Genetic heterogeneity within the HLA region in three distinct clinical subgroups of myasthenia gravis

•Differential genetic susceptibility to EOMG, LOMG and MuSK-MG has been confirmed.•HLA has been proved as the main region differing between the subgroups.•The role of MHC class I and CD8 T cells has been confirmed in EOMG.

This study aims to investigate genetic susceptibility to early-onset and late-onset anti-acetylcholine receptor antibody positive myasthenia gravis (EOMG and LOMG) and anti-muscle specific kinase antibody positive MG (MuSK-MG) at genome-wide level in a single population. Using a custom-designed array and imputing additional variants and the classical HLA alleles in 398 patients, we detected distinct associations. In EOMG, rs113519545 in the HLA class I region (OR = 5.71 [3.77-8.66], P = 2.24 × 10− 16), HLA-B*08:01 (OR = 7.04 [3.95-12.52], P = 3.34 × 10− 11) and HLA-C*07:01 (OR = 2.74 [1.97-3.81], P = 2.07− 9), in LOMG, rs111256513 in the HLA class II region (OR = 2.22 [1.59-3.09], P = 2.48 × 10− 6) and in MuSK-MG, an intronic variant within HLA-DQB1 (rs68081734, OR = 5.86, P = 2.25 × 10− 14) and HLA-DQB1*05:02 (OR = 8.56, P = 6.88 × 10− 13) revealed the most significant associations for genome-wide significance. Differential genetic susceptibility within the HLA to EOMG, LOMG and MuSK-MG has been established in a population from Turkey.