Kathy L Moser

Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, United States

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Publications (125)775.7 Total impact

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    ABSTRACT: Background Anxiety and depression are frequently associated with Sjogren’s syndrome and pain is a common complaint. Patients who experience these problems find their symptoms frightening and possibly more disabling than the sicca symptoms for which PSS is better known. Unfortunately the precise etiology of pain symptoms and the influence of psychological symptoms on pain perception is unknown. Objectives We investigated 1) the differential effect of depressive symptoms, anxiety, and catastrophizing on pain intensity and health status and 2) compared patients with neuropathic and non-neuropathic pain symptoms. Methods PSS patients who met AECG criteria (N=95) completed a survey to assess pain intensity: the Brief Pain Inventory1: BPI-S (0-10 scale), neuropathic pain symptoms: the Neuropathic Pain Questionnaire2 (NPP) and affective components of pain: the Pain Anxiety Symptom Scale3 (PASS) and the Pain Catastrophizing Scale4 (PCS). Health status was assessed with the SF-12, perceived stress with a visual analog scale. Linear regression was used to investigate the relationship between pain severity, pain catastrophizing and pain phenotype. Results PSS subjects were classified into those with neuropathic pain (NP, N=25) and those without neuropathic symptoms (Non-NP, N=59; 11 missing NP status). Daily pain for greater than 3 months was reported by 80% of NP and 49% of Non-NP patients. Based on weekly pain ratings, patients were also divided into: mild pain (N=49) and moderate-severe pain (N=42; 4 missing BPI score) groups. Perceived stress (p=0.015) was associated with more severe pain as were PASS (p=0.015) and PCS (p≤0.001). Pain severity correlated with physical domain of the SF-12(r=-.55), with HAD anxiety (r=0.38), HADs depression (r=0.48) and w/ PASS (r=0.48) and PCS (r=.61). The relationship between pain severity and pain catastrophizing was significant in PSS patients with a history of neuropathy(p=0.027) and in those with a diagnosis of FM (p=0.008). PCS also correlated with musculoskeletal pain severity (r=0.54) and with neuropathic pain symptoms (r=0.58). Conclusions Pain anxiety and pain catastrophizing are associated with increasing pain severity in PSS patients with different pain phenotypes. This study is consistent with psychological studies that have shown that “pain captures attention” and that patients with pain are hypervigilant for somatic sensations at the expense of other activities. Further study is needed to develop to develop discriminatory classifications of “central pain”, “nociceptive pain” and “neuropathic pain” which could provide insight into mechanistic pathways and a framework for more rationale therapy. Disclosure of Interest None Declared
    No preview · Article · Jan 2014 · Annals of the Rheumatic Diseases
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    ABSTRACT: Background PSS is characterized by pain, fatigue, lack of a cure, uncertainty and chronicity. Psychological factors are known to modulate health status in persons with chronic illness, but little data is available in PSS. Illness perceptions (especially perceived consequence and perceived control) are important factors influencing medical, psychological and behavioral outcomes in patients with rheumatic disorders. Objectives The aim of this study was to use a validated instrument: the Illness Perceptions Questionnaire (IPQ-R) to investigate potential links between illness perceptions and functional outcomes in patients with primary Sjogren’s syndrome (PSS) and to compare illness representations in patients with different disease characteristics. We compared seropositive and seronegative PSS patients to assess the effects of serologic status and illness perceptions on key outcomes including fatigue, pain and health status. Methods Demographics, clinical characteristics (sicca symptoms and objective sicca measures), health outcomes: fatigue (FSS), pain(BPI), sleep quality(PSQI), mood (HADS), generic health status (SF-12) and illness perceptions (IPQ-R) were evaluated by survey. Relationships between illness perceptions, clinical characteristics and SF-12 domains were assessed by spearman rank correlation. Psychological and clinical characteristics were compared in the two groups by t test and Pearson’s Chi-Squared Test. Results PSS patients (N=123) by AECG criteria were compared based on serologic status (SSA/and or SSB positive vs. SSA/SSB negative) Seronegative (N=45) and seropositive subjects (N=78) were similar in gender (95% F), education (77% college), ethnicity (95% Caucasian), whereas seronegative patients were slightly older (63 