Lina-Marcela Diaz-Gallo

Karolinska Institutet | KI · Department of Medicine, Solna

Objectives Emerging evidence demonstrate that anti-phosphatidylserine/prothrombin complex antibodies (anti-PS/PT) associate with thrombotic events. Genetic predisposition, including HLA-DRB1 alleles, is known to contribute to the occurrence of conventional antiphospholipid antibodies (aPL, anti-β2glycoprotein-I (β2GPI) and anti-cardiolipin (CL)). W...

Objective The heterogeneity of systemic lupus erythematosus (SLE) constitutes clinical and therapeutical challenges. We therefore studied whether unrecognized disease subgroups can be identified by using autoantibody profiling together with HLA-DRB1 alleles and immunological and clinical data. Methods An unsupervised cluster analysis was performed...

Understanding the genetic background of complex diseases requires the expansion of studies beyond univariate associations. Therefore, it is important to use interaction assessments of risk factors in order to discover whether, and how genetic risk variants act together on disease development. The principle of interaction analysis is to explore the...

Background Fine-mapping of human leukocyte antigen ( HLA ) region for rheumatoid arthritis (RA) risk factors has identified several HLA alleles and its corresponding amino acid residues as independent signals (i.e., HLA-A , HLA-B , HLA-DPB1 , and HLA-DQA1 genes), in addition to the well-established genetic factor in HLA-DRB1 gene. However, this was...

The influence and effect of cigarette smoking in sarcoidosis is unclear. Here, we evaluated gene-environment interaction between multiple genetic variants including HLA genes and smoking in sarcoidosis defined by two clinical phenotypes, Löfgren’s syndrome (LS) and patients without Löfgren’s syndrome (non-LS). To quantify smoking effects in sarcoid...

Interaction analysis is used to investigate the effect which two risk factors have on each other, and on disease risk. To study interactions, both additive and multiplicative models have been used, although their interpretations are not universally understood. In this study, we simulated several scenarios of risk factors relationships and investiga...

Objective In anti-citrullinated protein antibody positive rheumatoid arthritis (ACPA-positive RA), a particular subset of HLA-DRB1 alleles, called shared epitope (SE) alleles, is a highly influential genetic risk factor. Here, we investigated whether non-HLA single nucleotide polymorphisms (SNP), conferring low disease risk on their own, interact w...

The presence of the PTPN22 risk allele (1858T) is associated with several autoimmune diseases including rheumatoid arthritis (RA). Despite a number of studies exploring the function of PTPN22 in T cells, the exact impact of the PTPN22 risk allele on T-cell function in humans is still unclear. In this study, using RNA sequencing, we show that, upon...

In anti-citrullinated protein antibody positive rheumatoid arthritis (ACPA-positive RA), a particular subset of HLA-DRB1 alleles, called shared epitope alleles (SE), is the highest genetic risk factor. Here, we aimed to investigate whether gene-gene interactions influence this HLA-DRB1 related major disease risk; specifically, we set out to test if...

SLE is a heterogeneous disease including diverging clinical symptoms, autoantibodies and genetic susceptibility. Hitherto unrecognised patterns may define sub-phenotypes with different pathogenesis and specific treatment needs. Based on autoantibody profile we therefore investigated phenotypic clusters and explored cluster associations with clinica...

Background Here we integrate verified signals from previous genetic association studies with gene expression and pathway analysis for discovery of new candidate genes and signaling networks, relevant for rheumatoid arthritis (RA). MethodRNA-sequencing-(RNA-seq)-based expression analysis of 377 genes from previously verified RA-associated loci was p...

Objective: In rheumatoid arthritis (RA) several recent efforts have sought to discover means of predicting which patients would benefit from treatment. However, results have been discrepant with few successful replications. Our objective was to build a biobank with DNA, RNA and protein measurements to test the claim that the current state-of-the-a...

Mutations of the gene encoding four-and-a-half LIM domain 1 (FHL1) are the causative factor of several X-linked hereditary myopathies that are collectively termed FHL1-related myopathies. These disorders are characterized by severe muscle dysfunction and damage. Here, we have shown that patients with idiopathic inflammatory myopathies (IIMs) develo...

