Rheumatoid Arthritis: Gregersen PK

Gregersen PK, Batliwalla F. · No affiliation provided · Arthritis Rheum. · Pubmed #15986339 links to  free full text

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Gregersen PK, Bucala R. · No affiliation provided · Arthritis Rheum. · Pubmed #12746889 links to  free full text

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Jawaheer D, Gregersen PK. · No affiliation provided · Arthritis Rheum. · Pubmed #11920392 links to  free full text

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Gregersen PK. · No affiliation provided · J Rheumatol. · Pubmed #11128656 No free full text.

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Coenen MJ, Gregersen PK. · Department of Human Genetics of the Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. · Genes Immun. · Pubmed #18987647 No free full text.

Abstract: The field of genetics and autoimmune diseases is undergoing a rapid and unprecedented expansion with new genetic findings being reported at an astounding pace. It is now clear that multiple genes contribute to each of the major autoimmune disorders, with significant genetic overlaps among them. Rheumatoid arthritis (RA) is no exception to this, and emerging data are beginning to reveal the outlines of new diagnostic subgroups, complex overlapping relationships with other autoimmune disorders and potential new targets for therapy. This review describes the evolving genetic landscape of RA, with the full knowledge that our current view is far from complete. However, with the first round of genome-wide association scans now completed, it is reasonable to begin to take stock of the direction in which the major common genetic risk factors are leading us.

Korman BD, Kastner DL, Gregersen PK, Remmers EF. · National Institute of Arthritis, Musculoskeletal, and Skin Diseases, 9 Memorial Drive, NIH Building 9, Room 1W108, Bethesda, MD 20892, USA. · Curr Allergy Asthma Rep. · Pubmed #18682104 No free full text.

Abstract: Recent advances in genetics and technology have led to breakthroughs in understanding the genes that predispose individuals to autoimmune diseases. A common haplotype of the signal transducer and activator of transcription 4 (STAT4) gene has been shown to be associated with susceptibility to rheumatoid arthritis, systemic lupus erythematosus, and primary Sjögren's syndrome. STAT4 is a transcription factor that transduces interleukin-12, interleukin-23, and type 1 interferon cytokine signals in T cells and monocytes, leading to T-helper type 1 and T-helper type 17 differentiation, monocyte activation, and interferon-gamma production. Although the evidence for this association is very strong and well replicated, the exact mechanism by which polymorphisms in this gene lead to disease remains unknown. In concert with the identification of other disease-associated loci, elucidating how the variant form of STAT4 modulates immune function should lead to an improved understanding of the pathophysiology of autoimmunity.

Gregersen PK. · Robert S. Boas Center for Genomics and Human Genetics, The Institute for Medical Research at North Shore/LIJ, Manhasset, NY 11030, USA. · Immunol Rev. · Pubmed #15790351 No free full text.

Abstract: Rheumatoid arthritis (RA), like other autoimmune diseases, has a complex genetic basis. Rapid technical advances in high-throughput genotyping and analysis have now reached a point where genes of low-to-moderate risk can be identified using a variety of study designs, including whole genome association studies. The availability of large, well-characterized populations of cases and controls are critical to the success of these efforts. A functional variant (R620W) of the intracellular protein tyrosine phosphatase N22 (PTPN22) has now been conclusively shown to confer approximately two-fold risk for seropositive RA as well as several other autoimmune disorders. PTPN22 appears to act primarily by setting thresholds for T-cell receptor signaling, and the current data suggest that the PTPN22 620W allele is likely to be a general risk factor for the development of humoral autoimmunity. PTPN22 is expressed widely in hematopoietic cells, but other than in T cells, its role is unknown. These results provide strong evidence for the longstanding hypothesis that common genes underlie different autoimmune phenotypes and emphasize that finding genes of only moderate risk can provide important insights into disease pathogenesis.

Gregersen PK. · Center for Genomics and Human Genetics, North Shore Long Island Jewish Research Institute, 350 Community Drive, Manhasset, NY 11030, USA. · Clin Immunol. · Pubmed #12738244 No free full text.

