Analysis of gender differences in genetic risk: association of TNFAIP3 polymorphism with male childhood-onset systemic lupus erythematosus in the Japanese population

PLoS One. 2013 Aug 30;8(8):e72551. doi: 10.1371/journal.pone.0072551. eCollection 2013.

Abstract

Background: Systemic lupus erythematosus (SLE) is a systemic multisystem autoimmune disorder influenced by genetic background and environmental factors. Our aim here was to replicate findings of associations between 7 of the implicated single nucleotide polymorphisms (SNPs) in IRF5, BLK, STAT4, TNFAIP3, SPP1, TNIP1 and ETS1 genes with susceptibility to childhood-onset SLE in the Japanese population. In particular, we focused on gender differences in allelic frequencies.

Methodology/principal findings: The 7 SNPs were genotyped using TaqMan assays in 75 patients with childhood-onset SLE and in 190 healthy controls. The relationship between the cumulative number of risk alleles and SLE manifestations was explored in childhood-onset SLE. Logistic regression was used to test the effect of each polymorphism on susceptibility to SLE, and Wilcoxon rank sum testing was used for comparison of total risk alleles. Data on rs7574865 in the STAT4 gene and rs9138 in SPP1 were replicated for associations with SLE when comparing cases and controls (corrected P values ranging from 0.0043 to 0.027). The rs2230926 allele of TNFAIP3 was associated with susceptibility to SLE in males, but after Bonferroni correction there were no significant associations with any of the other four SNPs in IRF5, BLK, TNIP1 and ETS1 genes. The cumulative number of risk alleles was significantly increased in childhood-onset SLE relative to healthy controls (P = 0.0000041). Male SLE patients had a slightly but significantly higher frequency of the TNFAIP3 (rs2230926G) risk allele than female patients (odds ratio [OR] = 4.05, 95% confidence interval [95%CI] = 1.46-11.2 P<0.05).

Conclusions: Associations of polymorphisms in STAT4 and SPP1 with childhood-onset SLE were confirmed in a Japanese population. Although these are preliminary results for a limited number of cases, TNFAIP3 rs2230926G may be an important predictor of disease onset in males. We also replicated findings that the cumulative number of risk alleles was significantly increased in childhood-onset SLE.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age of Onset
  • Alleles
  • Asian Continental Ancestry Group / genetics*
  • Child
  • DNA-Binding Proteins / genetics*
  • Demography
  • Female
  • Genetic Predisposition to Disease*
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics*
  • Japan
  • Logistic Models
  • Lupus Erythematosus, Systemic / genetics*
  • Male
  • Nuclear Proteins / genetics*
  • Polymorphism, Single Nucleotide / genetics*
  • Risk Factors
  • Sex Characteristics*
  • Tumor Necrosis Factor alpha-Induced Protein 3

Substances

  • DNA-Binding Proteins
  • Intracellular Signaling Peptides and Proteins
  • Nuclear Proteins
  • TNFAIP3 protein, human
  • Tumor Necrosis Factor alpha-Induced Protein 3

Grant support

This work was supported by a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (No. 16790583). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.