A functional variant of PTPN22 confers risk for Vogt-Koyanagi-Harada syndrome but not for ankylosing spondylitis

PLoS One. 2014 May 9;9(5):e96943. doi: 10.1371/journal.pone.0096943. eCollection 2014.

Abstract

Background: Protein tyrosine phosphatase non-receptor 22 (PTPN22) is a key negative regulator of T lymphocytes and has emerged as an important candidate susceptibility factor for a number of immune-related diseases. This study aimed to examine the predisposition of PTPN22 SNPs to Vogt-Koyanagi-Harada (VKH) syndrome and acute anterior uveitis (AAU) associated with ankylosing spondylitis (AS).

Methods: A total of 1005 VKH syndrome, 302 AAU+AS+ patients and 2010 normal controls among the Chinese Han population were enrolled in the study. Genotyping, PTPN22 expression, cell proliferation, cytokine production and cell activation were examined by PCR-RFLP, Real-time PCR, CCK8, ELISA and Flow cytometry.

Results: The results showed significantly increased frequencies of the rs2488457 CC genotype and C allele but a decreased frequency of the GG genotype in VKH syndrome patients (PBonferroni correction (Pc) = 3.47×10(-7), OR = 1.54; Pc = 3.83×10(-8), OR = 1.40; Pc = 6.35×10(-4), OR = 0.62; respectively). No significant association of the tested SNPs with AAU+AS+ patients was observed. Functional studies showed a decreased PTPN22 expression, impaired cell proliferation and lower production of IL-10 in rs2488457 CC cases compared to GG cases (Pc = 0.009, Pc = 0.015 and Pc = 0.048 respectively). No significant association was observed concerning T cell activation and rs2488457 genotype.

Conclusions: The study showed that a functional variant of PTPN22 confers risk for VKH syndrome but not for AAU+AS+ in a Chinese Han population, which may be due to a modulation of the PTPN22 expression, PBMC proliferation and IL-10 production.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Case-Control Studies
  • Cell Proliferation / genetics
  • Cytokines / biosynthesis
  • Female
  • Gene Expression Regulation, Enzymologic
  • Gene Frequency
  • Genetic Predisposition to Disease / genetics*
  • Humans
  • Leukocytes, Mononuclear / cytology
  • Male
  • Mice
  • Polymorphism, Single Nucleotide*
  • Protein Tyrosine Phosphatase, Non-Receptor Type 22 / genetics*
  • Spondylitis, Ankylosing / enzymology*
  • Spondylitis, Ankylosing / genetics*
  • Uveomeningoencephalitic Syndrome / blood
  • Uveomeningoencephalitic Syndrome / enzymology*
  • Uveomeningoencephalitic Syndrome / genetics*
  • Uveomeningoencephalitic Syndrome / metabolism

Substances

  • Cytokines
  • PTPN22 protein, human
  • Protein Tyrosine Phosphatase, Non-Receptor Type 22

Grants and funding

This work was supported by Key Project of Natural Science Foundation (81130019), National Basic Research Program of China (973 Program) (2011CB510200), National Natural Science Foundation Project (81300754, 81270990, 81070722), Clinic Key Project of Ministry of Health, Basic Research program of Chongqing (cstc2013jcyjC10001), Chongqing Key Laboratory of Ophthalmology (CSTC, 2008CA5003), Key Project of Health Bureau of Chongqing (2012-1-003) and Fund for PAR-EU Scholars Program. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.