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Rachel Kaiser, Kimberly E Taylor,
Yun Deng,
Jian Zhao,
Yonghong Li,
Joanne Nititham,
Monica Chang,
Joseph Catanese,
Ann B Begovich,
Elizabeth E Brown, [......],
Edward K Wakeland,
Quan-Zhen Li,
Wanling Yang,
Yu-Lung Lau,
Fei-Lan Liu,
Deh-Ming Chang,
Chack-Yung Yu,
Yeong W Song,
Betty P Tsao,
Lindsey A Criswell
[show abstract]
[hide abstract]
ABSTRACT: OBJECTIVE: The increased risk of thrombosis in systemic lupus erythematosus (SLE) may be partially explained by interrelated genetic pathways for thrombosis and SLE. We investigated whether 33 established and novel single nucleotide polymorphisms (SNP) in 20 genes involved in hemostasis pathways that have been associated with deep venous thrombosis (DVT) in the general population were risk factors for SLE among Asians. METHODS: Patients in the discovery cohort were enrolled in one of two North American SLE cohorts. Patients in the replication cohort were enrolled in one of four Asian or two North American cohorts. We first genotyped 263 Asian SLE and 357 healthy Asian control individuals for 33 SNPs in the discovery phase, and then genotyped 5 SNPs in up to an additional 1496 cases and 993 controls in the replication phase. Patients were compared to controls for bivariate association with minor alleles. Principal components analysis was used to control for intra-Asian ancestry in the replication cohort. RESULTS: Two genetic variants in the gene VKORC1 were highly significant in both the discovery and replication cohorts: rs9934438 OR((disc)) 2.45 (p=2x10(-9) ), OR((rep)) 1.54 (p=4x10(-6) ) and rs9923231 OR((disc)) 2.40 (p=6x10(-9) ), OR((rep)) 1.53, (p=5x10(-6) ). These associations were significant in the replication cohort after adjustment for intra-Asian ancestry: rs9934438 OR((adj)) 1.34 (p=0.0029) and rs9923231 OR((adj)) 1.34 (p=0.0032). CONCLUSION: Genetic variants in VKORC1, involved in vitamin K reduction and associated with DVT, are associated with SLE development in Asians. These results suggest intersecting genetic pathways for the development of SLE and thrombosis. © 2012 American College of Rheumatology.
Arthritis & Rheumatism 11/2012; · 7.87 Impact Factor
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David L Morris, Kimberly E Taylor,
Michelle M A Fernando,
Joanne Nititham,
Marta E Alarcón-Riquelme,
Lisa F Barcellos,
Timothy W Behrens,
Chris Cotsapas,
Patrick M Gaffney,
Robert R Graham, [......],
Peter K Gregersen,
John B Harley,
Stephen L Hauser,
Geoffrey Hom,
Carl D Langefeld,
Janelle A Noble,
John D Rioux,
Michael F Seldin,
Lindsey A Criswell,
Timothy J Vyse
[show abstract]
[hide abstract]
ABSTRACT: We have performed a meta-analysis of the major-histocompatibility-complex (MHC) region in systemic lupus erythematosus (SLE) to determine the association with both SNPs and classical human-leukocyte-antigen (HLA) alleles. More specifically, we combined results from six studies and well-known out-of-study control data sets, providing us with 3,701 independent SLE cases and 12,110 independent controls of European ancestry. This study used genotypes for 7,199 SNPs within the MHC region and for classical HLA alleles (typed and imputed). Our results from conditional analysis and model choice with the use of the Bayesian information criterion show that the best model for SLE association includes both classical loci (HLA-DRB1(∗)03:01, HLA-DRB1(∗)08:01, and HLA-DQA1(∗)01:02) and two SNPs, rs8192591 (in class III and upstream of NOTCH4) and rs2246618 (MICB in class I). Our approach was to perform a stepwise search from multiple baseline models deduced from a priori evidence on HLA-DRB1 lupus-associated alleles, a stepwise regression on SNPs alone, and a stepwise regression on HLA alleles. With this approach, we were able to identify a model that was an overwhelmingly better fit to the data than one identified by simple stepwise regression either on SNPs alone (Bayes factor [BF] > 50) or on classical HLA alleles alone (BF > 1,000).
The American Journal of Human Genetics 10/2012; · 10.60 Impact Factor
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Ilana B Richman, Kimberly E Taylor,
Sharon A Chung,
Laura Trupin,
Michelle Petri,
Edward Yelin,
Robert R Graham,
Annette Lee,
Timothy W Behrens,
Peter K Gregersen,
Michael F Seldin,
Lindsey A Criswell
[show abstract]
[hide abstract]
ABSTRACT: African Americans, East Asians, and Hispanics with systemic lupus erythematosus (SLE) are more likely to develop renal disease than are SLE patients of European descent. This study was undertaken to investigate whether European genetic ancestry protects against the development of lupus nephritis, with the aim of exploring the genetic and socioeconomic factors that might explain this effect.