We performed gene-gene interaction analysis, with HLA-DRB1 shared epitope (SE) alleles for 195 SNPs within immunologically important MAP2Ks, MAP3Ks and MAP4Ks gene families, in 2010 rheumatoid arthritis (RA) patients and 2280 healthy controls. We found a significant statistical interaction for rs10468473 with SE in autoantibody-positive RA. Individ...

Systemic sclerosis (SSc) and systemic lupus erythematosus (SLE) are two archetypal systemic autoimmune diseases which have been shown to share multiple genetic susceptibility loci. In order to gain insight into the genetic basis of these diseases we performed a pan-meta-analysis of two genome-wide association studies (GWAS) together with a replicat...

Results observed using different expression quantitative trait loci (eQTL) tools to evaluate if there is any relationship between the rs9976767 variant and the UBASH3a expression (A) SNP-gene association plot for the rs9976767 and the UBASH3a gene based on Spearman's rank correlation coefficient (rho) using the Genevar 3.2 software (http://www.sang...

Pattern of linkage disequilibrium of the five studied SNPs and their location in the UBAHS3a gene. The values correspond to r2 calculated for the Spanish cohort. The rs2277798 polymorphism [G/A] is located in exon 1 of UBASH3a gene. It's a no-synonymous change in the position 18 of the protein (S[Ser]/G[Gly]). The rs2277800 polymorphism [C/T] is al...

The ubiquitin associated and Src-homology 3 (SH3) domain containing A (UBASH3a) is a suppressor of T-cell receptor signaling, underscoring antigen presentation to T-cells as a critical shared mechanism of diseases pathogenesis. The aim of the present study was to determine whether the UBASH3a gene influence the susceptibility to systemic lupus eryt...

Objective: To evaluate whether the systemic sclerosis (SSc)-associated IRAK1 non-synonymous single-nucleotide polymorphism rs1059702 is responsible for the Xq28 association with SSc or whether there are other independent signals in the nearby methyl-CpG-binding protein 2 gene (MECP2). Methods: We analysed a total of 3065 women with SSc and 2630...

Objective The interleukin 2 (IL-2) and interleukin 21 (IL-21) locus at chromosome 4q27 has been associated with several autoimmune diseases, and both genes are related to immune system functions. The aim of this study was to evaluate the role of the IL-2/IL-21 locus in systemic sclerosis (SSc). Patients and methods The case control study included 4...

C1858T single nucleotide polymorphism in PTPN22 encoding the R620W allele variant of Lyp-PTPN22 (a protein phosphatase negatively regulating T-cell activation) has been associated with autoimmunity. This work has investigated the possible association between PTPN22 C1858T (rs2476601) polymorphism and rheumatoid arthritis (RA), systemic lupus erythe...

Genetic variation in the protein tyrosine phosphatase non-receptor type gene 22 (PTPN22, encoding lymphoid tyrosine phosphatase, LYP) influences the risk of developing multiple autoimmune diseases, but the underlying mechanisms are not completely understood. In a recent study published in Genome Medicine, Ronninger et al. showed that there are diff...

A recent genome-wide association study (GWAS) of copy number variants (CNVs) in Crohn's disease (CD) confirmed association of three CNVs. The GWAS also provided evidence that a fourth CNV, CNVR7113.6, on chromosome 17 may alter susceptibility to CD (P = 0.0018). The aim of our study was to confirm the CNVR7113.6 association by genotyping two indepe...

Background: The PTPN22 gene is an important risk factor for human autoimmunity. The aim of this study was to evaluate for the first time the role of the R263Q PTPN22 polymorphism in ulcerative colitis (UC) and Crohn's disease (CD), and to reevaluate the association of the R620W PTPN22 polymorphism with both diseases. Methods: A total of 1677 UC...

[This corrects the article on p. e1002178 in vol. 7.].