yrs. vs. 58 yrs., p=.004). The seronegative group reported greater pain severity (p=.003) and had more negative physical domain SF-12 scores (p=.021) despite a trend toward less severe sicca and similar illness perceptions in all domains of the IPQ-R. Pessimistic beliefs about the consequences of illness were associated with fatigue, with pain severity and with reduced physical function in both patient groups. Mental domain SF-12 scores were negatively associated with fatigue and depression in the seropositive and with fatigue and anxiety in the seronegative group. Conclusions In other chronic illnesses in which fatigue and pain are prominent, coping styles, self-efficacy and catastrophizing are predictive of health outcome. We found that psychological factors, particularly pessimistic beliefs about the consequences of illness, contribute to fatigue and pain as well as to health status in PSS. Assessment of illness perceptions and appropriately designed cognitive behavioral interventions could be helpful to reduce fatigue, pain and psychological distress. Disclosure of Interest None Declared
    No preview · Article · Jan 2014 · Annals of the Rheumatic Diseases
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    ABSTRACT: Genome wide association studies have identified variants in PXK that confer risk for humoral autoimmune diseases, including systemic lupus erythematosus (SLE or lupus), rheumatoid arthritis and more recently systemic sclerosis. While PXK is involved in trafficking of epidermal growth factor Receptor (EGFR) in COS-7 cells, mechanisms linking PXK to lupus pathophysiology have remained undefined. In an effort to uncover the mechanism at this locus that increases lupus-risk, we undertook a fine-mapping analysis in a large multi-ancestral study of lupus patients and controls. We define a large (257kb) common haplotype marking a single causal variant that confers lupus risk detected only in European ancestral populations and spans the promoter through the 3' UTR of PXK. The strongest association was found at rs6445972 with P < 4.62 × 10(-10), OR 0.81 (0.75-0.86). Using stepwise logistic regression analysis, we demonstrate that one signal drives the genetic association in the region. Bayesian analysis confirms our results, identifying a 95% credible set consisting of 172 variants spanning 202 kb. Functionally, we found that PXK operates on the B-cell antigen receptor (BCR); we confirmed that PXK influenced the rate of BCR internalization. Furthermore, we demonstrate that individuals carrying the risk haplotype exhibited a decreased rate of BCR internalization, a process known to impact B cell survival and cell fate. Taken together, these data define a new candidate mechanism for the genetic association of variants around PXK with lupus risk and highlight the regulation of intracellular trafficking as a genetically regulated pathway mediating human autoimmunity.
    Full-text · Article · Jan 2014 · Frontiers in Genetics
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    ABSTRACT: Recent reports have associated NCF2, encoding a core component of the multi-protein NADPH oxidase (NADPHO), with systemic lupus erythematosus (SLE) susceptibility in individuals of European ancestry. To identify ethnicity-specific and -robust variants within NCF2, we assessed 145 SNPs in and around the NCF2 gene in 5325 cases and 21 866 controls of European-American (EA), African-American (AA), Hispanic (HS) and Korean (KR) ancestry. Subsequent imputation, conditional, haplotype and bioinformatic analyses identified seven potentially functional SLE-predisposing variants. Association with non-synonymous rs17849502, previously reported in EA, was detected in EA, HS and AA (PEA = 1.01 × 10-54, PHS = 3.68 × 10-10, PAA = 0.03); synonymous rs17849501 was similarly significant. These SNPs were monomorphic in KR. Novel associations were detected with coding variants at rs35937854 in AA (PAA = 1.49 × 10-9), and rs13306575 in HS and KR (PHS = 7.04 × 10-7, PKR = 3.30 × 10-3). In KR, a 3-SNP haplotype was significantly associated (P = 4.20 × 10-7), implying that SLE predisposing variants were tagged. Significant SNP-SNP interaction (P = 0.02) was detected between rs13306575 and rs17849502 in HS, and a dramatically increased risk (OR = 6.55) with a risk allele at each locus. Molecular modeling predicts that these non-synonymous mutations could disrupt NADPHO complex assembly. The risk allele of rs17849501, located in a conserved transcriptional regulatory region, increased reporter gene activity, suggesting in vivo enhancer function. Our results not only establish allelic heterogeneity within NCF2 associated with SLE, but also emphasize the utility of multi-ethnic cohorts to identify predisposing variants explaining additional phenotypic variance ('missing heritability') of complex diseases like SLE.