This was a cross-sectional study of SLE patients from a multiethnic case collection. Participants were genotyped for 126 single-nucleotide polymorphisms (SNPs) informative for ancestry. A subset of participants was also genotyped for 80 SNPs in 14 candidate genes for renal disease in SLE. Logistic regression was used to test the association between European ancestry and renal disease. Analyses were adjusted for continental ancestries, socioeconomic status (SES), and candidate genes.
Participants (n = 1,906) had, on average, 62.4% European, 15.8% African, 11.5% East Asian, 6.5% Amerindian, and 3.8% South Asian ancestry. Among the participants, 656 (34%) had renal disease. A 10% increase in the proportion of European ancestry estimated in each participant was associated with a 15% reduction in the odds of having renal disease, after adjustment for disease duration and sex (odds ratio 0.85, 95% confidence interval 0.82-0.87; P = 1.9 × 10(-30) ). Adjustment for other genetic ancestries, measures of SES, or SNPs in the genes most associated with renal disease (IRF5 [rs4728142], BLK [rs2736340], STAT4 [rs3024912], and HLA-DRB1*0301 and DRB1*1501) did not substantively alter this relationship.
European ancestry is protective against the development of renal disease in SLE, an effect that is independent of other genetic ancestries, candidate risk alleles, and socioeconomic factors.
Arthritis & Rheumatism 10/2012; 64(10):3374-82. · 7.87 Impact Factor
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Rachel Kaiser,
Yonghong Li,
Monica Chang,
Joseph Catanese,
Ann B Begovich,
Elizabeth E Brown,
Jeffrey C Edberg,
Gerald McGwin,
Graciela S Alarcón,
Rosalind Ramsey-Goldman,
John D Reveille,
Luis M Vilá,
Michelle A Petri,
Robert P Kimberly, Kimberly E Taylor,
Lindsey A Criswell
[show abstract]
[hide abstract]
ABSTRACT: Thrombosis is a serious complication of systemic lupus erythematosus (SLE). We investigated whether genetic variants implicated in thrombosis pathways are associated with thrombosis among 2 ethnically diverse SLE cohorts.
Our discovery cohort consisted of 1698 patients with SLE enrolled in the University of California, San Francisco, Lupus Genetics Project and our replication cohort included 1361 patients with SLE enrolled in the PROFILE cohort. Patients fulfilled American College of Rheumatology SLE criteria, and data relevant to thrombosis were available. Thirty-three single nucleotide polymorphisms (SNP) previously shown to be associated with risk of deep venous thrombosis in the general population or implicated in thrombosis pathways were genotyped and tested for association with thrombosis in bivariate allelic analyses. SNP with p < 0.1 in the bivariate analyses were further tested in multivariable logistic regression models adjusted for age, sex, disease duration, antiphospholipid antibody status, smoking, nephritis, and medications.
In the discovery cohort, 23% of patients with SLE experienced a thrombotic event. SNP in the following genes demonstrated association with thrombosis risk overall in the discovery or replication cohorts and were assessed using metaanalytic methods: factor V Leiden (FVL) rs6025 (OR 1.85, p = 0.02) and methylenetetrahydrofolate reductase (MTHFR) rs1801133 (OR 0.75, p = 0.04) in whites, and fibrinogen gamma (FGG) rs2066865 (OR 1.91, p = 0.01) in Hispanic Americans. SNP in these genes showed association with venous thrombosis risk in whites: MTHFR rs1801131 (OR 1.51, p = 0.01), MTHFR rs1801133 (OR 0.70, p = 0.04), FVL rs6025 (OR 2.69, p = 0.002), and FGG rs2066865 (OR 1.49, p = 0.02) in whites. A SNP in FGG rs2066865 (OR 2.19, p = 0.003) demonstrated association with arterial thrombosis risk in Hispanics.
Our results implicate specific genetic risk factors for thrombosis in patients with SLE and suggest that genetic risk for thrombosis differs across ethnic groups.