Manhattan plot and QQ plot showing the -log10 of the Mantel-Haenszel P value of all 279,621 SNPs in the lcSSc individuals of the GWAS cohorts comprising 1,400 cases and 5,171 controls. All P values are GC corrected, and λ was 1.058. (TIF)

Manhattan plot and QQ plot showing the -log10 of the Mantel-Haenszel P value of all 279,621 SNPs in the dcSSc individuals of the GWAS cohorts comprising 740 cases and 5,171 controls. All P values are GC corrected, and λ was 1.034. (TIF)

Manhattan plot showing the analysis in the GWAS cohorts imputed data. The different subphenotypes considered are represented in different colors. (TIF)

Manhattan plot and QQ plot showing the -log10 of the Mantel-Haenszel P value of all 279,621 SNPs in the ATA positive individuals of the GWAS cohorts comprising 447 cases and 5,171 controls. All P values are GC corrected, and λ was 1.061. (TIF)

Analysis for GWAS cohorts, replication cohorts and combined analysis for all non-HLA, non-previously described associations with ACA positive subgroup of the disease. †P values for GWAS cohorts are Mantel-Haenszel meta-analysis GC corrected according to the set λ and in the replication and combined analysis Mantel-Haenszel meta-analysis P value. ‡P...

Power calculations and genomic inflation factors (λ) in the whole SSc cohorts (GWAS and replication) and the lcSSc, dcSSc, ACA and ATA positive subphenotypes. 5×10−8 was used as significance threshold. (DOC)

Independent associations found in the HLA region in the ATA positive subgroup of patients in the separate four GWAS cohorts. †Uncorrected χ2 P value of each separated cohort. (DOC)

Previously described genetic associations with SSc subphenotypes which were present in the present study's GWAS panel of SNPs. A total of 2,296 SSc cases and 5,172 controls were included in this analysis. The SSc cases included 1,400 lcSSc individuals, 740 dcSSc individuals, 761 ACA+ individuals and 447 ATA+ individuals. Best P value in each subgro...

Analysis for GWAS cohorts, replication cohorts and combined analysis for all non-HLA, non-previously described associations with dcSSc subtype of the disease. †P values for GWAS cohorts are Mantel-Haenszel meta-analysis GC corrected according to the set λ and in the replication and combined analysis Mantel-Haenszel meta-analysis P value. ‡P value f...

Manhattan plot and QQ plot showing the -log10 of the Mantel-Haenszel P value of all 279,621 SNPs in the ACA positive individuals of the GWAS cohorts comprising 761 cases and 5,171 controls. All P values are GC corrected, and λ was 1.050. (TIF)

Analysis for GWAS cohorts, replication cohorts and combined analysis for all non-HLA, non-previously described associations with lcSSc subtype of the disease. †P values for GWAS cohorts are Mantel-Haenszel meta-analysis GC corrected according to the set λ and in the replication and combined analysis Mantel-Haenszel meta-analysis P value. ‡P value f...

Analysis for GWAS cohorts, replication cohorts and combined analysis for all non-HLA, non-previously described associations with ATA positive subgroup of the disease. †P values for GWAS cohorts are Mantel-Haenszel meta-analysis GC corrected according to the set λ and in the replication and combined analysis Mantel-Haenszel meta-analysis P value. ‡P...

Conditional logistic regression analysis of all the independently associated SNPs in the HLA region in the ACA positive patients. †P values for Mantel-Haenszel meta-analysis GC corrected according to the set λ. (DOC)

Conditional logistic regression analysis of all the independently associated SNPs in the HLA region in the ATA positive patients. †P values for Mantel-Haenszel meta-analysis GC corrected according to the set λ. (DOC)

Independent associations found in the HLA region in the ACA positive subgroup of patients in the separate four GWAS cohorts. †Uncorrected χ2 P value of each separated cohort. (DOC)

Members of the Spanish Scleroderma Group. (DOC)

Composition and size of all the populations used in the study for the considered features of the disease. (DOC)

URLs. Internet Uniform Resource Locator (URL) for each of the software packages used in this study. (DOC)

The aim of this study was to determine, through a genome-wide association study (GWAS), the genetic components contributing to different clinical sub-phenotypes of systemic sclerosis (SSc). We considered limited (lcSSc) and diffuse (dcSSc) cutaneous involvement, and the relationships with presence of the SSc-specific auto-antibodies, anti-centromer...

