetic heterogeneity of SLE susceptibility between Chinese Han and European populations. This study not only advances our understanding of the genetic basis of SLE but also highlights the value of performing GWAS in diverse ancestral populations.
Circulating angiotensin I-converting enzyme (ACE) levels are influenced by a major quantitative trait locus (QTL) that maps to the ACE gene. Phylogenetic and measured haplotype analyses have suggested that the ACE-linked QTL lies downstream of a putative ancestral breakpoint located near to position 6435. However, strong linkage disequilibrium between markers in the 3' portion of the gene has prevented further resolution of the QTL in Caucasian subjects. We have examined 10 ACE gene polymorphisms in Afro-Caribbean families recruited in Jamaica. Variance components analyses showed strong evidence of linkage and association to circulating ACE levels. When the linkage results were contrasted with those from a set of British Caucasian families, there was no evidence for heterogeneity between the samples. However, patterns of allelic association between the markers and circulating ACE levels differed significantly in the two data sets. In the British families, three markers [G2215A, Alu insertion/deletion and G2350A] were in complete disequilibrium with the ACE-linked QTL. In the Jamaican families, only marker G2350A showed strong but incomplete disequilibrium with the ACE-linked QTL. These results suggest that additional unobserved polymorphisms have an effect on circulating ACE levels in Jamaican families. Furthermore, our results show that a variance components approach combined with structured, quantitative comparisons between families from different ethnic groups may be a useful strategy for helping to determine which, if any, variants in a small genomic region directly influence a quantitative trait.
Genome-wide association studies have identified hundreds of genetic variants associated with complex human diseases and traits, and have provided valuable insights into their genetic architecture. Most variants identified so far confer relatively small increments in risk, and explain only a small proportion of familial clustering, leading many to question how the remaining, 'missing' heritability can be explained. Here we examine potential sources of missing heritability and propose research strategies, including and extending beyond current genome-wide association approaches, to illuminate the genetics of complex diseases and enhance its potential to enable effective disease prevention or treatment.
Genome-wide association studies (GWAS) have identified over 300 regions associated with more than 70 common diseases. However, identifying causal genes within an associated region remains a major challenge. One approach to resolving causal genes is through the dissection of gene-phenotype correlations. Here we use polychromatic flow cytometry to show that differences in surface expression of the human interleukin-2 (IL-2) receptor alpha (IL2RA, or CD25) protein are restricted to particular immune cell types and correlate with several haplotypes in the IL2RA region that have previously been associated with two autoimmune diseases, type 1 diabetes (T1D) and multiple sclerosis. We confirm our strongest gene-phenotype correlation at the RNA level by allele-specific expression (ASE). We also define key parameters for the design and implementation of post-GWAS gene-phenotype investigations and demonstrate the usefulness of a large bioresource of genotype-selectable normal donors from whom fresh, primary cells can be analyzed.
Much of the public media discussion of genetics of common diseases has centered on opportunities for targeted preventive actions. At the same time, in the specialist literature, there has been extensive discussion of “interaction,” both between genes and between genes and environment. These two topics concern the use and interpretation of statistical models for risk of diseases with several, perhaps many, etiological risk factors, and were both the subject of lively debate some 30 to 40 years ago when such models first came into widespread use in epidemiology. Here these debates are revisited and illustrated with results from an analysis of the genetics of type 1 diabetes (T1D). Details of this analysis are provided in section 1 of Text S1.
Translating a set of disease regions into insight about pathogenic mechanisms requires not only the ability to identify the key disease genes within them, but also the biological relationships among those key genes. Here we describe a statistical method, Gene Relationships Among Implicated Loci (GRAIL), that takes a list of disease regions and automatically assesses the degree of relatedness of implicated genes using 250,000 PubMed abstracts. We first evaluated GRAIL by assessing its ability to identify subsets of highly related genes in common pathways from validated lipid and height SNP associations from recent genome-wide studies. We then tested GRAIL, by assessing its ability to separate true disease regions from many false positive disease regions in two separate practical applications in human genetics. First, we took 74 nominally associated Crohn's disease SNPs and applied GRAIL to identify a subset of 13 SNPs with highly related genes. Of these, ten convincingly validated in follow-up genotyping; genotyping results for the remaining three were inconclusive. Next, we applied GRAIL to 165 rare deletion events seen in schizophrenia cases (less than one-third of which are contributing to disease risk). We demonstrate that GRAIL is able to identify a subset of 16 deletions containing highly related genes; many of these genes are expressed in the central nervous system and play a role in neuronal synapses. GRAIL offers a statistically robust approach to identifying functionally related genes from across multiple disease regions--that likely represent key disease pathways. An online version of this method is available for public use (http://www.broad.mit.edu/mpg/grail/).
