PTPN22 genetic variation: evidence for multiple variants associated with rheumatoid arthritis.
Journal: 2005/November - American Journal of Human Genetics
ISSN: 0002-9297
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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Am J Hum Genet 77(4): 567-581

<em>PTPN22</em> Genetic Variation: Evidence for Multiple Variants Associated with Rheumatoid Arthritis

+9 authors
Celera Diagnostics, Alameda, CA; Celera Genomics, Rockville, MD; Genomics Collaborative Division of SeraCare Life Sciences, Cambridge, MA; Genetics and Genomics Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD; Rowe Program of Human Genetics, Department of Medicine, University of California–Davis, Davis; Rosalind Russell Medical Research Center for Arthritis, Department of Medicine, University of California–San Francisco, San Francisco; Robert S. Boas Center for Genomics and Human Genetics, North Shore–Long Island Jewish Institute for Medical Research, Manhasset, NY; Department of Integrative Biology, University of California–Berkeley, Berkeley; and Department of Epidemiology, University of Texas M. D. Anderson Cancer Center, University of Texas, Houston
Address for correspondence and reprints: Dr. Ann B. Begovich, Celera Diagnostics, 1401 Harbor Bay Parkway, Alameda, CA 94502. E-mail: moc.scitsongaidarelec@hcivogeb.nna
These two authors contributed equally to this work.
Present affiliation: ParAllele BioScience, South San Francisco.
Address for correspondence and reprints: Dr. Ann B. Begovich, Celera Diagnostics, 1401 Harbor Bay Parkway, Alameda, CA 94502. E-mail: moc.scitsongaidarelec@hcivogeb.nna
Received 2005 May 26; Accepted 2005 Jul 19.

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.

Abstract

Acknowledgments

We are grateful to the patients with RA, the control individuals, and the collaborating clinicians, for participation in this study; members of the Celera Diagnostics (CDx) High Throughput and Computational Biology groups, for invaluable help; J. Law and V. Garcia, for development and implementation of the automated CDx statistical programs; R. Lundsten, M. Kern, H. Khalili, A. Rodrigues-Brown, and A. T. Lee, for database and sample management of the NARAC collection; J. Lemaire and S. Mahan, for database and sample management at Genomics Collaborative; and S. Broder, M. Cargill, W. V. Chen, A. Clark, C. Rowland, J. Sninsky, T. White, and X. Zhou, for discussions and insightful comments on the manuscript. Collection of the NARAC cohort has been funded by a National Arthritis Foundation grant and by 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 (contracts N01-AR-7-2232 and R01-AR44222). These studies were performed in part at the General Clinical Research Center, Moffitt Hospital, University of California–San Francisco, with funds provided by the National Center for Research Resources (U.S. Public Health Service grant 5 M01 RR-00079). Support was also provided by National Institutes of Health grants HG02275 and GM35326.

Acknowledgments

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