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PTPN22 genetic variation: evidence for multiple variants associated with rheumatoid arthritis |
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| Authors: | Carlton Victoria E H Hu Xiaolan Chokkalingam Anand P Schrodi Steven J Brandon Rhonda Alexander Heather C Chang Monica Catanese Joseph J Leong Diane U Ardlie Kristin G Kastner Daniel L Seldin Michael F Criswell Lindsey A Gregersen Peter K Beasley Ellen Thomson Glenys Amos Christopher I Begovich Ann B |
| Affiliation: | 1 Celera Diagnostics, Alameda, CA 2 Celera Genomics, Rockville, MD 3 Genomics Collaborative Division of SeraCare Life Sciences, Cambridge, MA 4 Genetics and Genomics Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 5 Rowe Program of Human Genetics, Department of Medicine, University of California-Davis, Davis 6 Rosalind Russell Medical Research Center for Arthritis, Department of Medicine, University of California-San Francisco, San Francisco 7 Robert S. Boas Center for Genomics and Human Genetics, North Shore-Long Island Jewish Institute for Medical Research, Manhasset, NY 8 Department of Integrative Biology, University of California-Berkeley, Berkeley 9 Department of Epidemiology, University of Texas M. D. Anderson Cancer Center, University of Texas, Houston |
| Abstract: | The minor allele of the R620W missense single-nucleotide polymorphism (SNP) (rs2476601) in the hematopoietic-specific protein tyrosine phosphatase gene, PTPN22, has been associated with multiple autoimmune diseases, including rheumatoid arthritis (RA). These genetic data, combined with biochemical evidence that this SNP affects PTPN22 function, suggest that this phosphatase is a key regulator of autoimmunity. To determine whether other genetic variants in PTPN22 contribute to the development of RA, we sequenced the coding regions of this gene in 48 white North American patients with RA and identified 15 previously unreported SNPs, including 2 coding SNPs in the catalytic domain. We then genotyped 37 SNPs in or near PTPN22 in 475 patients with RA and 475 individually matched controls (sample set 1) and selected a subset of markers for replication in an additional 661 patients with RA and 1,322 individually matched controls (sample set 2). Analyses of these results predict 10 common (frequency >1%) PTPN22 haplotypes in white North Americans. The sole haplotype found to carry the previously identified W620 risk allele was strongly associated with disease in both sample sets, whereas another haplotype, identical at all other SNPs but carrying the R620 allele, showed no association. R620W, however, does not fully explain the association between PTPN22 and RA, since significant differences between cases and controls persisted in both sample sets after the haplotype data were stratified by R620W. Additional analyses identified two SNPs on a single common haplotype that are associated with RA independent of R620W, suggesting that R620W and at least one additional variant in the PTPN22 gene region influence RA susceptibility. |
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