We have developed an online catalog of SNP-trait associations from published genome-wide association studies for use in investigating genomic characteristics of trait/disease-associated SNPs (TASs). Reported TASs were common [median risk allele frequency 36%, interquartile range (IQR) 21%-53%] and were associated with modest effect sizes [median odds ratio (OR) 1.33, IQR 1.20-1.61]. Among 20 genomic annotation sets, reported TASs were significantly overrepresented only in nonsynonymous sites [OR = 3.9 (2.2-7.0), p = 3.5 x 10(-7)] and 5kb-promoter regions [OR = 2.3 (1.5-3.6), p = 3 x 10(-4)] compared to SNPs randomly selected from genotyping arrays. Although 88% of TASs were intronic (45%) or intergenic (43%), TASs were not overrepresented in introns and were significantly depleted in intergenic regions [OR = 0.44 (0.34-0.58), p = 2.0 x 10(-9)]. Only slightly more TASs than expected by chance were predicted to be in regions under positive selection [OR = 1.3 (0.8-2.1), p = 0.2]. This new online resource, together with bioinformatic predictions of the underlying functionality at trait/disease-associated loci, is well-suited to guide future investigations of the role of common variants in complex disease etiology.
Following recent success in genome-wide association studies, a critical focus of human genetics is to understand how genetic variation at implicated loci influences cellular and disease processes. Crohn's disease (CD) is associated with SNPs around IRGM, but coding-sequence variation has been excluded as a source of this association. We identified a common, 20-kb deletion polymorphism, immediately upstream of IRGM and in perfect linkage disequilibrium (r2 = 1.0) with the most strongly CD-associated SNP, that causes IRGM to segregate in the population with two distinct upstream sequences. The deletion (CD risk) and reference (CD protective) haplotypes of IRGM showed distinct expression patterns. Manipulation of IRGM expression levels modulated cellular autophagy of internalized bacteria, a process implicated in CD. These results suggest that the CD association at IRGM arises from an alteration in IRGM regulation that affects the efficacy of autophagy and identify a common deletion polymorphism as a likely causal variant.
Author Summary
Multiple sclerosis (MS) and type 1 diabetes (T1D) are common, organ-specific inflammatory disorders that continue to increase in global prevalence. The processes leading to both T1D and MS are genetically determined and are thought to involve an autoimmune mechanism. After decades of research into the genetic basis of both MS and T1D, the Human Leukocyte Antigen Complex was the only known susceptibility locus for both T1D and MS. The sequencing of the human genome followed by the generation of the haplotype map, a catalogue of common genetic variation, has allowed the elucidation of allelic variants that define disease risk. Our groups have performed genome-wide association scans and candidate gene studies in both T1D and MS; the final results have identified loci outside the HLA harboring fully replicated risk alleles. Here, we show that the IL-2RA gene encoding a critical regulator of immune responses, the alpha chain of the interleukin-2 receptor, harbors variants that differentially confer risk to MS and T1D. In addition, several independent variants correlate with levels of soluble interleukin-2 receptor in the serum. This finding has critical implications for the field of complex disease genetics as it emphasizes the caution that must be taken when interpreting results for such a complex region with multiple susceptibility alleles.
Two inflammatory disorders, type 1 diabetes and celiac disease, cosegregate in populations, suggesting a common genetic origin. Since both diseases are associated with the HLA class II genes on chromosome 6p21, we tested whether non-HLA loci are shared.
We evaluated the association between type 1 diabetes and eight loci related to the risk of celiac disease by genotyping and statistical analyses of DNA samples from 8064 patients with type 1 diabetes, 9339 control subjects, and 2828 families providing 3064 parent-child trios (consisting of an affected child and both biologic parents). We also investigated 18 loci associated with type 1 diabetes in 2560 patients with celiac disease and 9339 control subjects.
Three celiac disease loci--RGS1 on chromosome 1q31, IL18RAP on chromosome 2q12, and TAGAP on chromosome 6q25--were associated with type 1 diabetes (P<1.00x10(-4)). The 32-bp insertion-deletion variant on chromosome 3p21 was newly identified as a type 1 diabetes locus (P=1.81x10(-8)) and was also associated with celiac disease, along with PTPN2 on chromosome 18p11 and CTLA4 on chromosome 2q33, bringing the total number of loci with evidence of a shared association to seven, including SH2B3 on chromosome 12q24. The effects of the IL18RAP and TAGAP alleles confer protection in type 1 diabetes and susceptibility in celiac disease. Loci with distinct effects in the two diseases included INS on chromosome 11p15, IL2RA on chromosome 10p15, and PTPN22 on chromosome 1p13 in type 1 diabetes and IL12A on 3q25 and LPP on 3q28 in celiac disease.