The Journal of Rheumatology 06/2012; 39(8):1603-10. · 3.69 Impact Factor
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Gianna Elena Hammer,
Emre E Turer, Kimberly E Taylor,
Celia J Fang,
Rommel Advincula,
Shigeru Oshima,
Julio Barrera,
Eric J Huang,
Baidong Hou,
Barbara A Malynn,
Boris Reizis,
Anthony DeFranco,
Lindsey A Criswell,
Mary C Nakamura,
Averil Ma
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ABSTRACT: Dendritic cells (DCs), which are known to support immune activation during infection, may also regulate immune homeostasis in resting animals. Here we show that mice lacking the ubiquitin-editing molecule A20 specifically in DCs spontaneously showed DC activation and population expansion of activated T cells. Analysis of DC-specific epistasis in compound mice lacking both A20 and the signaling adaptor MyD88 specifically in DCs showed that A20 restricted both MyD88-independent signals, which drive activation of DCs and T cells, and MyD88-dependent signals, which drive population expansion of T cells. In addition, mice lacking A20 specifically in DCs spontaneously developed lymphocyte-dependent colitis, seronegative ankylosing arthritis and enthesitis, conditions stereotypical of human inflammatory bowel disease (IBD). Our findings indicate that DCs need A20 to preserve immune quiescence and suggest that A20-dependent DC functions may underlie IBD and IBD-associated arthritides.
Nature Immunology 12/2011; 12(12):1184-93. · 26.01 Impact Factor
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Sharon A Chung, Kimberly E Taylor,
Robert R Graham,
Joanne Nititham,
Annette T Lee,
Ward A Ortmann,
Chaim O Jacob,
Marta E Alarcón-Riquelme,
Betty P Tsao,
John B Harley,
Patrick M Gaffney,
Kathy L Moser,
Michelle Petri,
F Yesim Demirci,
M Ilyas Kamboh,
Susan Manzi,
Peter K Gregersen,
Carl D Langefeld,
Timothy W Behrens,
Lindsey A Criswell
[show abstract]
[hide abstract]
ABSTRACT: Systemic lupus erythematosus (SLE) is a clinically heterogeneous, systemic autoimmune disease characterized by autoantibody formation. Previously published genome-wide association studies (GWAS) have investigated SLE as a single phenotype. Therefore, we conducted a GWAS to identify genetic factors associated with anti-dsDNA autoantibody production, a SLE-related autoantibody with diagnostic and clinical importance. Using two independent datasets, over 400,000 single nucleotide polymorphisms (SNPs) were studied in a total of 1,717 SLE cases and 4,813 healthy controls. Anti-dsDNA autoantibody positive (anti-dsDNA +, n = 811) and anti-dsDNA autoantibody negative (anti-dsDNA -, n = 906) SLE cases were compared to healthy controls and to each other to identify SNPs associated specifically with these SLE subtypes. SNPs in the previously identified SLE susceptibility loci STAT4, IRF5, ITGAM, and the major histocompatibility complex were strongly associated with anti-dsDNA + SLE. Far fewer and weaker associations were observed for anti-dsDNA - SLE. For example, rs7574865 in STAT4 had an OR for anti-dsDNA + SLE of 1.77 (95% CI 1.57-1.99, p = 2.0E-20) compared to an OR for anti-dsDNA - SLE of 1.26 (95% CI 1.12-1.41, p = 2.4E-04), with p(heterogeneity)<0.0005. SNPs in the SLE susceptibility loci BANK1, KIAA1542, and UBE2L3 showed evidence of association with anti-dsDNA + SLE and were not associated with anti-dsDNA - SLE. In conclusion, we identified differential genetic associations with SLE based on anti-dsDNA autoantibody production. Many previously identified SLE susceptibility loci may confer disease risk through their role in autoantibody production and be more accurately described as autoantibody propensity loci. Lack of strong SNP associations may suggest that other types of genetic variation or non-genetic factors such as environmental exposures have a greater impact on susceptibility to anti-dsDNA - SLE.