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Jawaheer D, Gregersen PK. · Division of Biology and Human Genetics, North Shore University Hospital, Manhasset, New York, USA. · Rheum Dis Clin North Am. · Pubmed #11840692 No free full text.

Abstract: Rheumatoid arthritis is a multifactorial disease, with genetic, environmental, and stochastic components to its susceptibility. The search for susceptibility genes is still in progress. Preliminary results suggest the involvement of multiple genes, each with relatively modest effect. Genes within the major histocompatibility complex appear to have the strongest influence on disease susceptibility.

Gregersen PK. · Division of Biology and Human Genetics, North Shore University Hospital, Manhasset, New York 11030, USA. · Arthritis Res. · Pubmed #11094412 links to  free full text

Abstract: The genetic basis for rheumatoid arthritis (RA) is likely to be extremely complex. Even the role of MHC genes remains to be fully defined, and may involve interactive genetic effects. The difficulty of precisely defining the clinical phenotype, as well as underlying genetic heterogeneity, complicates the problem. In addition, stochastic genetic or physiologic events may contribute to the low penetrance of susceptibility genes. This situation parallels developing paradigms for other autoimmune disorders, in which many different genes each appear to contribute a small amount to overall risk for disease, and where severity and specific phenotypic subtypes are subject to genetic effects. The completion of the human genome project, along with advances in informatics, will be required to reach a deeper understanding of RA. It is likely that this will involve an iterative and interactive process between several different scientific disciplines.

Seldin MF, Amos CI, Ward R, Gregersen PK. · University of California, Davis, USA. · Arthritis Rheum. · Pubmed #10366098 links to  free full text

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Gregersen PK, Amos CI, Lee AT, Lu Y, Remmers EF, Kastner DL, Seldin MF, Criswell LA, Plenge RM, Holers VM, Mikuls TR, Sokka T, Moreland LW, Bridges SL, Xie G, Begovich AB, Siminovitch KA. · The Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhasset, NY, USA. · Nat Genet. · Pubmed #19503088 No free full text.

Abstract: We conducted a genome-wide association study of rheumatoid arthritis in 2,418 cases and 4,504 controls from North America and identified an association at the REL locus, encoding c-Rel, on chromosome 2p13 (rs13031237, P = 6.01 x 10(-10)). Replication in independent case-control datasets comprising 2,604 cases and 2,882 controls confirmed this association, yielding an allelic OR = 1.25 (P = 3.08 x 10(-14)) for marker rs13031237 and an allelic OR = 1.21 (P = 2.60 x 10(-11)) for marker rs13017599 in the combined dataset. The combined dataset also provides definitive support for associations at both CTLA4 (rs231735; OR = 0.85; P = 6.25 x 10(-9)) and BLK (rs2736340; OR = 1.19; P = 5.69 x 10(-9)). c-Rel is an NF-kappaB family member with distinct functional properties in hematopoietic cells, and its association with rheumatoid arthritis suggests disease pathways that involve other recently identified rheumatoid arthritis susceptibility genes including CD40, TRAF1, TNFAIP3 and PRKCQ.

Hueber W, Tomooka BH, Batliwalla F, Li W, Monach PA, Tibshirani RJ, Van Vollenhoven RF, Lampa J, Saito K, Tanaka Y, Genovese MC, Klareskog L, Gregersen PK, Robinson WH. · Department of Medicine, Division of Immunology & Rheumatology, Stanford University, Stanford, CA 94305, USA. · Arthritis Res Ther. · Pubmed #19460157 links to  free full text