A genetic susceptibility to both type 1 diabetes and celiac disease shares common alleles. These data suggest that common biologic mechanisms, such as autoimmunity-related tissue damage and intolerance to dietary antigens, may be etiologic features of both diseases.
The genetic risk factors predisposing individuals to the development of inflammatory bowel disease are beginning to be deciphered by genome-wide association studies. Surprisingly, these new data point towards a critical role of autophagy in the pathogenesis of Crohn's disease. A single common coding variant in the autophagy protein ATG16L1 predisposes individuals to the development of Crohn's disease: while ATG16L1 encoding threonine at amino acid position 300 (ATG16L1*300T) confers protection, ATG16L1 encoding for alanine instead of threonine (ATG16L1*300A, also known as T300A) mediates risk towards the development of Crohn's disease. Here we report that, in human epithelial cells, the Crohn's disease-associated ATG16L1 coding variant shows impairment in the capture of internalized Salmonella within autophagosomes. Thus, we propose that the association of ATG16L1*300A with increased risk of Crohn's disease is due to impaired bacterial handling and lowered rates of bacterial capture by autophagy.
Epidemiological and experimental evidence suggests that high levels of vitamin D, a potent immunomodulator, may decrease the risk of multiple sclerosis. There are no prospective studies addressing this hypothesis.
To examine whether levels of 25-hydroxyvitamin D are associated with risk of multiple sclerosis.
Prospective, nested case-control study among more than 7 million US military personnel who have serum samples stored in the Department of Defense Serum Repository. Multiple sclerosis cases were identified through Army and Navy physical disability databases for 1992 through 2004, and diagnoses were confirmed by medical record review. Each case (n = 257) was matched to 2 controls by age, sex, race/ethnicity, and dates of blood collection. Vitamin D status was estimated by averaging 25-hydroxyvitamin D levels of 2 or more serum samples collected before the date of initial multiple sclerosis symptoms.
Odds ratios of multiple sclerosis associated with continuous or categorical levels (quantiles or a priori-defined categories) of serum 25-hydroxyvitamin D within each racial/ethnic group.
Among whites (148 cases, 296 controls), the risk of multiple sclerosis significantly decreased with increasing levels of 25-hydroxyvitamin D (odds ratio [OR] for a 50-nmol/L increase in 25-hydroxyvitamin D, 0.59; 95% confidence interval, 0.36-0.97). In categorical analyses using the lowest quintile (<63.3 nmol/L) as the reference, the ORs for each subsequent quintile were 0.57, 0.57, 0.74, and 0.38 (P = .02 for trend across quintiles). Only the OR for the highest quintile, corresponding to 25-hydroxyvitamin D levels higher than 99.1 nmol/L, was significantly different from 1.00 (OR, 0.38; 95% confidence interval, 0.19-0.75; P = .006). The inverse relation with multiple sclerosis risk was particularly strong for 25-hydroxyvitamin D levels measured before age 20 years. Among blacks and Hispanics (109 cases, 218 controls), who had lower 25-hydroxyvitamin D levels than whites, no significant associations between vitamin D and multiple sclerosis risk were found.
The results of our study suggest that high circulating levels of vitamin D are associated with a lower risk of multiple sclerosis.
Systematic genome-wide studies to map genomic regions associated with human diseases are becoming more practical. Increasingly, efforts will be focused on the identification of the specific functional variants responsible for the disease. The challenges of identifying causal variants include the need for complete ascertainment of genetic variants and the need to consider the possibility of multiple causal alleles. We recently reported that risk of systemic lupus erythematosus (SLE) is strongly associated with a common SNP in IFN regulatory factor 5 (IRF5), and that this variant altered spicing in a way that might provide a functional explanation for the reproducible association to SLE risk. Here, by resequencing and genotyping in patients with SLE, we find evidence for three functional alleles of IRF5: the previously described exon 1B splice site variant, a 30-bp in-frame insertion/deletion variant of exon 6 that alters a proline-, glutamic acid-, serine- and threonine-rich domain region, and a variant in a conserved polyA+ signal sequence that alters the length of the 3′ UTR and stability of IRF5 mRNAs. Haplotypes of these three variants define at least three distinct levels of risk to SLE. Understanding how combinations of variants influence IRF5 function may offer etiological and therapeutic insights in SLE; more generally, IRF5 and SLE illustrates how multiple common variants of the same gene can together influence risk of common disease.
• interferon pathway
• systemic lupus erythematosus