Screening the genome for rheumatoid arthritis susceptibility genes: a replication study and combined analysis of 512 multicase families.

Published

Journal Article

OBJECTIVE: A number of non-HLA loci that have shown evidence (P < 0.05) for linkage with rheumatoid arthritis (RA) have been previously identified. The present study attempts to confirm these findings. METHODS: We performed a second genome-wide screen of 256 new multicase RA families recruited from across the United States by the North American Rheumatoid Arthritis Consortium. Affected sibling pair analysis on the new data set was performed using SIBPAL. We subsequently combined our first and second data sets in an attempt to enhance the evidence for linkages in a larger sample size. We also evaluated the impact of covariates on the support for linkage, using LODPAL. RESULTS: Evidence of linkage at 1p13 (D1S1631), 6p21.3 (the HLA complex), and 18q21 (D18S858) (P < 0.05) was replicated in this independent data set. In addition, there was new evidence for linkage at 9p22 (D9S1121 [P = 0.001]) and 10q21 (D10S1221 [P = 0.0002] and D10S1225 [P = 0.0038]) in the current data set. The combined analysis of both data sets (512 families) showed evidence for linkage at the level of P < 0.005 at 1p13 (D1S1631), 1q43 (D1S235), 6q21 (D6S2410), 10q21 (D10S1221), 12q12 (D12S398), 17p13 (D17S1298), and 18q21 (D18S858). Linkage at HLA was also confirmed (P < 5 x 10(-12)). Inclusion of DRB1*04 as a covariate significantly increased the probability of linkage on chromosome 6. In addition, some linkages on chromosome 1 showed improved significance when modeling DRB1*04 or rheumatoid factor positivity as covariates. CONCLUSION: These results provide a rational basis for pursuing high-density linkage and association studies of RA in several regions outside of the HLA region, particularly on chromosomes 1p, 1q, and 18q.

Full Text

Duke Authors

Cited Authors

  • Jawaheer, D; Seldin, MF; Amos, CI; Chen, WV; Shigeta, R; Etzel, C; Damle, A; Xiao, X; Chen, D; Lum, RF; Monteiro, J; Kern, M; Criswell, LA; Albani, S; Nelson, JL; Clegg, DO; Pope, R; Schroeder, HW; Bridges, SL; Pisetsky, DS; Ward, R; Kastner, DL; Wilder, RL; Pincus, T; Callahan, LF; Flemming, D; Wener, MH; Gregersen, PK; North American Rheumatoid Arthritis Consortium,

Published Date

  • April 2003

Published In

Volume / Issue

  • 48 / 4

Start / End Page

  • 906 - 916

PubMed ID

  • 12687532

Pubmed Central ID

  • 12687532

International Standard Serial Number (ISSN)

  • 0004-3591

Digital Object Identifier (DOI)

  • 10.1002/art.10989

Language

  • eng

Conference Location

  • United States