PLoS Genetics 03/2011; 7(3):e1001323. · 8.69 Impact Factor
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Kimberly E. Taylor,
Sharon A. Chung,
Robert R. Graham,
Ward A. Ortmann,
Annette T. Lee,
Carl D. Langefeld,
Chaim O. Jacob,
M. Ilyas Kamboh,
Marta E. Alarcón-Riquelme,
Betty P. Tsao,
Kathy L. Moser,
Patrick M. Gaffney,
John B. Harley,
Michelle Petri,
Susan Manzi,
Peter K. Gregersen,
Timothy W. Behrens,
Lindsey A. Criswell
[show abstract]
[hide abstract]
ABSTRACT: Systemic lupus erythematosus (SLE) is a genetically complex disease with heterogeneous clinical manifestations. Recent studies have greatly expanded the number of established SLE risk alleles, but the distribution of multiple risk alleles in cases versus controls and their relationship to subphenotypes have not been studied. We studied 22 SLE susceptibility polymorphisms with previous genome-wide evidence of association (p
PLoS Genetics 02/2011; 7(2). · 8.69 Impact Factor
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Kimberly E Taylor,
Sharon A Chung,
Robert R Graham,
Ward A Ortmann,
Annette T Lee,
Carl D Langefeld,
Chaim O Jacob,
M Ilyas Kamboh,
Marta E Alarcón-Riquelme,
Betty P Tsao,
Kathy L Moser,
Patrick M Gaffney,
John B Harley,
Michelle Petri,
Susan Manzi,
Peter K Gregersen,
Timothy W Behrens,
Lindsey A Criswell
[show abstract]
[hide abstract]
ABSTRACT: Systemic lupus erythematosus (SLE) is a genetically complex disease with heterogeneous clinical manifestations. Recent studies have greatly expanded the number of established SLE risk alleles, but the distribution of multiple risk alleles in cases versus controls and their relationship to subphenotypes have not been studied. We studied 22 SLE susceptibility polymorphisms with previous genome-wide evidence of association (p < 5 x 10⁻¹²⁸) in 1919 SLE cases from 9 independent Caucasian SLE case series and 4813 independent controls. The mean number of risk alleles in cases was 15.1 (SD 3.1) while the mean in controls was 13.1 (SD 2.8), with trend p = 4 x 10⁻⁸. We defined a genetic risk score (GRS) for SLE as the number of risk alleles with each weighted by the SLE risk odds ratio (OR). The OR for high-low GRS tertiles, adjusted for intra-European ancestry, sex, and parent study, was 4.4 (95% CI 3.8-5.1). We studied associations of individual SNPs and the GRS with clinical manifestations for the cases: age at diagnosis, the 11 American College of Rheumatology classification criteria, and double-stranded DNA antibody (anti-dsDNA) production. Six subphenotypes were significantly associated with the GRS, most notably anti-dsDNA (OR(high-low) = 2.36, p = 9e-9), the immunologic criterion (OR(high-low) = 2.23, p = 3e-7), and age at diagnosis (OR(high-low) = 1.45, p = 0.0060). Finally, we developed a subphenotype-specific GRS (sub-GRS) for each phenotype with more power to detect cumulative genetic associations. The sub-GRS was more strongly associated than any single SNP effect for 5 subphenotypes (the above plus hematologic disorder and oral ulcers), while single loci are more significantly associated with renal disease (HLA-DRB1, OR = 1.37, 95% CI 1.14-1.64) and arthritis (ITGAM, OR = 0.72, 95% CI 0.59-0.88). We did not observe significant associations for other subphenotypes, for individual loci or the sub-GRS. Thus our analysis categorizes SLE subphenotypes into three groups: those having cumulative, single, and no known genetic association with respect to the currently established SLE risk loci.
PLoS Genetics 02/2011; 7(2):e1001311. · 8.69 Impact Factor
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Vesela Gateva,
Johanna K Sandling,
Geoff Hom, Kimberly E Taylor,
Sharon A Chung,
Xin Sun,
Ward Ortmann,
Roman Kosoy,
Ricardo C Ferreira,
Gunnel Nordmark, [......],
Susan Manzi,
Michelle A Petri,
Annette Lee,
Peter K Gregersen,
Michael F Seldin,
Lars Rönnblom,
Lindsey A Criswell,
Ann-Christine Syvänen,
Timothy W Behrens,
Robert R Graham
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[hide abstract]
ABSTRACT: Genome-wide association studies have recently identified at least 15 susceptibility loci for systemic lupus erythematosus (SLE). To confirm additional risk loci, we selected SNPs from 2,466 regions that showed nominal evidence of association to SLE (P < 0.05) in a genome-wide study and genotyped them in an independent sample of 1,963 cases and 4,329 controls. This replication effort identified five new SLE susceptibility loci (P < 5 x 10(-8)): TNIP1 (odds ratio (OR) = 1.27), PRDM1 (OR = 1.20), JAZF1 (OR = 1.20), UHRF1BP1 (OR = 1.17) and IL10 (OR = 1.19). We identified 21 additional candidate loci with P< or = 1 x 10(-5). A candidate screen of alleles previously associated with other autoimmune diseases suggested five loci (P < 1 x 10(-3)) that may contribute to SLE: IFIH1, CFB, CLEC16A, IL12B and SH2B3. These results expand the number of confirmed and candidate SLE susceptibility loci and implicate several key immunologic pathways in SLE pathogenesis.
