A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis.

By A. Begovich, V. Carlton, L. Honigberg, Steven J. Schrodi, A. Chokkalingam, H. Alexander, Kristin G. Ardlie, Qiqing Huang, Ashley M. Smith, J. Spoerke and 18 more. American Journal of Human Genetics, 2004

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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.

Subfields: Genetics, Immunology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/2a21457bd0b3fbb1c3f3bb3f4957c83eb6603a39

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Citations in the corpus

Genetic association of the R620W polymorphism of protein tyrosine phosphatase PTPN22 with human SLE. (2004, methodology): “…frequencies of cohort A, in which a single subject with SLE was randomly selected from each of 185 white families with SLE-affected sib pairs from the University of Minnesota collection (Gaffney et al. 2000), with results generated from 926 white controls (control 1) (Begovich et al. 2004).”
A Dynamic Network Approach for the Study of Human Phenotypes (2009, background): “dity based relationships compares with that of heredity and known genetic markers. Of the two measures discussed above, the Relative Risk (RR) enjoys the most widespread use in the medical literature [21, 22, 23, 24, 25, 26, 27, 28, 29, 30], making it the most suitable for such comparison. We find t”
Emerging Role of Endosomal Toll-Like Receptors in Rheumatoid Arthritis (2013, background): “Protein tyrosine phosphatase non-receptor type 22 (PTPN22),a gene associated with RA susceptibility, has been shown to be required for IFN production upon TLR3, 4, 7, and 9 stimulation (40).”
A haplotype map of the human genome (2003, background): “1); (4) targeted sequencing of the ten ENCODE regions, including evaluations of false-positive and falsenegative rates; (5) genotyping for the genome-wide map; (6) intense efforts that monitored and established the high quality of the data; and (7) data coordination and distribution through the proj”
Replication of putative candidate-gene associations with rheumatoid arthritis in >4,000 samples from North America and Sweden: association of susceptibility with PTPN22, CTLA4, and PADI4. (2005, methodology): “Genotype data from the NARAC cohort for two genes (PTPN22 [Begovich et al. 2004; Lee et al. 2005] and CARD15 [Addo et al. 2005]) have been reported elsewhere.”
Analysis of families in the multiple autoimmune disease genetics consortium (MADGC) collection: the PTPN22 620W allele associates with multiple autoimmune phenotypes. (2005, neutral): “It should also be pointed out that PTPN22 is broadly expressed in hematopoietic cells, and, thus, the mechanism for disease susceptibility may extend beyond T cells (Begovich et al. 2004).”
Accounting for linkage disequilibrium in genome-wide association studies: A penalized regression method (2013, background): “Particularly, association with rheumatoid arthritis at SNP rs2476601 in gene PTPN22 has been reported previously [2].”