The aim of this study was to determine, through a genome-wide association study (GWAS), the genetic components contributing to different clinical sub-phenotypes of systemic sclerosis (SSc). We considered limited (lcSSc) and diffuse (dcSSc) cutaneous involvement, and the relationships with presence of the SSc-specific auto-antibodies, anti-centromer...

Impaired innate inflammatory response has a key role in the Crohn's disease (CD) pathogenesis. The aim of this study was to investigate the possible role of the TLR10-TLR1-TLR6 gene cluster in CD susceptibility. A total of 508 CD patients (284, cohort 1 and 224, cohort 2) and 576 controls were included. TLR10-TLR1-TLR6 cluster single-nucleotide pol...

The aim of this study was to evaluate the possible implication of CD24 gene in the genetic predisposition to inflammatory bowel disease (IBD). Our study population consisted of 1321 female Spanish individuals (369 Crohn's disease [CD] patients, 323 ulcerative colitis [UC] patients, and 629 healthy matched controls). Two putative functional polymorp...

Two functional single nucleotide polymorphisms (SNP) in the PTPN22 gene (rs24746601 and rs33996649) have been associated with autoimmunity. The aim of this study was to investigate the role of the R263Q SNP for the first time and to re-evaluate the role of the R620W SNP in the genetic predisposition to systemic sclerosis (SSc) susceptibility and cl...

Systemic sclerosis or scleroderma (SSc) is an autoimmune pathology with a variable clinical expression grouped within genetically complex diseases, in which environmental and genetical factors combine. Genes of the HLA regions were those first associated with susceptibility to present SSc, mainly the HLA-DRB1⁎11/⁎06/⁎16 allelles. However, through a...

Systemic sclerosis or scleroderma (SSc) is an autoimmune pathology with a variable clinical expression grouped within genetically complex diseases, in which environmental and genetical factors combine. Genes of the HLA regions were those first associated with susceptibility to present SSc, mainly the HLA-DRB1⁎11/⁎06/⁎16 allelles. However, through a...

[This corrects the article on p. e11520 in vol. 5.].

A functional polymorphism located at -1 from the start codon of the CD40 gene, rs1883832, was previously reported to disrupt a Kozak sequence essential for translation. It has been consistently associated with Graves' disease risk in populations of different ethnicity and genetic proxies of this variant evaluated in genome-wide association studies...

To examine the influence of STAT4 rs7574865 gene polymorphism on patients with primary Sjögren's syndrome (SS). Two different cohorts were studied: 69 patients with primary SS and 296 controls from Colombia and 108 patients with primary SS and 227 controls from Germany. Samples were genotyped for the STAT4 rs7574865 single-nucleotide polymorphism w...

Recently, the signal transducer and activator of transcription 4 (STAT4) gene has been associated with multiple autoimmune diseases. Interestingly, a recent work showed that the T allele of the rs7574865 STAT4 SNP was associated with inflammatory bowel disease (IBD) in a Spanish population. The aim of the present study was to reevaluate the role of...

Bcl-2 antagonist killer 1 (BAK1) is a Bcl-2 family proapoptotic member suggested as a candidate gene for autoimmune diseases. The influence of BAK1 polymorphisms on the risk of developing autoimmune rheumatic diseases (AIRDs) in women was investigated. A total of 719 Colombian women were included in the present study: 209 had systemic lupus erythem...

To estimate the common effect size of HLA-DRB1 and -DQB1 alleles on systemic lupus erythematosus (SLE) susceptibility across Latin America populations through a meta-analysis. Case-control studies on HLA class II association with SLE in Latin America were searched up to August 2007. The effect summary odds ratios (ORs) and 95% confidence intervals...