    Full-text · Article · Nov 2013 · Human Molecular Genetics
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    ABSTRACT: Comparison of recombination at TNFSF4 in African-American TNFSF4risk and TNFSF4non-risk individuals. Phased chromosomes from African-American SLE individuals homozygous for TNFSF4risk (n = 10) and TNFSF4non-risk(n = 10) were tested for recombination using Rhomap from the LDHAT2.0 package. A fine-scale map of recombination rate (4Ner/kb) across 250 kb of chromosome 1q25 which encompassed TNFSF4 and extended 5′ and 3′ regions was inferred. Individuals were identified as homozygous for TNFSF4risk or TNFSF4non-risk. We ran Rhomap for a total of 1,100,000 rjMCMC iterations including a burn-in of 100000 iterations, sampling the chain after every 100. Grey diamonds indicate the location to scale of SNPs significantly associated with risk of SLE in this cohort, the TNFSF4 gene is also located to scale under the graph. (EPS)
    Preview · Dataset · Jul 2013
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    ABSTRACT: Genomes allele frequencies for rs1234314 and rs2205960. (DOCX)
    Preview · Dataset · Jul 2013
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    ABSTRACT: Left, Principal component (PC) 1 versus PC2 analyses of four Hapmap III African (yellow) and two Hapmap III European (red) populations and our African-American SLE-control cohort (black). Right. Population stratification between African-American cases (red) and controls (black) was minimised by principal components analysis using 367 major ancestry informative markers. This figure depicts the most profound ancestry differences along continuous axis of variation between cases and controls after QC filtering of the AA cohort. (EPS)
    Preview · Dataset · Jul 2013
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    ABSTRACT: TNFSF4 markers in African- Americans, Gullah and combined AA-Gullah (non-imputed). (DOCX)
    Preview · Dataset · Jul 2013
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    ABSTRACT: (Case-only) and (Case-control) phenotype analysis. (DOCX)
    Preview · Dataset · Jul 2013
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    ABSTRACT: PC-based analysis of the Mestizo Native American cohort (grey) and Hispanic Mestizo cohort (black) use 347 AIM SNPs. (EPS)
    Preview · Dataset · Jul 2013
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    ABSTRACT: We previously established an 80 kb haplotype upstream of TNFSF4 as a susceptibility locus in the autoimmune disease SLE. SLE-associated alleles at this locus are associated with inflammatory disorders, including atherosclerosis and ischaemic stroke. In Europeans, the TNFSF4 causal variants have remained elusive due to strong linkage disequilibrium exhibited by alleles spanning the region. Using a trans-ancestral approach to fine-map the locus, utilising 17,900 SLE and control subjects including Amerindian/Hispanics (1348 cases, 717 controls), African-Americans (AA) (1529, 2048) and better powered cohorts of Europeans and East Asians, we find strong association of risk alleles in all ethnicities; the AA association replicates in African-American Gullah (152,122). The best evidence of association comes from two adjacent markers: rs2205960-T (P = 1.71×10(-34) , OR = 1.43[1.26-1.60]) and rs1234317-T (P = 1.16×10(-28) , OR = 1.38[1.24-1.54]). Inference of fine-scale recombination rates for all populations tested finds the 80 kb risk and non-risk haplotypes in all except African-Americans. In this population the decay of recombination equates to an 11 kb risk haplotype, anchored in the 5' region proximal to TNFSF4 and tagged by rs2205960-T after 1000 Genomes phase 1 (v3) imputation. Conditional regression analyses delineate the 5' risk signal to rs2205960-T and the independent non-risk signal to rs1234314-C. Our case-only and SLE-control cohorts demonstrate robust association of rs2205960-T with autoantibody production. The rs2205960-T is predicted to form part of a decameric motif which binds NF-κBp65 with increased affinity compared to rs2205960-G. ChIP-seq data also indicate NF-κB interaction with the DNA sequence at this position in LCL cells. Our research suggests association of rs2205960-T with SLE across multiple groups and an independent non-risk signal at rs1234314-C. rs2205960-T is associated with autoantibody production and lymphopenia. Our data confirm a global signal at TNFSF4 and a role for the expressed product at multiple stages of lymphocyte dysregulation during SLE pathogenesis. We confirm the validity of trans-ancestral mapping in a complex trait.