Nature Genetics 11/2009; 41(11):1228-33. · 35.53 Impact Factor
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Lisa F Barcellos,
Suzanne L May,
Patricia P Ramsay,
Hong L Quach,
Julie A Lane,
Joanne Nititham,
Janelle A Noble, Kimberly E Taylor,
Diana L Quach,
Sharon A Chung,
Jennifer A Kelly,
Kathy L Moser,
Timothy W Behrens,
Michael F Seldin,
Glenys Thomson,
John B Harley,
Patrick M Gaffney,
Lindsey A Criswell
[show abstract]
[hide abstract]
ABSTRACT: A substantial genetic contribution to systemic lupus erythematosus (SLE) risk is conferred by major histocompatibility complex (MHC) gene(s) on chromosome 6p21. Previous studies in SLE have lacked statistical power and genetic resolution to fully define MHC influences. We characterized 1,610 Caucasian SLE cases and 1,470 parents for 1,974 MHC SNPs, the highly polymorphic HLA-DRB1 locus, and a panel of ancestry informative markers. Single-marker analyses revealed strong signals for SNPs within several MHC regions, as well as with HLA-DRB1 (global p = 9.99 x 10(-16)). The most strongly associated DRB1 alleles were: *0301 (odds ratio, OR = 2.21, p = 2.53 x 10(-12)), *1401 (OR = 0.50, p = 0.0002), and *1501 (OR = 1.39, p = 0.0032). The MHC region SNP demonstrating the strongest evidence of association with SLE was rs3117103, with OR = 2.44 and p = 2.80 x 10(-13). Conditional haplotype and stepwise logistic regression analyses identified strong evidence for association between SLE and the extended class I, class I, class III, class II, and the extended class II MHC regions. Sequential removal of SLE-associated DRB1 haplotypes revealed independent effects due to variation within OR2H2 (extended class I, rs362521, p = 0.006), CREBL1 (class III, rs8283, p = 0.01), and DQB2 (class II, rs7769979, p = 0.003, and rs10947345, p = 0.0004). Further, conditional haplotype analyses demonstrated that variation within MICB (class I, rs3828903, p = 0.006) also contributes to SLE risk independent of HLA-DRB1*0301. Our results for the first time delineate with high resolution several MHC regions with independent contributions to SLE risk. We provide a list of candidate variants based on biologic and functional considerations that may be causally related to SLE risk and warrant further investigation.
PLoS Genetics 10/2009; 5(10):e1000696. · 8.69 Impact Factor
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Sharon A Chung,
Chao Tian, Kimberly E Taylor,
Annette T Lee,
Ward A Ortmann,
Geoffrey Hom,
Robert R Graham,
Joanne Nititham,
Jennifer A Kelly,
Jean Morrisey, [......],
John B Harley,
Patrick M Gaffney,
Kathy L Moser,
Susan Manzi,
Michelle Petri,
Peter K Gregersen,
Carl D Langefeld,
Timothy W Behrens,
Michael F Seldin,
Lindsey A Criswell
[show abstract]
[hide abstract]
ABSTRACT: To determine whether genetic substructure in European-derived populations is associated with specific manifestations of systemic lupus erythematosus (SLE), including mucocutaneous phenotypes, autoantibody production, and renal disease.
SLE patients of European descent (n=1,754) from 8 case collections were genotyped for >1,400 ancestry informative markers that define a north-south gradient of European substructure. Using the Structure program, each SLE patient was characterized in terms of percent Northern (versus percent Southern) European ancestry based on these genetic markers. Nonparametric methods, including tests for trend, were used to identify associations between Northern European ancestry and specific SLE manifestations.
In multivariate analyses, increasing levels of Northern European ancestry were significantly associated with photosensitivity (Ptrend=0.0021, odds ratio for highest quartile of Northern European ancestry versus lowest quartile [ORhigh-low] 1.64, 95% confidence interval [95% CI] 1.13-2.35) and discoid rash (Ptrend=0.014, ORhigh-low 1.93, 95% CI 0.98-3.83). In contrast, increasing levels of Northern European ancestry had a protective effect against the production of anticardiolipin autoantibodies (Ptrend=1.6x10(-4), ORhigh-low 0.46, 95% CI 0.30-0.69) and anti-double-stranded DNA autoantibodies (Ptrend=0.017, ORhigh-low 0.67, 95% CI 0.46-0.96).
This study demonstrates that specific SLE manifestations vary according to Northern versus Southern European ancestry. Thus, genetic ancestry may contribute to the clinical heterogeneity and variation in disease outcomes among SLE patients of European descent. Moreover, these results suggest that genetic studies of SLE subphenotypes will need to carefully address issues of population substructure based on genetic ancestry.