Abstract: INTRODUCTION: Anti-TNF therapies have revolutionized the treatment of rheumatoid arthritis (RA), a common systemic autoimmune disease involving destruction of the synovial joints. However, in the practice of rheumatology approximately one-third of patients demonstrate no clinical improvement in response to treatment with anti-TNF therapies, while another third demonstrate a partial response, and one-third an excellent and sustained response. Since no clinical or laboratory tests are available to predict response to anti-TNF therapies, great need exists for predictive biomarkers. METHODS: Here we present a multi-step proteomics approach using arthritis antigen arrays, a multiplex cytokine assay, and conventional ELISA, with the objective to identify a biomarker signature in three ethnically diverse cohorts of RA patients treated with the anti-TNF therapy etanercept. RESULTS: We identified a 24-biomarker signature that enabled prediction of a positive clinical response to etanercept in all three cohorts (positive predictive values 58 to 72%; negative predictive values 63 to 78%). CONCLUSIONS: We identified a multi-parameter protein biomarker that enables pretreatment classification and prediction of etanercept responders, and tested this biomarker using three independent cohorts of RA patients. Although further validation in prospective and larger cohorts is needed, our observations demonstrate that multiplex characterization of autoantibodies and cytokines provides clinical utility for predicting response to the anti-TNF therapy etanercept in RA patients.

Lee YC, Raychaudhuri S, Cui J, De Vivo I, Ding B, Alfredsson L, Padyukov L, Costenbader KH, Seielstad M, Graham RR, Klareskog L, Gregersen PK, Plenge RM, Karlson EW. · Brigham and Women's Hospital, Boston, Massachusetts 02115, USA. · Arthritis Rheum. · Pubmed #19404952 No free full text.

Abstract: OBJECTIVE: Previous studies have demonstrated that the PRL -1149 T (minor) allele decreases prolactin expression and may be associated with autoimmune disease. The aim of this study was to determine the role of the PRL -1149 G/T polymorphism (rs1341239) in rheumatoid arthritis (RA) susceptibility. METHODS: We examined the association between PRL -1149 G/T and RA risk in 4 separate study populations, consisting of a total of 3,405 RA cases and 4,111 controls of self-reported white European ancestry. Samples were genotyped using 1 of 3 genotyping platforms, and strict quality control metrics were applied. We tested for association using a 2-tailed Cochran-Mantel-Haenszel additive, fixed-effects model. RESULTS: In the individual populations, odds ratios (ORs) for an association between PRL -1149 T and RA risk ranged from 0.80 to 0.97. In a joint meta-analysis across all 4 populations, the OR for an association between PRL -1149 T and RA risk was 0.90 (95% confidence interval 0.84-0.96, P=0.001). CONCLUSION: Our findings indicate a possible association between the PRL -1149 T allele and decreased RA risk. The effect size is small but similar to ORs for other genetic polymorphisms associated with complex traits, including RA.

Feser M, Derber LA, Deane KD, Lezotte DC, Weisman MH, Buckner JH, Mikuls T, O'Dell J, Gregersen PK, Holers VM, Norris JM. · Department of Epidemiology, Colorado School of Public Health, University of Colorado Denver, Denver, Colorado, USA. · J Rheumatol. · Pubmed #19286844 No free full text.

Abstract: OBJECTIVE: To evaluate the association between rheumatoid arthritis (RA)-related autoantibodies and plasma 25,OH vitamin D in subjects at risk for RA. METHODS: In 1210 subjects without RA, 76 were positive for anti-cyclic citrullinated peptide antibodies or for at least 2 rheumatoid factors (RF; by nephelometry: RF-IgM, RF-IgG, RF-IgA). 25,OH vitamin D was measured in these cases and 154 autoantibody-negative controls from this cohort. RESULTS: 25,OH vitamin D levels did not differ between cases and controls (adjusted OR 1.23, 95% CI 0.93-1.63). CONCLUSION: Vitamin D concentrations are not associated with RA-related autoimmunity in unaffected subjects at increased risk for RA.

Lee HS, Korman BD, Le JM, Kastner DL, Remmers EF, Gregersen PK, Bae SC. · Hanyang University College of Medicine and the Hospital for Rheumatic Diseases, Seoul, South Korea. · Arthritis Rheum. · Pubmed #19180477 No free full text.