    Full-text · Article · Jul 2013 · PLoS Genetics
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    ABSTRACT: We used the Immunochip array to analyze 2,816 individuals with juvenile idiopathic arthritis (JIA), comprising the most common subtypes (oligoarticular and rheumatoid factor-negative polyarticular JIA), and 13,056 controls. We confirmed association of 3 known JIA risk loci (the human leukocyte antigen (HLA) region, PTPN22 and PTPN2) and identified 14 loci reaching genome-wide significance (P < 5 x 10(-8)) for the first time. Eleven additional new regions showed suggestive evidence of association with JIA (P < 1 x 10(-6)). Dense mapping of loci along with bioinformatics analysis refined the associations to one gene in each of eight regions, highlighting crucial pathways, including the interleukin (IL)-2 pathway, in JIA disease pathogenesis. The entire Immunochip content, the HLA region and the top 27 loci (P < 1 x 10(-6)) explain an estimated 18, 13 and 6% of the risk of JIA, respectively. In summary, this is the largest collection of JIA cases investigated so far and provides new insight into the genetic basis of this childhood autoimmune disease.
    Full-text · Dataset · Jun 2013
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    ABSTRACT: Objective: Little is known about the genetic etiology of systemic lupus erythematosus (SLE) in individuals of African ancestry, despite its higher prevalence and greater disease severity. Overproduction of nitric oxide (NO) and reactive oxygen species are implicated in the pathogenesis and severity of SLE, making NO synthases and other reactive intermediate-related genes biological candidates for disease susceptibility. We analyzed variation in reactive intermediate genes for association with SLE in 2 populations with African ancestry. Methods: A total of 244 single-nucleotide polymorphisms (SNP) from 53 regions were analyzed in non-Gullah African Americans (AA; 1432 cases and 1687 controls) and the genetically more homogeneous Gullah of the Sea Islands of South Carolina (133 cases and 112 controls). Single-marker, haplotype, and 2-locus interaction tests were computed for these populations. Results: The glutathione reductase gene GSR (rs2253409; p = 0.0014, OR 1.26, 95% CI 1.09-1.44) was the most significant single SNP association in AA. In the Gullah, the NADH dehydrogenase NDUFS4 (rs381575; p = 0.0065, OR 2.10, 95% CI 1.23-3.59) and NO synthase gene NOS1 (rs561712; p = 0.0072, OR 0.62, 95% CI 0.44-0.88) were most strongly associated with SLE. When both populations were analyzed together, GSR remained the most significant effect (rs2253409; p = 0.00072, OR 1.26, 95% CI 1.10-1.44). Haplotype and 2-locus interaction analyses also uncovered different loci in each population. Conclusion: These results suggest distinct patterns of association with SLE in African-derived populations; specific loci may be more strongly associated within select population groups.
    No preview · Article · May 2013 · The Journal of Rheumatology
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    ABSTRACT: Systemic lupus erythematosus (SLE) is an inflammatory autoimmune disease with a strong genetic component. African-Americans (AA) are at increased risk of SLE, but the genetic basis of this risk is largely unknown. To identify causal variants in SLE loci in AA, we performed admixture mapping followed by fine mapping in AA and European-Americans (EA). Through genome-wide admixture mapping in AA, we identified a strong SLE susceptibility locus at 2q22-24 (LOD = 6.28), and the admixture signal is associated with the European ancestry (ancestry risk ratio ∼1.5). Large-scale genotypic analysis on 19,726 individuals of African and European ancestry revealed three independently associated variants in the IFIH1 gene: an intronic variant, rs13023380 [P(meta) = 5.20×10(-14); odds ratio, 95% confidence interval = 0.82 (0.78-0.87)], and two missense variants, rs1990760 (Ala946Thr) [P(meta) = 3.08×10(-7); 0.88 (0.84-0.93)] and rs10930046 (Arg460His) [P(dom) = 1.16×10(-8); 0.70 (0.62-0.79)]. Both missense variants produced dramatic phenotypic changes in apoptosis and inflammation-related gene expression. We experimentally validated function of the intronic SNP by DNA electrophoresis, protein identification, and in vitro protein binding assays. DNA carrying the intronic risk allele rs13023380 showed reduced binding efficiency to a cellular protein complex including nucleolin and lupus autoantigen Ku70/80, and showed reduced transcriptional activity in vivo. Thus, in SLE patients, genetic susceptibility could create a biochemical imbalance that dysregulates nucleolin, Ku70/80, or other nucleic acid regulatory proteins. This could promote antibody hypermutation and auto-antibody generation, further destabilizing the cellular network. Together with molecular modeling, our results establish a distinct role for IFIH1 in apoptosis, inflammation, and autoantibody production, and explain the molecular basis of these three risk alleles for SLE pathogenesis.