Arthritis & Rheumatism 07/2009; 60(8):2448-56. · 7.87 Impact Factor
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Jing Cui, Kimberly E Taylor,
Anita L Destefano,
Lindsey A Criswell,
Elena S Izmailova,
Alex Parker,
Ronenn Roubenoff,
Robert M Plenge,
Michael E Weinblatt,
Nancy A Shadick,
Elizabeth W Karlson
[show abstract]
[hide abstract]
ABSTRACT: We carried out a genome-wide association study of genetic predictors of anti-cyclic citrullinated peptide antibody (anti-CCP) level in 531 self-reported non-Hispanic Caucasian Rheumatoid Arthritis (RA) patients enrolled in the Brigham Rheumatoid Arthritis Sequential Study (BRASS). For replication, we then analyzed 289 single nucleotide polymorphisms (SNPs) with P < 0.001 in BRASS in an independent population of 849 RA patients from the North American Rheumatoid Arthritis Consortium (NARAC). BRASS and NARAC samples were genotyped using the Affymetrix 100K and Illumina 550K platforms respectively. Association between SNPs and anti-CCP titer was tested using general linear models. The five most significant SNPs from BRASS all were within the major histocompatibility complex (MHC) region (P < or = 3.5 x 10(-6)). After controlling for the human leukocyte antigen shared epitope (HLA-SE), the top SNPs still yielded P values < 0.0002. In NARAC, a single SNP from the MHC region near BTNL2 and HLA-DRA, rs1980493 (r(2) = 0.85 with the top five SNPs from BRASS), was associated significantly with CCP titer (P = 6.1 x 10(-5)) even after adjustment for the HLA-SE (P = 0.0002). The top SNPs found in BRASS and NARAC had r(2) = 0.46 and 0.64, respectively, to HLA-DRB1 DR3 alleles. These results confirm that the most significant genome region affecting anti-CCP titers in RA is the MHC region. We identified a SNP in moderate linkage disequilibrium (LD) with HLA-DR3, which may influence anti-CCP titer independently of the HLA-SE.
Molecular Medicine 04/2009; 15(5-6):136-43. · 3.76 Impact Factor
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Benjamin D Korman,
Michael F Seldin, Kimberly E Taylor,
Julie M Le,
Annette T Lee,
Robert M Plenge,
Christopher I Amos,
Lindsey A Criswell,
Peter K Gregersen,
Daniel L Kastner,
Elaine F Remmers
[show abstract]
[hide abstract]
ABSTRACT: The single-nucleotide polymorphism (SNP) rs11761231 on chromosome 7q has been reported to be sexually dimorphic marker for rheumatoid arthritis (RA) susceptibility in a British population. We sought to replicate this finding and to better characterize susceptibility alleles in the region in a North American population.
DNA from 2 North American collections of RA patients and controls (1,605 cases and 2,640 controls) was genotyped for rs11761231 and 16 additional chromosome 7q tag SNPs using Sequenom iPlex assays. Association tests were performed for each collection and also separately, contrasting male cases with male controls and female cases with female controls. Principal components analysis (EigenStrat) was used to determine association with RA before and after adjusting for population stratification in the subset of the samples for which there were whole-genome SNP data (772 cases and 1,213 controls).
We failed to replicate an association of the 7q region with RA. Initially, rs11761231 showed evidence for association with RA in the North American Rheumatoid Arthritis Consortium (NARAC) collection (P=0.0073), and rs11765576 showed association with RA in both the NARAC (P=0.038) and RA replication (P = 0.0013) collections. These markers also exhibited sex differentiation. However, in the whole-genome subset, neither SNP showed significant association with RA after correction for population stratification.
While 2 SNPs on chromosome 7q appeared to be associated with RA in a North American cohort, the significance of this finding did not withstand correction for population substructure. Our results emphasize the need to carefully account for population structure to avoid false-positive disease associations.
Arthritis & Rheumatism 01/2009; 60(1):47-52. · 7.87 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: ABSTRACT : For Genetic Analysis Workshop 16 Problem 1, we provided data for genome-wide association analysis of rheumatoid arthritis. Single-nucleotide polymorphism (SNP) genotype data were provided for 868 cases and 1194 controls that had been assayed using an Illumina 550 k platform. In addition, phenotypic data were provided from genotyping DRB1 alleles, which were classified according to the rheumatoid arthritis shared epitope, levels of anti-cyclic citrullinated peptide, and levels of rheumatoid factor IgM. Several questions could be addressed using the data, including analysis of genetic associations using single SNPs or haplotypes, as well as gene-gene and genetic analysis of SNPs for qualitative and quantitative factors.
BMC proceedings 01/2009; 3 Suppl 7:S2.
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[show abstract]
[hide abstract]
ABSTRACT: ABSTRACT : We performed a whole-genome association study of rheumatoid arthritis susceptibility using Illumina 550k single-nucleotide polymorphism (SNP) genotypes of 868 cases and 1194 controls from the North American Rheumatoid Arthritis Consortium (NARAC). Structured association analysis with adjustment for potential population stratification yielded 200 SNPs with p < 1 x 10-8 for association with RA, all of which were on chromosome 6 in a 2.7-Mb region of the major histocompatibility complex (MHC). Given the extensive linkage equilibrium in the region and known risk of HLA-DRB1 alleles, we then applied conditional analyses to ascertain independent signals for RA susceptibility among these 200 candidate SNPs. Conditional analyses incorporating risk categories of the HLA-DRB1 "shared epitope" revealed three SNPs having independent associations with RA (conditional p < 0.001). This supports the presence of significant effects on RA susceptibility in the MHC in addition to the shared epitope.
