TY - JOUR
T1 - Replication of putative candidate-gene associations with rheumatoid arthritis in >4,000 samples from North America and Sweden
T2 - Association of susceptibility with PTPN22, CTLA4, and PADI4
AU - Plenge, Robert M.
AU - Padyukov, Leonid
AU - Remmers, Elaine F.
AU - Purcell, Shaun
AU - Lee, Annette T.
AU - Karlson, Elizabeth W.
AU - Wolfe, Frederick
AU - Kastner, Daniel L.
AU - Alfredsson, Lars
AU - Altshuler, David
AU - Gregersen, Peter K.
AU - Klareskog, Lars
AU - Rioux, John D.
N1 - Funding Information:
R.M.P. is supported for this work by the National Institutes of Health (NIH) (grant K08 AI 55314). P.K.G. is supported for this work by the NIH (grants NO1-AR-2-2263 and R01-AR44222) and the National Arthritis Foundation. J.D.R. is supported by the National Institute of Diabetes and Digestive and Kidney Diseases and by the Crohn's and Colitis Foundation of America. This research was supported in part by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the NIH. E.W.K. is supported by NIH grants R01 AR49880-01, K24 AR0524-01, P60 AR47782-05. We are grateful to Abbott Laboratories, for the support of the SONORA study, and to Clair Bombardier, Elena Massarotti, and Michael Weisman, for their critical roles in the design and implementation of the SONORA cohort. We appreciate Julie Le's technical contribution to genotyping done at the National Institute of Arthritis and Musculoskeletal and Skin Diseases and Noel Burtt and Christine Curley's technical assistance at the Broad Institute.
PY - 2005/12
Y1 - 2005/12
N2 - Candidate-gene association studies in rheumatoid arthritis (RA) have lead to encouraging yet apparently inconsistent results. One explanation for the inconsistency is insufficient power to detect modest effects in the context of a low prior probability of a true effect. To overcome this limitation, we selected alleles with an increased probability of a disease association, on the basis of a review of the literature on RA and other autoimmune diseases, and tested them for association with RA susceptibility in a sample collection powered to detect modest genetic effects. We tested 17 alleles from 14 genes in 2,370 RA cases and 1,757 controls from the North American Rheumatoid Arthritis Consortium (NARAC) and the Swedish Epidemiological Investigation of Rheumatoid Arthritis (EIRA) collections. We found strong evidence of an association of PTPN22 with the development of anti-citrulline antibody-positive RA (odds ratio [OR] 1.49; P = .00002), using previously untested EIRA samples. We provide support for an association of CTLA4 (CT60 allele, OR 1.23; P = .001) and PAD/4 (PADI4_94, OR 1.24; P = .001) with the development of RA, but only in the NARAC cohort. The CTLA4 association is stronger in patients with RA from both cohorts who are seropositive for anti-citrulline antibodies (P = .0006). Exploration of our data set with clinically relevant subsets of RA reveals that PTPN22 is associated with an earlier age at disease onset (P = .004) and that PTPN22 has a stronger effect in males than in females (P = .03). A meta-analysis failed to demonstrate an association of the remaining alleles with RA susceptibility, suggesting that the previously published associations may represent false-positive results. Given the strong statistical power to replicate a true-positive association in this study, our results provide support for PTPN22, CTLA4, and PADI4 as RA susceptibility genes and demonstrate novel associations with clinically relevant subsets of RA.
AB - Candidate-gene association studies in rheumatoid arthritis (RA) have lead to encouraging yet apparently inconsistent results. One explanation for the inconsistency is insufficient power to detect modest effects in the context of a low prior probability of a true effect. To overcome this limitation, we selected alleles with an increased probability of a disease association, on the basis of a review of the literature on RA and other autoimmune diseases, and tested them for association with RA susceptibility in a sample collection powered to detect modest genetic effects. We tested 17 alleles from 14 genes in 2,370 RA cases and 1,757 controls from the North American Rheumatoid Arthritis Consortium (NARAC) and the Swedish Epidemiological Investigation of Rheumatoid Arthritis (EIRA) collections. We found strong evidence of an association of PTPN22 with the development of anti-citrulline antibody-positive RA (odds ratio [OR] 1.49; P = .00002), using previously untested EIRA samples. We provide support for an association of CTLA4 (CT60 allele, OR 1.23; P = .001) and PAD/4 (PADI4_94, OR 1.24; P = .001) with the development of RA, but only in the NARAC cohort. The CTLA4 association is stronger in patients with RA from both cohorts who are seropositive for anti-citrulline antibodies (P = .0006). Exploration of our data set with clinically relevant subsets of RA reveals that PTPN22 is associated with an earlier age at disease onset (P = .004) and that PTPN22 has a stronger effect in males than in females (P = .03). A meta-analysis failed to demonstrate an association of the remaining alleles with RA susceptibility, suggesting that the previously published associations may represent false-positive results. Given the strong statistical power to replicate a true-positive association in this study, our results provide support for PTPN22, CTLA4, and PADI4 as RA susceptibility genes and demonstrate novel associations with clinically relevant subsets of RA.
UR - http://www.scopus.com/inward/record.url?scp=28144441356&partnerID=8YFLogxK
U2 - 10.1086/498651
DO - 10.1086/498651
M3 - Article
C2 - 16380915
AN - SCOPUS:28144441356
SN - 0002-9297
VL - 77
SP - 1044
EP - 1060
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 6
ER -