Journal
AMERICAN JOURNAL OF HUMAN GENETICS
Volume 75, Issue 2, Pages 330-337Publisher
UNIV CHICAGO PRESS
DOI: 10.1086/422827
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Funding
- NCRR NIH HHS [5 M01 RR-00079, M01 RR000079] Funding Source: Medline
- NHGRI NIH HHS [R01 HG002275, HG 02275] Funding Source: Medline
- NIAMS NIH HHS [R01-AR44222, N01-AR-7-2232] Funding Source: Medline
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Rheumatoid arthritis (RA) is the most common systemic autoimmune disease, affecting similar to1% of the adult population worldwide, with an estimated heritability of 60%. To identify genes involved in RA susceptibility, we investigated the association between putative functional single-nucleotide polymorphisms (SNPs) and RA among white individuals by use of a case-control study design; a second sample was tested for replication. Here we report the association of RA susceptibility with the minor allele of a missense SNP in PTPN22 (discovery-study allelic P = 6.6 x 10(-4); replication-study allelic P = 5.6 x 10(-8)), which encodes a hematopoietic-specific protein tyrosine phosphatase also known as Lyp. We show that the risk allele, which is present in similar to17% of white individuals from the general population and in similar to28% of white individuals with RA, disrupts the P1 proline-rich motif that is important for interaction with Csk, potentially altering these proteins' normal function as negative regulators of T-cell activation. The minor allele of this SNP recently was implicated in type 1 diabetes, suggesting that the variant phosphatase may increase overall reactivity of the immune system and may heighten an individual carrier's risk for autoimmune disease.
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