BMC proceedings 01/2009; 3 Suppl 7:S36.
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Stacy L Musone, Kimberly E Taylor,
Timothy T Lu,
Joanne Nititham,
Ricardo C Ferreira,
Ward Ortmann,
Nataliya Shifrin,
Michelle A Petri,
M Ilyas Kamboh,
Susan Manzi,
Michael F Seldin,
Peter K Gregersen,
Timothy W Behrens,
Averil Ma,
Pui-Yan Kwok,
Lindsey A Criswell
[show abstract]
[hide abstract]
ABSTRACT: The TNFAIP3 (tumor necrosis factor alpha-induced protein 3) gene encodes a ubiquitin editing enzyme, A20, that restricts NF-kappaB-dependent signaling and prevents inflammation. We show that three independent SNPs in the TNFAIP3 region (rs13192841, rs2230926 and rs6922466) are associated with systemic lupus erythematosus (SLE) among individuals of European ancestry. These findings provide critical links between A20 and the etiology of SLE.
Nature Genetics 10/2008; 40(9):1062-4. · 35.53 Impact Factor
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Geoffrey Hom,
Robert R Graham,
Barmak Modrek, Kimberly E Taylor,
Ward Ortmann,
Sophie Garnier,
Annette T Lee,
Sharon A Chung,
Ricardo C Ferreira,
P V Krishna Pant, [......],
Anders A Bengtsson,
Solbritt Rantapää-Dahlqvist,
Michelle Petri,
Susan Manzi,
Michael F Seldin,
Lars Rönnblom,
Ann-Christine Syvänen,
Lindsey A Criswell,
Peter K Gregersen,
Timothy W Behrens
[show abstract]
[hide abstract]
ABSTRACT: Systemic lupus erythematosus (SLE) is a clinically heterogeneous disease in which the risk of disease is influenced by complex genetic and environmental contributions. Alleles of HLA-DRB1, IRF5, and STAT4 are established susceptibility genes; there is strong evidence for the existence of additional risk loci.
We genotyped more than 500,000 single-nucleotide polymorphisms (SNPs) in DNA samples from 1311 case subjects with SLE and 1783 control subjects; all subjects were North Americans of European descent. Genotypes from 1557 additional control subjects were obtained from public data repositories. We measured the association between the SNPs and SLE after applying strict quality-control filters to reduce technical artifacts and to correct for the presence of population stratification. Replication of the top loci was performed in 793 case subjects and 857 control subjects from Sweden.
Genetic variation in the region upstream from the transcription initiation site of the gene encoding B lymphoid tyrosine kinase (BLK) and C8orf13 (chromosome 8p23.1) was associated with disease risk in both the U.S. and Swedish case-control series (rs13277113; odds ratio, 1.39; P=1x10(-10)) and also with altered levels of messenger RNA in B-cell lines. In addition, variants on chromosome 16p11.22, near the genes encoding integrin alpha M (ITGAM, or CD11b) and integrin alpha X (ITGAX), were associated with SLE in the combined sample (rs11574637; odds ratio, 1.33; P=3x10(-11)).
We identified and then confirmed through replication two new genetic loci for SLE: a promoter-region allele associated with reduced expression of BLK and increased expression of C8orf13 and variants in the ITGAM-ITGAX region.
New England Journal of Medicine 03/2008; 358(9):900-9. · 53.30 Impact Factor
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John B Harley,
Marta E Alarcón-Riquelme,
Lindsey A Criswell,
Chaim O Jacob,
Robert P Kimberly,
Kathy L Moser,
Betty P Tsao,
Timothy J Vyse,
Carl D Langefeld,
Swapan K Nath, [......],
Joan T Merrill,
Gary S Gilkeson,
Michael F Seldin,
Hong Yin,
Emily C Baechler,
Quan-Zhen Li,
Edward K Wakeland,
Gail R Bruner,
Kenneth M Kaufman,
Jennifer A Kelly
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ABSTRACT: Systemic lupus erythematosus (SLE) is a common systemic autoimmune disease with complex etiology but strong clustering in families (lambda(S) = approximately 30). We performed a genome-wide association scan using 317,501 SNPs in 720 women of European ancestry with SLE and in 2,337 controls, and we genotyped consistently associated SNPs in two additional independent sample sets totaling 1,846 affected women and 1,825 controls. Aside from the expected strong association between SLE and the HLA region on chromosome 6p21 and the previously confirmed non-HLA locus IRF5 on chromosome 7q32, we found evidence of association with replication (1.1 x 10(-7) < P(overall) < 1.6 x 10(-23); odds ratio = 0.82-1.62) in four regions: 16p11.2 (ITGAM), 11p15.5 (KIAA1542), 3p14.3 (PXK) and 1q25.1 (rs10798269). We also found evidence for association (P < 1 x 10(-5)) at FCGR2A, PTPN22 and STAT4, regions previously associated with SLE and other autoimmune diseases, as well as at > or =9 other loci (P < 2 x 10(-7)). Our results show that numerous genes, some with known immune-related functions, predispose to SLE.
