Next-generation sequencing identifies contribution of both class I and II HLA genes on susceptibility of multiple sclerosis in Japanese

Background The spectrum of classical and non-classical HLA genes related to the risk of multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) in the Japanese population has not been studied in detail. We conducted a case-control analysis of classical and non-classical HLA genes. Methods We used next-generation sequencing (NGS)-based HLA genotyping methods for mapping risk for 45 MS patients, 31 NMOSD patients, and 429 healthy controls. We evaluated the association of the HLA variants with the risk of MS and NMOSD using logistic regression analysis and Fisher's exact test. Results We confirmed that HLA-DRB1*15:01 showed the strongest association with MS (P = 2.1 x 10(-5); odds ratio [OR] = 3.44, 95% confidence interval [95% CI] = 1.95-6.07). Stepwise conditional analysis identified HLA-DRB1*04:05, HLA-B*39:01, and HLA-B*15:01 as being associated with independent MS susceptibility (P-Conditional < 8.3 x 10(-4)). With respect to amino acid polymorphisms in HLA genes, we found that phenylalanine at HLA-DQ beta 1 position 9 had the strongest effect on MS susceptibility (P = 3.7 x 10(-8), OR = 3.48, 95% CI = 2.23-5.43). MS risk at HLA-DQ beta 1 Phe9 was independent of HLA-DRB1*15:01 (P-Conditional = 1.5 x 10(-5), OR = 2.91, 95% CI = 1.79-4.72), while HLA-DRB1*15:01 was just significant when conditioned on HLA-DQ beta 1 Phe9 (P-Conditional = 0.037). Regarding a case-control analysis for NMOSD, HLA-DQA1*05:03 had a significant association with NMOSD (P = 1.5 x 10(-4), OR = 6.96, 95% CI = 2.55-19.0). Conclusions We identified HLA variants associated with the risk of MS and NMOSD. Our study contributes to the understanding of the genetic architecture of MS and NMOSD in the Japanese population.