CTLA4 variants and haplotype contribute genetic susceptibility to myasthenia gravis in northern Chinese population

Abstract

Background: Cytotoxic T lymphocyte-associated antigen-4 (CTLA4), a critical negative regulator of the T-cell response, has been considered a candidate for many autoimmune diseases. Evidence from Caucasians supported a genetic predisposition of CTLA4 to myasthenia gravis (MG), but the contribution in East Asians has not been established.

Objectives: To investigate the role of CTLA4 variants in the susceptibility to MG and the contribution to subtypes of MG.

Methods: Six autoimmune disease-related risk alleles of CTLA4 (rs1863800, rs733618, rs4553808, rs5742909, rs231775, and rs3087243) were investigated for MG in northern Chinese. 168 patients with MG (mean age 37.1±20.5 years, 64 men and 104 women) and 233 healthy controls (mean age 53.3±8.7 years, 96 men and 137 women) were screened, and the contribution of CTLA4 to the general risk of MG and each subgroup was explored.

Results: rs1863800*C, rs733618*C, and rs231775*G were significantly associated with the whole cohort of patients with MG after permutation correction for multiple-testing adjustment (P = 0.027, 0.001, and 0.032, respectively). A risk haplotype (CCACG) [odds ratio (OR) = 1.535, range = 1.150-2.059, P = 0.004)] was also identified. The stratified subtype analysis indicated that the positive contribution was possibly derived from early onset MG (EOMG), seropositive MG (SPMG), female patients, and MG without thymoma. No association was observed in juvenile MG/LOMG, and MG coupled with thymoma.

Conclusion: A predisposing effect of rs1863800*C, rs733618*C, and rs231775*G of CTLA4 gene to general risk of MG in Chinese was demonstrated for the first time, which was likely derived from EOMG, SPMG, MG without thymoma and the female patients.

Figure 1. Haplotype block and LD test of candidate CTLA4 variants in 36.5 kb genomic region.

Generated by Haploview (version 4.2), and each box represents the D′ valuebetween pairs of SNPs (ranging from 0 to 1). Dark red, strong LD; light red, weak LD.

Figure 2. Odds ratios and 95% confidence intervals (CI) of 3 CTLA4 risk alleles with MG subgroups.

JMG = juvenile MG; EOMG = early-onset MG; LOMG = late-onset MG; SPMG = Seropositive MG; SNMG = Seronegative MG; OMG = ocular myasthenia gravis; GMG = generalized myasthenia gravis.