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

Damini Jawaheer, Michael F Seldin, Christopher I. Amos, Wei V. Chen, Russell Shigeta, Carol Etzel, Aarti Damle, Xiangli Xiao, Dong Chen, Raymond F. Lum, Joanita Monteiro, Marlene Kern, Lindsey A. Criswell, Salvatore Albani, J. Lee Nelson, Daniel O. Clegg, Richard Pope, Harry W. Schroeder, S. Louis Bridges, David S. PisetskyRyk Ward, Daniel L. Kastner, Ronald L. Wilder, Theodore Pincus, Leigh F. Callahan, Donald Flemming, Mark H. Wener, Peter K. Gregersen

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186 Scopus citations

Abstract

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 × 10-12). Inclusion of DRBI*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 DRBI*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.

Original languageEnglish (US)
Pages (from-to)906-916
Number of pages11
JournalArthritis and Rheumatism
Volume48
Issue number4
DOIs
StatePublished - Apr 1 2003

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ASJC Scopus subject areas

  • Immunology
  • Rheumatology

Cite this

Jawaheer, D., Seldin, M. F., Amos, C. I., Chen, W. V., Shigeta, R., Etzel, C., Damle, A., Xiao, X., Chen, D., Lum, R. F., Monteiro, J., Kern, M., Criswell, L. A., Albani, S., Nelson, J. L., Clegg, D. O., Pope, R., Schroeder, H. W., Bridges, S. L., ... Gregersen, P. K. (2003). Screening the genome for rheumatoid arthritis susceptibility genes: A replication study and combined analysis of 512 multicase families. Arthritis and Rheumatism, 48(4), 906-916. https://doi.org/10.1002/art.10989