Abstract: OBJECTIVE: Recent studies have identified a number of novel rheumatoid arthritis (RA) susceptibility loci in Caucasian populations. The aim of this study was to determine whether the genetic variants at 4q27, 6q23, CCL21, TRAF1/C5, and CD40 identified in Caucasians are also associated with RA in a Korean case-control collection. We also comprehensively evaluated the genetic variation within PTPN22, a well-established autoimmune disease-associated gene. METHODS: We designed an experiment to thoroughly evaluate the PTPN22 linkage disequilibrium region, using tag single-nucleotide polymorphisms (SNPs) and disease-associated SNPs at 5 RA-associated loci recently identified in Caucasians, in 1,128 Korean patients with RA and 1,022 ethnically matched control subjects. We also resequenced the PTPN22 gene to seek novel coding variants that might be contributing to disease in this population. RESULTS: None of the susceptibility loci identified in Caucasian patients with RA contributed significantly to disease in Koreans. Although tag SNPs covering the PTPN22 linkage disequilibrium block were polymorphic, they did not reveal any disease association, and resequencing did not identify any new common coding region variants in this population. The 6q23 and 4q27 SNPs assayed were nonpolymorphic in this population, and the TRAF1/C5, CD40, and CCL21 SNPs did not show any evidence for association with RA in this population of Korean patients. CONCLUSION: The genetic risk factors for RA are different in Caucasian and Korean patients. Although patients of different ethnic groups share the HLA region as a major genetic risk locus, most other genes shown to be significantly associated with disease in Caucasians appear not to play a role in Korean patients with RA.

Korman BD, Seldin MF, Taylor KE, Le JM, Lee AT, Plenge RM, Amos CI, Criswell LA, Gregersen PK, Kastner DL, Remmers EF. · National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, Maryland 20892-1849, USA. · Arthritis Rheum. · Pubmed #19116934 No free full text.

Abstract: OBJECTIVE: 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. METHODS: 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). RESULTS: 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. CONCLUSION: 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.

Ding B, Padyukov L, Lundström E, Seielstad M, Plenge RM, Oksenberg JR, Gregersen PK, Alfredsson L, Klareskog L. · Karolinska Institutet, Stockholm, Sweden. · Arthritis Rheum. · Pubmed #19116921 No free full text.

Abstract: OBJECTIVE: To identify additional variants in the major histocompatibility complex (MHC) region that independently contribute to risk in 2 disease subsets of rheumatoid arthritis (RA) defined according to the presence or absence of antibodies to citrullinated protein antigens (ACPAs). METHODS: In a multistep analytical strategy using unmatched as well as matched analyses to adjust for HLA-DRB1 genotype, we analyzed 2,221 single-nucleotide polymorphisms (SNPs) spanning 10.7 Mb, from 6p22.2 to 6p21.31, across the MHC. For ACPA-positive RA, we analyzed samples from the Swedish Epidemiological Investigation of Rheumatoid Arthritis (EIRA) and the North American Rheumatoid Arthritis Consortium (NARAC) studies (totaling 1,255 cases and 1,719 controls). For ACPA-negative RA, we used samples from the EIRA study (640 cases and 670 controls). Plink and SAS statistical packages were used to conduct all statistical analyses. RESULTS: A total of 299 SNPs reached locus-wide significance (P<2.3x10(-5)) for ACPA-positive RA, whereas surprisingly, no SNPs reached this significance for ACPA-negative RA. For ACPA-positive RA, we adjusted for known DRB1 risk alleles and identified additional independent associations with SNPs near HLA-DPB1 (rs3117213; odds ratio 1.42 [95% confidence interval 1.17-1.73], Pcombined=0.0003 for the strongest association). CONCLUSION: There are distinct genetic patterns of MHC associations in the 2 disease subsets of RA defined according to ACPA status. HLA-DPB1 is an independent risk locus for ACPA-positive RA. We did not identify any associations with SNPs within the MHC for ACPA-negative RA.