    Full-text · Article · Feb 2013 · PLoS Genetics
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    ABSTRACT: Systemic lupus erythematosus (SLE) disease manifestations are highly variable among patients, and the prevalence of individual clinical features differs significantly by ancestry. Serum tumor necrosis factor α (TNFα) levels are elevated in some SLE patients and may play a role in disease pathogenesis. The aim of this study was to look for associations between serum TNFα levels, clinical manifestations of SLE, autoantibodies, and serum interferon-α (IFNα) levels in a large multiancestral SLE cohort. We studied serum TNFα levels in 653 SLE patients (214 African Americans, 298 European Americans, and 141 Hispanic Americans). TNFα was measured using an enzyme-linked immunosorbent assay, and IFNα was measured with a functional reporter cell assay. Stratified and multivariate analyses were used to detect associations in each ancestral background separately, with meta-analysis when appropriate. Serum TNFα levels were significantly higher in SLE patients than in non-autoimmune disease controls (P < 5.0 × 10(-3) for each ancestral background). High serum TNFα levels were positively correlated with high serum IFNα levels when tested in the same sample across all ancestral backgrounds (odds ratio range 1.76-1.86, P = 4.8 × 10(-3) by Fisher's combined probability test). While serum TNFα levels alone did not differ significantly among SLE patients of different ancestral backgrounds, the proportion of patients with concurrently high levels of TNFα and IFNα was highest in African Americans and lowest in European Americans (P = 5.0 × 10(-3) ). Serum TNFα levels were not associated with autoantibodies, clinical criteria for the diagnosis of SLE, or age at the time of sampling. Serum TNFα levels are high in many SLE patients, and we observed a positive correlation between serum TNFα and IFNα levels. These data support a role for TNFα in the pathogenesis of SLE across all ancestral backgrounds and suggest important cytokine subgroups within the disease.
    Full-text · Article · Sep 2012 · Arthritis & Rheumatology
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    ABSTRACT: Background: Sjögren syndrome is a common, chronic autoimmune disease that typically produces inflammation and poor function of the salivary and lacrimal glands. Other organs can be affected, including the nervous system. Sensory peripheral neuropathy is a common manifestation of the disease. Methods: Eight-eight patients attending a dry eyes-dry mouth clinic were diagnosed to have primary Sjögren syndrome and underwent a neurological examination. Anti-Ro (or SSA) and anti-La (or SSB) were determined using immunodiffusion as well as Inno-Lia and BioPlex ANA screen. Serum vitamin B(12) levels were determined using an enzyme-linked microtiter plate assay. Results: Twenty-seven (31%) of the 88 patients had peripheral neuropathy as defined by loss of light touch, proprioception, or vibratory sensation. Anti-Ro and anti-La were found by immunodiffusion in 12 patients, and 8 of these 12 had neuropathy (χ(2) = 8.46, P = 0.0036, odds ratio = 6.0 compared to those without precipitating anti-Ro and anti-La). Of the 27 patients with only anti-Ro by immunodiffusion, 13 (48.1%) had neuropathy (χ(2) = 5.587, P = 0.018, compared to those without anti-Ro). There was no relationship of the other, more sensitive measures of anti-Ro and anti-La to neuropathy. In addition, we found no association of serum vitamin B(12) levels to neuropathy among these patients with Sjögren syndrome. Conclusions: Sensory peripheral neuropathy is common among patients with Sjögren syndrome and is associated with the presence of anti-Ro and anti-La when determined by immunodiffusion.
