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Cited by 1,253Rheumatoid Arthritis Research and TherapiesGenetic Associations and EpidemiologySystemic Lupus Erythematosus Research

Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci

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BIRAC Consortium, Stahl, Eli A, YEAR Consortium, Raychaudhuri, Soumya, Remmers, Elaine F, Xie, Gang, Eyre, Stephen, Thomson, Brian P +62 more·2010·Nature Genetics
DOI 10.1038/ng.582PMC PMC4243840
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Abstract

To identify new genetic risk factors for rheumatoid arthritis, we conducted a genome-wide association study meta-analysis of 5,539 autoantibody-positive individuals with rheumatoid arthritis (cases) and 20,169 controls of European descent, followed by replication in an independent set of 6,768 rheumatoid arthritis cases and 8,806 controls. Of 34 SNPs selected for replication, 7 new rheumatoid arthritis risk alleles were identified at genome-wide significance (P < 5 x 10(-8)) in an analysis of all 41,282 samples. The associated SNPs are near genes of known immune function, including IL6ST, SPRED2, RBPJ, CCR6, IRF5 and PXK. We also refined associations at two established rheumatoid arthritis risk loci (IL2RA and CCL21) and confirmed the association at AFF3. These new associations bring the total number of confirmed rheumatoid arthritis risk loci to 31 among individuals of European ancestry. An additional 11 SNPs replicated at P < 0.05, many of which are validated autoimmune risk alleles, suggesting that most represent genuine rheumatoid arthritis risk alleles.

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  • GWAS, meta-analysis, exome analysis and SNP mapping have associated IL-6, IL-6R and gp130 with inflammatory diseases such as RA and coronary artery disease.

    “Genome-wide association studies (GWAS), meta-analysis, exome analysis and single nucleotide polymorphism (SNP) mapping have associated IL-6, IL-6R and gp130 with inflammatory diseases such as RA and coronary artery disease (263–269).”

    From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [269]

    The paper’s Abstract reports a GWAS meta-analysis associating SNPs near IL6ST with rheumatoid arthritis and identifies gp130 as the IL6ST protein product. It also says IL6ST lies outside the region of linkage disequilibrium with the associated SNPs, so it does not establish a gp130 association. The cited passages do not support associations for IL-6 or IL-6R, coronary artery disease, or exome analysis. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Five of 145 significant independent signals for CAD from mixed-ancestry samples and 2 of 7 significant loci for rheumatoid arthritis from the study conducted by Stahl et al. were pQTLs in our dataset.

    “For example, 5 of 145 significant independent signals for CAD from mixed-ancestry samples67 and 2 of 7 significant loci for rheumatoid arthritis from the study conducted by Stahl et al.68 were pQTLs in our dataset.”

    From Genetic determinants of plasma protein levels in the Estonian population (2024) · cites this paper as [68]

