[PDF][PDF] A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis
AB Begovich, VEH Carlton, LA Honigberg… - The American Journal of …, 2004 - cell.com
AB Begovich, VEH Carlton, LA Honigberg, SJ Schrodi, AP Chokkalingam, HC Alexander…
The American Journal of Human Genetics, 2004•cell.comRheumatoid arthritis (RA) is the most common systemic autoimmune disease, affecting∼
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 …
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 …
Rheumatoid arthritis (RA) is the most common systemic autoimmune disease, affecting ∼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=6.6×10−4; replication-study allelic P=5.6×10−8), which encodes a hematopoietic-specific protein tyrosine phosphatase also known as "Lyp." We show that the risk allele, which is present in ∼17% of white individuals from the general population and in ∼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.
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