Raychaudhuri S, Remmers EF, Lee AT, Hackett R, Guiducci C, Burtt NP, Gianniny L, Korman BD, Padyukov L, Kurreeman FA, Chang M, Catanese JJ, Ding B, Wong S, van der Helm-van Mil AH, Neale BM, Coblyn J, Cui J, Tak PP, Wolbink GJ, Crusius JB, van der Horst-Bruinsma IE, Criswell LA, Amos CI, Seldin MF, Kastner DL, Ardlie KG, Alfredsson L, Costenbader KH, Altshuler D, Huizinga TW, Shadick NA, Weinblatt ME, de Vries N, Worthington J, Seielstad M, Toes RE, Karlson EW, Begovich AB, Klareskog L, Gregersen PK, Daly MJ, Plenge RM. · Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA. · Nat Genet. · Pubmed #18794853 No free full text.

Abstract: To identify rheumatoid arthritis risk loci in European populations, we conducted a meta-analysis of two published genome-wide association (GWA) studies totaling 3,393 cases and 12,462 controls. We genotyped 31 top-ranked SNPs not previously associated with rheumatoid arthritis in an independent replication of 3,929 autoantibody-positive rheumatoid arthritis cases and 5,807 matched controls from eight separate collections. We identified a common variant at the CD40 gene locus (rs4810485, P = 0.0032 replication, P = 8.2 x 10(-9) overall, OR = 0.87). Along with other associations near TRAF1 (refs. 2,3) and TNFAIP3 (refs. 4,5), this implies a central role for the CD40 signaling pathway in rheumatoid arthritis pathogenesis. We also identified association at the CCL21 gene locus (rs2812378, P = 0.00097 replication, P = 2.8 x 10(-7) overall), a gene involved in lymphocyte trafficking. Finally, we identified evidence of association at four additional gene loci: MMEL1-TNFRSF14 (rs3890745, P = 0.0035 replication, P = 1.1 x 10(-7) overall), CDK6 (rs42041, P = 0.010 replication, P = 4.0 x 10(-6) overall), PRKCQ (rs4750316, P = 0.0078 replication, P = 4.4 x 10(-6) overall), and KIF5A-PIP4K2C (rs1678542, P = 0.0026 replication, P = 8.8 x 10(-8) overall).

Zhao X, Okeke NL, Sharpe O, Batliwalla FM, Lee AT, Ho PP, Tomooka BH, Gregersen PK, Robinson WH. · GRECC, VA Palo Alto Health Care System, Palo Alto, CA 94304, USA. · Arthritis Res Ther. · Pubmed #18710572 links to  free full text

Abstract: INTRODUCTION: There is increasing evidence that autoantibodies and immune complexes (ICs) contribute to synovitis in rheumatoid arthritis (RA), yet the autoantigens incorporated in ICs in RA remain incompletely characterised. METHODS: We used the C1q protein to capture ICs from plasma derived from human RA and control patients. Antibodies specific for immunoglobulin were used to detect ICs, and fibrinogen antibodies were used to detect fibrinogen-containing ICs. RA and control plasma were separated by liquid chromatography, and fractions then characterised by ELISA, immunoblotting and mass spectrometry. Immunohistochemical staining was performed on rheumatoid synovial tissue. RESULTS: C1q-immunoassays demonstrated increased levels of IgG (p = 0.01) and IgM (p = 0.0002) ICs in plasma derived from RA patients possessing anti-cyclic citrullinated peptide (CCP+) autoantibodies as compared with healthy controls. About one-half of the anti-CCP+ RA possessed circulating ICs containing fibrinogen (p = 0.0004). Fractionation of whole RA plasma revealed citrullinated fibrinogen in the high molecular weight fractions that contained ICs. Positive correlations were observed between fibrinogen-containing ICs and anti-citrullinated fibrinogen autoantibodies, anti-CCP antibody, rheumatoid factor and certain clinical characteristics. Immunohistochemical staining demonstrated co-localisation of fibrinogen, immunoglobulin and complement component C3 in RA pannus tissue. Mass spectrometry analysis of immune complexes immunoprecipitated from RA pannus tissue lysates demonstrated the presence of citrullinated fibrinogen. CONCLUSION: Circulating ICs containing citrullinated fibrinogen are present in one-half of anti-CCP+ RA patients, and these ICs co-localise with C3 in the rheumatoid synovium suggesting that they contribute to synovitis in a subset of RA patients.