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Authors
BIRAC Consortium, Stahl, E. A., YEAR Consortium, Raychaudhuri, S., Remmers, E. F., Xie, G., Eyre, S., Thomson, B. P., Li, Y., Kurreeman, F. A. S., Zhernakova, A., Hinks, A., Guiducci, C., Chen, R., Alfredsson, L., Amos, C. I., Ardlie, K. G., Barton, A., Bowes, J., Brouwer, E., Burtt, N. P., Catanese, J. J., Coblyn, J., Coenen, M. J. H., Costenbader, K. H., Criswell, L. A., Crusius, J. B. A., Cui, J., de Bakker, P. I. W., De Jager, P. L., Ding, B., Emery, P., Flynn, E., Harrison, P., Hocking, L. J., Huizinga, T. W. J., Kastner, D. L., Ke, X., Lee, A. T., Liu, X., Martin, P., Morgan, A. W., Padyukov, L., Posthumus, M. D., Radstake, T. R. D. J., Reid, D. M., Seielstad, M., Seldin, M. F., Shadick, N. A., Steer, S., Tak, P. P., Thomson, W., van der Helm-van Mil, A. H. M., van der Horst-Bruinsma, I. E., van der Schoot, C. E., van Riel, P. L. C. M., Weinblatt, M. E., Wilson, A. G., Wolbink, G. J., Wordsworth, B. P., Wijmenga, C., Karlson, E. W., Toes, R. E. M., de Vries, N., Begovich, A. B., Worthington, J., Siminovitch, K. A., Gregersen, P. K., Klareskog, L., & Plenge, R. M.
Affiliations
  • Brigham and Women's Hospital (US)
  • Broad Institute (US)
  • National Institutes of Health (US)
  • University of Manchester (GB)
  • University Medical Center Groningen (NL)
  • Karolinska Institutet (SE)
  • The University of Texas MD Anderson Cancer Center (US)
  • Radboud University Medical Center (NL)
  • University of California, San Francisco (US)
  • Amsterdam UMC Location Vrije Universiteit Amsterdam (NL)
  • University of Leeds (GB)
  • University of Oxford (GB)
  • University of Aberdeen (GB)
  • Leiden University Medical Center (NL)
  • Northwell Health (US)
  • Mount Sinai Hospital (CA)
  • Karolinska University Hospital (SE)
  • Genome Institute of Singapore (SG)
  • University of California, Davis (US)
  • National Health Service (GB)
  • Amsterdam UMC Location University of Amsterdam (NL)
  • University of Sheffield (GB)
Corresponding author
Plenge, Robert M
ORCID
Venue
Nature Genetics
Publisher
Springer Science and Business Media LLC
Published
2010-05-09
Volume
42
Issue
6
Pages
508-514
ISSN
  • 1061-4036 (ISSN-L)
  • 1546-1718
DOI
10.1038/ng.582
PMC
PMC4243840
OpenAlex
W2115783720
Cited by
1,253
References
6
Citations by year
2026: 20 · 2025: 26 · 2024: 34 · 2023: 49 · 2022: 63 · 2021: 63 · 2020: 51 · 2019: 64 · 2018: 69 · 2017: 92 · 2016: 111 · 2015: 96 · 2014: 100 · 2013: 141 · 2012: 127
FWCI
92.01
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Genetics (publishedVersion)
  • PubMed (publishedVersion)
  • Pure Amsterdam UMC (publishedVersion)
  • Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
  • University of Groningen research database (University of Groningen / Centre for Information Technology) (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • Data Archiving and Networked Services (DANS) (submittedVersion)
  • Leiden Repository (Leiden University) (submittedVersion)
  • Digital Academic REpository of VU University Amsterdam (Vrije Universiteit Amsterdam) (submittedVersion)
  • UCL Discovery (University College London) (submittedVersion)
  • Research Portal (King's College London) (submittedVersion)
  • Pure Amsterdam UMC (submittedVersion)
  • Research Explorer (The University of Manchester) (submittedVersion)
  • Radboud Repository (Radboud University) (submittedVersion)
  • University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion)
Funders
  • National Institute for Health and Care Research (NF-SI-0508-10299)
  • Versus Arthritis (19356, /17552, 18475)
  • National Institutes of Health (5r01ca049449-18, 5r01ai065841-05, 6u54rr020278-06, 5m01rr000079-42)
  • Canadian Institutes of Health Research (MOP79321, IIN84042)
  • National Heart, Lung, and Blood Institute (R01HL087676)
  • National Cancer Institute (CA-49449, U01CA067262, CA67262, P01CA087969, R01‐CA049449, CA50385, R01CA050385, U01CA049449, R01CA067262, [P01 CA87969)
  • National Institute of Allergy and Infectious Diseases (R01-AI-065841)
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR044422, N01-AR-22263, AR049880-06, AR‐47782, P60AR047782, R01 AR44422, R01AR049880, K08AR055688, R01AR059648, R01AR056768, R01AR057108)
  • National Center for Research Resources (U54-RR020278, 5M01-RR00079, M01-RR000079)
Topics
  • Health Sciences › Medicine › Rheumatology › Rheumatoid Arthritis Research and Therapies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Health Sciences › Medicine › Rheumatology › Systemic Lupus Erythematosus Research
Keywords
rheumatoid arthritis, genetic susceptibility loci, single nucleotide polymorphisms, gp130, SPRED2, RBPJ, CCR6, IRF5, IL2RA, CCL21, AFF3, European ancestry
MeSH terms
Arthritis, Rheumatoid, Autoantibodies, Humans, Risk Factors, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Genome-Wide Association Study, Genetic Loci

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