NDLI: Replication of Putative Candidate-Gene Associations with Rheumatoid Arthritis in >4,000 Samples from North America and Sweden: Association of Susceptibility with PTPN22, CTLA4, and PADI4

Content Provider	PubMed Central
Author	Plenge, Robert M. Padyukov, Leonid Remmers, Elaine F. Purcell, Shaun Lee, Annette T. Karlson, Elizabeth W. Wolfe, Frederick Kastner, Daniel L. Alfredsson, Lars Altshuler, David Gregersen, Peter K. Lars, Klareskog Rioux, John D.
Copyright Year	2005
Abstract	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 PADI4 (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.
Related Links	http://dx.doi.org/10.1086/498651
Ending Page	1060
Page Count	17
Starting Page	1044
File Format	PDF
ISSN	00029297
e-ISSN	15376605
Journal	American Journal of Human Genetics
Issue Number	6
Volume Number	77
Language	English
Publisher	The American Society of Human Genetics
Publisher Date	2005-12-01
Access Restriction	Open
Rights Holder	The American Society of Human Genetics
Subject Keyword	Genetics(clinical) Genetics Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Genetics Genetics (clinical)

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