Chang M, Rowland CM, Garcia VE, Schrodi SJ, Catanese JJ, van der Helm-van Mil AH, Ardlie KG, Amos CI, Criswell LA, Kastner DL, Gregersen PK, Kurreeman FA, Toes RE, Huizinga TW, Seldin MF, Begovich AB. · Celera, Alameda, California, United States of America. · PLoS Genet. · Pubmed #18648537 links to  free full text

Abstract: Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease affecting both joints and extra-articular tissues. Although some genetic risk factors for RA are well-established, most notably HLA-DRB1 and PTPN22, these markers do not fully account for the observed heritability. To identify additional susceptibility loci, we carried out a multi-tiered, case-control association study, genotyping 25,966 putative functional SNPs in 475 white North American RA patients and 475 matched controls. Significant markers were genotyped in two additional, independent, white case-control sample sets (661 cases/1322 controls from North America and 596 cases/705 controls from The Netherlands) identifying a SNP, rs1953126, on chromosome 9q33.2 that was significantly associated with RA (OR(common) = 1.28, trend P(comb) = 1.45E-06). Through a comprehensive fine-scale-mapping SNP-selection procedure, 137 additional SNPs in a 668 kb region from MEGF9 to STOM on 9q33.2 were chosen for follow-up genotyping in a staged-approach. Significant single marker results (P(comb)<0.01) spanned a large 525 kb region from FBXW2 to GSN. However, a variety of analyses identified SNPs in a 70 kb region extending from the third intron of PHF19 across TRAF1 into the TRAF1-C5 intergenic region, but excluding the C5 coding region, as the most interesting (trend P(comb): 1.45E-06 --> 5.41E-09). The observed association patterns for these SNPs had heightened statistical significance and a higher degree of consistency across sample sets. In addition, the allele frequencies for these SNPs displayed reduced variability between control groups when compared to other SNPs. Lastly, in combination with the other two known genetic risk factors, HLA-DRB1 and PTPN22, the variants reported here generate more than a 45-fold RA-risk differential.

Liu C, Batliwalla F, Li W, Lee A, Roubenoff R, Beckman E, Khalili H, Damle A, Kern M, Furie R, Dupuis J, Plenge RM, Coenen MJ, Behrens TW, Carulli JP, Gregersen PK. · Biogen Idec Inc., Cambridge, Massachusetts, USA. · Mol Med. · Pubmed #18615156 links to  free full text

Abstract: The prediction of response (or non-response) to anti-TNF treatment for rheumatoid arthritis (RA) is a pressing clinical problem. We conducted a genome-wide association study using the Illumina HapMap300 SNP chip on 89 RA patients prospectively followed after beginning anti-TNF therapy as part of Autoimmune Biomarkers Collaborative Network (ABCoN [Autoimmune Bio-markers Collaborative Network]) patient cohort. Response to therapy was determined by the change in Disease Activity Score (DAS28) observed after 14 wks. We used a two-part analysis that treated the change in DAS28 as a continuous trait and then incorporated it into a dichotomous trait of "good responder" and "nonresponder" by European League Against Rheumatism (EULAR) criteria. We corrected for multiple tests by permutation, and adjusted for potential population stratification using EIGENSTRAT. Multiple single nucleotide polymorphism (SNP) markers showed significant associations near or within loci including: the v-maf musculoaponeurotic fibrosarcoma oncogene homolog B (MAFB) gene on chromosome 20; the type I interferon gene IFNk on chromosome 9; and in a locus on chromosome 7 that includes the paraoxonase I (PON1) gene. An SNP in the IL10 promoter (rs1800896) that was previously reported as associated with anti-TNF response was weakly associated with response in this cohort. Replications of these results in independent and larger data sets clearly are required. We provide a reference list of candidate SNPs (P < 0.01) that can be investigated in future pharmacogenomic studies.

