Human Leukocyte Antigens and Systemic Lupus Erythematosus: A Protective Role for the HLA-DR6 Alleles DRB1*13:02 and *14:03

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.

Brief Report: Influence of HLA–DRB1 Susceptibility Alleles on the Clinical Subphenotypes of Systemic Lupus Erythematosus in Koreans

“…The strong significant association between the *08:03 or *07:01 allele and SLE in Koreans is a novel result, although high frequencies of the *08:03 allele in Japanese and the *07:01 allele in Malay patients with SLE have been reported . In addition, this study is the first to identify a negative association between the HLA–DRB1*12:02 and *11:01 alleles and SLE in Koreans; these results are not the same as those observed in studies in other ethnic groups .…”

The HLA-DRβ1 amino acid positions 11–13–26 explain the majority of SLE–MHC associations

“…In addition, our haplotype association results further suggested SLE-risk or SLE-protective roles for classical alleles based on the effect estimates of each amino acid haplotype. The effect directions of most classical alleles, such as *01:01, *04, *07:01, *08, *09:01, *11, *13 and *14, have been consistently observed in previous Asian studies [20][21][22] . We further evaluated if the effect sizes of the amino acid haplotypes are concordant with the previously reported effect sizes for classical alleles.…”

“…6) as well as other Asian population studies ( Supplementary Fig. 5) 9,[20][21][22] . In addition, we note that SLE associations at several reported SLE-risk SNPs listed in the NHGRI GWAS Catalog 23 and two independent SLE-risk SNPs in the largest fine-mapping study 9 were much weaker than that at the amino acid positions during the stepwise conditional analysis.…”

“…We further evaluated if the effect sizes of the amino acid haplotypes are concordant with the previously reported effect sizes for classical alleles. The observed effect size of each amino acid haplotype was compared with published results from the largest Asian study 20 investigating the association of classical HLA-DRB1 alleles with SLE susceptibility using 1,697 Japanese case-control subjects. In the Japanese study, seven common haplotypes were present based on the frequency and number of HLA-DRB1 classical alleles.…”

Association of HLA-DQB1∗06 with susceptibility to systemic lupus erythematosus in Egyptians

“…MHC is the strongest genetic factor for SLE. Altered frequencies of human leukocyte antigen (HLA) alleles are known to be associated with SLE [18], with the HLA class II DRB1 and DQB1 loci demonstrating the strongest association [19].…”