    No preview · Article · Sep 2012 · Journal of clinical rheumatology: practical reports on rheumatic & musculoskeletal diseases
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    ABSTRACT: Sarcoidosis is a systemic inflammatory disease characterized by the formation of granulomas in affected organs. Genome-wide association studies (GWASs) of this disease have been conducted only in European population. We present the first sarcoidosis GWAS in African Americans (AAs, 818 cases and 1,088 related controls) followed by replication in independent sets of AAs (455 cases and 557 controls) and European Americans (EAs, 442 cases and 2,284 controls). We evaluated >6 million SNPs either genotyped using the Illumina Omni1-Quad array or imputed from the 1000 Genomes Project data. We identified a novel sarcoidosis-associated locus, NOTCH4, that reached genome-wide significance in the combined AA samples (rs715299, P(AA-meta) = 6.51×10(-10)) and demonstrated the independence of this locus from others in the MHC region in the same sample. We replicated previous European GWAS associations within HLA-DRA, HLA-DRB5, HLA-DRB1, BTNL2, and ANXA11 in both our AA and EA datasets. We also confirmed significant associations to the previously reported HLA-C and HLA-B regions in the EA but not AA samples. We further identified suggestive associations with several other genes previously reported in lung or inflammatory diseases.
    Full-text · Article · Aug 2012 · PLoS ONE
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    ABSTRACT: Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by autoantibody production and altered type I interferon expression. Genetic surveys and genome-wide association studies have identified >30 SLE susceptibility genes. One of these genes, TNIP1, encodes the ABIN1 protein. ABIN1 functions in the immune system by restricting NF-κB signaling. The present study was undertaken to investigate the genetic factors that influence association with SLE in genes that regulate the NF-κB pathway. We analyzed a dense set of genetic markers spanning TNIP1 and TAX1BP1, as well as the TNIP1 homolog TNIP2, in case–control populations of diverse ethnic origins. TNIP1, TNIP2, and TAX1BP1 were fine-mapped in a total of 8,372 SLE cases and 7,492 healthy controls from European-ancestry, African American, Hispanic, East Asian, and African American Gullah populations. Levels of TNIP1 messenger RNA (mRNA) and ABIN1 protein in Epstein-Barr virus–transformed human B cell lines were analyzed by quantitative reverse transcription–polymerase chain reaction and Western blotting, respectively. We found significant associations between SLE and genetic variants within TNIP1, but not in TNIP2 or TAX1BP1. After resequencing and imputation, we identified 2 independent risk haplotypes within TNIP1 in individuals of European ancestry that were also present in African American and Hispanic populations. Levels of TNIP1 mRNA and ABIN1 protein were reduced among subjects with these haplotypes, suggesting that they harbor hypomorphic functional variants that influence susceptibility to SLE by restricting ABIN1 expression. Our results confirm the association signals between SLE and TNIP1 variants in multiple populations and provide new insight into the mechanism by which TNIP1 variants may contribute to SLE pathogenesis.
    Full-text · Article · Jul 2012 · Arthritis & Rheumatology
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    ABSTRACT: Objective Systemic lupus erythematosus (SLE; OMIM 152700) is a chronic autoimmune disease for which the aetiology includes genetic and environmental factors. ITGAM, integrin αM (complement component 3 receptor 3 subunit) encoding a ligand for intracellular adhesion molecule (ICAM) proteins, is an established SLE susceptibility locus. This study aimed to evaluate the independent and joint effects of genetic variations in the genes that encode ITGAM and ICAM. Methods The authors examined several markers in the ICAM1–ICAM4–ICAM5 locus on chromosome 19p13 and the single ITGAM polymorphism (rs1143679) using a large-scale case–control study of 17 481 unrelated participants from four ancestry populations. The single-marker association and gene–gene interaction were analysed for each ancestry, and a meta-analysis across the four ancestries was performed. Results The A-allele of ICAM1–ICAM4–ICAM5 rs3093030, associated with elevated plasma levels of soluble ICAM1, and the A-allele of ITGAM rs1143679 showed the strongest association with increased SLE susceptibility in each of the ancestry populations and the trans-ancestry meta-analysis (ORmeta=1.16, 95% CI 1.11 to 1.22; p=4.88×10−10 and ORmeta=1.67, 95% CI 1.55 to 1.79; p=3.32×10−46, respectively). The effect of the ICAM single-nucleotide polymorphisms (SNPs) was independent of the effect of the ITGAM SNP rs1143679, and carriers of both ICAM rs3093030-AA and ITGAM rs1143679-AA had an OR of 4.08 compared with those with no risk allele in either SNP (95% CI 2.09 to 7.98; p=3.91×10−5). Conclusion These findings are the first to suggest that an ICAM–integrin-mediated pathway contributes to susceptibility to SLE.