Johnsen AK, Plenge RM, Butty V, Campbell C, Dieguez-Gonzalez R, Gomez-Reino JJ, Shadick N, Weinblatt M, Gonzalez A, Gregersen PK, Benoist C, Mathis D. · Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA. · Arthritis Rheum. · Pubmed #18576312 links to  free full text

Abstract: OBJECTIVE: It has been suggested that polymorphisms in IL1 are correlated with severe and/or erosive rheumatoid arthritis (RA), but the implicated alleles have differed among studies. The aim of this study was to perform a broad and well-powered search for association between allelic polymorphism in IL1A and IL1B and the susceptibility to or severity of RA. METHODS: Key coding and regulatory regions in IL1A and IL1B were sequenced in 24 patients with RA, revealing 4 novel single-nucleotide polymorphisms (SNPs) in IL1B. These and a comprehensive set of 24 SNPs tagging most of the underlying genetic diversity were genotyped in 3 independent RA case-control sample sets and 1 longitudinal RA cohort, totaling 3,561 patients and 3,062 control subjects. RESULTS: No fully significant associations were observed. Analysis of the discovery case-control sample sets indicated a potential association of IL1B promoter region SNPs with susceptibility to RA (for RA3/A, odds ratio [OR] 1.27, P = 0.0021) or with the incidence of radiographic erosions (for RA4/C, OR 1.56, P = 0.036), but these findings were not replicated in independent case-control samples. No association with rheumatoid factor, anti-cyclic citrullinated peptide, or the Disease Activity Score in 28 joints was found. None of the associations previously observed in other studies were replicated here. CONCLUSION: In spite of a broad and highly powered study, we observed no robust, reproducible association between IL1A/B variants and the susceptibility to or severity of RA in white individuals of European descent. Our results provide evidence that, in the majority of cases, polymorphism in IL1A and IL1B is not a major contributor to genetic susceptibility to RA.

Chang M, Saiki RK, Cantanese JJ, Lew D, van der Helm-van Mil AH, Toes RE, Huizinga TW, Ardlie KG, Criswell LA, Seldin MF, Amos CI, Kastner DL, Gregersen PK, Schrodi SJ, Begovich AB. · Celera, Alameda, CA, USA. · Arthritis Rheum. · Pubmed #18512797 links to  free full text

This publication has no abstract.

Chen WV, Amos CI, Etzel CJ, Shete S, Gregersen PK. · Department of Epidemiology, U,T, M,D, Anderson Cancer Center, Houston, Texas 77030, USA. · BMC Proc. · Pubmed #18466601 links to  free full text

Abstract: ABSTRACT : We performed linkage analysis on families with rheumatoid arthritis, stratifying by ethnic origin. We compared results using either Kong and Cox nonparametric LOD scores or MOD score analysis using the software GeneHunter MODSCORE. We first applied SNPLINK to remove markers showing excess linkage disequilibrium from the SNPs in the Illumina IV SNP Linkage panel. In this analysis there were 659 self-reported Caucasian families and 29 self-reported Hispanic families in the NARAC collection. Chromosome 19 yielded MOD scores > 3.00 in the Hispanic group, while chromosomes 2, 6, 7, 11, and XY had MOD scores > 3.00 in the Caucasian group. We performed simulation studies to evaluate the empirical distribution of the MOD score for autosomal loci separately in Hispanics and Caucasians. Results showed genome-wide significant evidence for linkage in Caucasians for chromosomes 2q and 6p, but no significant evidence for any linkages in the Hispanics, including little evidence for linkage to chromosome 6p in this group. An examination of the difference of phenotypes in two ethnic groups suggested significantly earlier mean age of onset, higher percentage of anti-cyclic citrullinated peptide positive people, and lower percentage of affected people carrying shared epitopes in Hispanics than those in Caucasians. A larger sample size of the Hispanic group is needed to identify linkage regions.