Human leukocyte antigens and systemic lupus erythematosus: a protective role for the HLA-DR6 alleles DRB1*13:02 and *14:03

PLoS One. 2014 Feb 3;9(2):e87792. doi: 10.1371/journal.pone.0087792. eCollection 2014.

Abstract

Many studies on associations between human leukocyte antigen (HLA) allele frequencies and susceptibility to systemic lupus erythematosus (SLE) have been performed. However, few protective associations with HLA-DRB1 alleles have been reported. Here, we sought protective, as well as predispositional, alleles of HLA-DRB1 in Japanese SLE patients. An association study was conducted for HLA-DRB1 in Japanese SLE patients. Relative predispositional effects were analyzed by sequential elimination of carriers of each allele with the strongest association. We also explored the association of DRB1 alleles with SLE phenotypes including the presence of autoantibody and clinical manifestations. Significantly different carrier frequencies of certain DRB1 alleles were found to be associated with SLE as follows: increased DRB1*15:01 (P = 5.48×10⁻¹⁰, corrected P (Pc) = 1.59×10⁻⁸, odds ratio [OR] 2.17, 95% confidence interval [CI] 1.69-2.79), decreased DRB1*13:02 (P = 7.17×10⁻⁵, Pc = 0.0020, OR 0.46, 95% CI 0.34-0.63) and decreased DRB1*14:03 (P = 0.0010, Pc = 0.0272, OR 0.34, 95% CI 0.18-0.63). Additionally, the "*15:01/*13:02 or *14:03" genotype tended to be negatively associated with SLE (P = 0.4209, OR 0.66), despite there being significant positive associations with *15:01 when present together with alleles other than *13:02 or *14:03 (P = 1.79×10⁻¹¹, OR 2.39, 95% CI 1.84-3.10). This protective effect of *13:02 and *14:03 was also confirmed in SLE patients with different clinical phenotypes. To the best of our knowledge, this is the first report of a protective association between the carrier frequencies of HLA-DRB1*13:02 and *14:03 and SLE in the Japanese population.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Alleles
  • Asian People / genetics*
  • Case-Control Studies
  • DNA / analysis
  • Female
  • Genetic Predisposition to Disease
  • Genotype
  • HLA-DR6 Antigen / genetics*
  • HLA-DR6 Antigen / immunology
  • HLA-DRB1 Chains / genetics*
  • HLA-DRB1 Chains / immunology
  • Humans
  • Lupus Erythematosus, Systemic / genetics*
  • Lupus Erythematosus, Systemic / immunology*
  • Lupus Erythematosus, Systemic / prevention & control
  • Male
  • Middle Aged
  • Odds Ratio
  • Polymerase Chain Reaction

Substances

  • HLA-DR6 Antigen
  • HLA-DRB1 Chains
  • DNA

Grants and funding

This work was supported by Grants-in-Aid for Scientific Research (B, C) (22390199, 22591090), for Exploratory Research (25670458) and for Young Scientists (B) (24791018) from the Japan Society for the Promotion of Science, Health and Labour Science Research Grants from the Ministry of Health, Labour and Welfare of Japan, Grants-in-Aid for Clinical Research from National Hospital Organization, Research Grants from Daiwa Securities Health Foundation, Research Grants from Japan Research Foundation for Clinical Pharmacology, Research Grants from The Nakatomi Foundation, Research Grants from Takeda Science Foundation, Research Grants from Mitsui Sumitomo Insurance Welfare Foundation, Research Grants from SENSHIN Medical Research Foundation and research grants from pharmaceutical companies: Abbott Japan Co., Ltd., Astellas Pharma Inc., Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Merck Sharp and Dohme Inc., Pfizer Japan Inc., Takeda Pharmaceutical Company Limited, Teijin Pharma Limited. The funders had no role in study design, data collection and analysis, decision to publish or preparing the manuscript.