Nature Genetics 02/2008; 40(2):204-10. · 35.53 Impact Factor
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Kimberly E Taylor,
Elaine F Remmers,
Annette T Lee,
Ward A Ortmann,
Robert M Plenge,
Chao Tian,
Sharon A Chung,
Joanne Nititham,
Geoffrey Hom,
Amy H Kao,
F Yesim Demirci,
M Ilyas Kamboh,
Michelle Petri,
Susan Manzi,
Daniel L Kastner,
Michael F Seldin,
Peter K Gregersen,
Timothy W Behrens,
Lindsey A Criswell
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ABSTRACT: Systemic lupus erythematosus (SLE) is a genetically complex disease with heterogeneous clinical manifestations. A polymorphism in the STAT4 gene has recently been established as a risk factor for SLE, but the relationship with specific SLE subphenotypes has not been studied. We studied 137 SNPs in the STAT4 region genotyped in 4 independent SLE case series (total n = 1398) and 2560 healthy controls, along with clinical data for the cases. Using conditional testing, we confirmed the most significant STAT4 haplotype for SLE risk. We then studied a SNP marking this haplotype for association with specific SLE subphenotypes, including autoantibody production, nephritis, arthritis, mucocutaneous manifestations, and age at diagnosis. To prevent possible type-I errors from population stratification, we reanalyzed the data using a subset of subjects determined to be most homogeneous based on principal components analysis of genome-wide data. We confirmed that four SNPs in very high LD (r(2) = 0.94 to 0.99) were most strongly associated with SLE, and there was no compelling evidence for additional SLE risk loci in the STAT4 region. SNP rs7574865 marking this haplotype had a minor allele frequency (MAF) = 31.1% in SLE cases compared with 22.5% in controls (OR = 1.56, p = 10(-16)). This SNP was more strongly associated with SLE characterized by double-stranded DNA autoantibodies (MAF = 35.1%, OR = 1.86, p<10(-19)), nephritis (MAF = 34.3%, OR = 1.80, p<10(-11)), and age at diagnosis<30 years (MAF = 33.8%, OR = 1.77, p<10(-13)). An association with severe nephritis was even more striking (MAF = 39.2%, OR = 2.35, p<10(-4) in the homogeneous subset of subjects). In contrast, STAT4 was less strongly associated with oral ulcers, a manifestation associated with milder disease. We conclude that this common polymorphism of STAT4 contributes to the phenotypic heterogeneity of SLE, predisposing specifically to more severe disease.
PLoS Genetics 01/2008; 4(5):e1000084. · 8.69 Impact Factor
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ABSTRACT: We applied nonparametric quantitative trait linkage analysis to two rheumatoid arthritis quantitative phenotypes, IgM rheumatoid factor (RF) and anti-cyclic citrullinated peptide autoantibody titer measurements, using 5700 genome-wide Illumina single-nucleotide polymorphism genotypes on 658 Caucasian North American Rheumatoid Arthritis Consortium families. Peak LOD scores for both quantitative traits were located in the human leukocyte antigen region 6p21 (15.8 and 13.8 for RF and anti-cyclic citrullinated peptide, respectively) followed by 11p12 (3.2 and 3.6). In addition, there were LOD scores of 3.2 on 2q32 for RF and 3.6 on 4q24 for anti-cyclic citrullinated peptide. The resulting linkage signals for both phenotypes are very similar to previous results for rheumatoid arthritis as a qualitative variable, with rheumatoid factor measurements being most closely aligned. Interestingly, anti-cyclic citrullinated peptide exhibits a stronger linkage peak on 2p14 than rheumatoid factor and rheumatoid arthritis, and stronger linkage on 4q24. Finally, we used ordered subset analyses to determine if sub-ranges of these two traits increased rheumatoid arthritis linkage signals; however, our analyses did not reveal significant effects of the quantitative traits on rheumatoid arthritis linkage signals in this population.
BMC proceedings 02/2007; 1 Suppl 1:S105.