    Full-text · Article · Apr 2012 · Annals of the rheumatic diseases
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    ABSTRACT: Systemic lupus erythematosus (SLE) is a chronic heterogeneous autoimmune disorder characterized by the loss of tolerance to self-antigens and dysregulated interferon responses. The etiology of SLE is complex, involving both heritable and environmental factors. Candidate-gene studies and genome-wide association (GWA) scans have been successful in identifying new loci that contribute to disease susceptibility; however, much of the heritable risk has yet to be identified. In this study, we sought to replicate 1,580 variants showing suggestive association with SLE in a previously published GWA scan of European Americans; we tested a multiethnic population consisting of 7,998 SLE cases and 7,492 controls of European, African American, Asian, Hispanic, Gullah, and Amerindian ancestry to find association with the disease. Several genes relevant to immunological pathways showed association with SLE. Three loci exceeded the genome-wide significance threshold: interferon regulatory factor 8 (IRF8; rs11644034; p(meta-Euro) = 2.08 × 10(-10)), transmembrane protein 39A (TMEM39A; rs1132200; p(meta-all) = 8.62 × 10(-9)), and 17q21 (rs1453560; p(meta-all) = 3.48 × 10(-10)) between IKAROS family of zinc finger 3 (AIOLOS; IKZF3) and zona pellucida binding protein 2 (ZPBP2). Fine mapping, resequencing, imputation, and haplotype analysis of IRF8 indicated that three independent effects tagged by rs8046526, rs450443, and rs4843869, respectively, were required for risk in individuals of European ancestry. Eleven additional replicated effects (5 × 10(-8) < p(meta-Euro) < 9.99 × 10(-5)) were observed with CFHR1, CADM2, LOC730109/IL12A, LPP, LOC63920, SLU7, ADAMTSL1, C10orf64, OR8D4, FAM19A2, and STXBP6. The results of this study increase the number of confirmed SLE risk loci and identify others warranting further investigation.
    Full-text · Article · Apr 2012 · The American Journal of Human Genetics

Publication Stats

7k Citations
775.70 Total Impact Points

Institutions

  • 1997-2014
    • Oklahoma Medical Research Foundation
      • Arthritis and Clinical Immunology Program
      Oklahoma City, Oklahoma, United States
  • 2009-2013
    • Oklahoma City University
      Oklahoma City, Oklahoma, United States
    • Montreal Heart Institute
      • Research Centre
      Montréal, Quebec, Canada
    • University of Southern California
      Los Ángeles, California, United States
    • Hanyang University
      • Major in Internal Medicine
      Sŏul, Seoul, South Korea
  • 2011
    • University of California, San Francisco
      San Francisco, California, United States
  • 2001-2008
    • University of Minnesota Duluth
      • Medical School
      Duluth, Minnesota, United States
  • 2005
    • Molecular and Cellular Biology Program
      Seattle, Washington, United States
  • 2004
    • University of Minnesota Twin Cities
      • Department of Medicine
      Minneapolis, Minnesota, United States
  • 2002
    • Case Western Reserve University
      • Department of Epidemiology and Biostatistics
      Cleveland, OH, United States
  • 1994
    • University of Oklahoma Health Sciences Center
      • College of Medicine
      Oklahoma City, Oklahoma, United States