Author(s): Begovich AB, Carlton VE, Honigberg LA, Schrodi SJ, Chokkalingam AP,
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Abstract Rheumatoid arthritis (RA) is the most common systemic autoimmune disease, affecting approximately 1\% 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 approximately 17\% of white individuals from the general population and in approximately 28\% 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.
This article was published in Am J Hum Genet
and referenced in Journal of Clinical & Cellular Immunology