Abstract
Rheumatoid arthritis (RA) is an autoimmune/inflammatory disorder with a complex genetic component. We report the first major genomewide screen of multiplex families with RA gathered in the United States. The North American Rheumatoid Arthritis Consortium, using well-defined clinical criteria, has collected 257 families containing 301 affected sibling pairs with RA. A genome screen for allele sharing was performed, using 379 microsatellite markers. A nonparametric analysis using SIBPAL confirmed linkage of the HLA locus to RA (P < .00005), with λHLA = 1.79. However, the analysis also revealed a number of non-HLA loci on chromosomes 1 (D1S235), 4 (D4S1647), 12 (D12S373), 16 (D16S403), and 17 (D17S1301), with evidence for linkage at a significance level of P < .005. Analysis of X-linked markers using the MLOD method from ASPEX also suggests linkage to the telomeric marker DXS6807. Stratifying the families into white or seropositive subgroups revealed some additional markers that showed improvement insignificance over the full data set. Several of the regions that showed evidence for nominal significance (P < .05) in our data set had previously been implicated in RA (D16S516 and D17S1301) or in other diseases of an autoimmune nature, including systemic lupus erythematosus (D1S235), inflammatory bowel disease (D4S1647, D5S1462, and D16S516), multiple sclerosis (D12S1052), and ankylosing spondylitis (D16S516). Therefore, genes in the HLA complex play a major role in RA susceptibility, but several other regions also contribute significantly to overall genetic risk.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 927-936 |
| Number of pages | 10 |
| Journal | American journal of human genetics |
| Volume | 68 |
| Issue number | 4 |
| DOIs | |
| State | Published - 2001 |
Funding
We would like to thank the following people for their contributions to the work described in this article: Aarti Damle, Susan Dowbak, Silvia Jaeger, and Dong Chen, for sample preparations and genotyping; Dr. Dorothy Guzowski, for synthesis of oligonucleotides; Nancy Giannola and Nina Kohn, for data management; Dakai Zhu and Wenfu Wang, for enabling us to perform error checking of the data through the Web; Jianfang Chen and Qingsong Liu, for the binning and error-handling programs used; Tracy Costello, for data processing design; and Sally Kaplan, Mary Noelle Holly, Clarine Cleveland, Peggy Rasmussen, Dana DePew, Carol Blalock, Karen Rodin, Linda Ingles, Diane Amox, Kay Randall, Donna McGregor, Marianna Crane, Pat Cummins, Phyllis Daum, and Jennifer Pearce, for outstanding field work in recruiting RA families. We are indebted to Clay Kasow and the staff at Empatheon, Inc. (formerly PatternRx, Inc.), for creating and maintaining the NARAC Web site to support this project. This project has been funded, in large part, by funds provided by the National Arthritis Foundation and federal funds from the National Institutes of Health, acting through the National Institute of Arthritis and Musculoskeletal and Skin Diseases and the National Institute of Allergy and Infectious Diseases, under grant RO1-AR44222 and contract NO1-AR-7-2232. These studies were performed, in part, in the General Clinical Research Center, Moffitt Hospital, University of California, San Francisco, with funds provided by the National Center for Research Resources, grant 5 M01 RR-00079, U.S. Public Health Service. The results in this article were obtained by using the program package SAGE, which is supported by a U.S. Public Health Service Resource Grant (1 P41 RR03655), from the National Center for Research Resources. We would like to extend our thanks to all the patients and their families for participating in the NARAC and making this study possible.
ASJC Scopus subject areas
- Genetics(clinical)
- Genetics