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

Kotaro Ogawa,Akiko Hosokawa,Ken Suzuki,Kazuyoshi Hosomichi,Hideki Mochizuki,Tatsusada Okuno,Jun Hirata,Saori Sakaue,Yukinori Okada,Ituro Inoue,Yoshihiro Asano,Makoto Kinoshita,Susumu Kusunoki,Katsuichi Miyamoto

doi:10.1186/s12974-019-1551-z

Abstract

BackgroundThe 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.MethodsWe 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.ResultsWe confirmed that HLA-DRB1*15:01 showed the strongest association with MS (P = 2.1 × 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 (PConditional < 8.3 × 10−4). With respect to amino acid polymorphisms in HLA genes, we found that phenylalanine at HLA-DQβ1 position 9 had the strongest effect on MS susceptibility (P = 3.7 × 10−8, OR = 3.48, 95% CI = 2.23–5.43). MS risk at HLA-DQβ1 Phe9 was independent of HLA-DRB1*15:01 (PConditional = 1.5 × 10−5, OR = 2.91, 95% CI = 1.79–4.72), while HLA-DRB1*15:01 was just significant when conditioned on HLA-DQβ1 Phe9 (PConditional = 0.037). Regarding a case-control analysis for NMOSD, HLA-DQA1*05:03 had a significant association with NMOSD (P = 1.5 × 10−4, OR = 6.96, 95% CI = 2.55–19.0).ConclusionsWe 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.

Highlights

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
Associations of HLA alleles with MS susceptibility We evaluated the associations of the 4-digit HLA alleles with MS risk and found the most significant association to be with HLA-DRB1*15:01 (P = 2.1 × 10−5, odds ratio [OR] = 3.44, 95% confidence interval [95% CI] = 1.95– 6.07; Table 2)
HLA-DQB1*06:02, which was in linkage disequilibrium with HLA-DRB1*15:01 (r2 = 0.94 in the controls), was significantly associated with MS (P = 3.0 × 10−5, OR = 3.45, 95% CI = 1.93–6.17; Table 2)

Summary

Introduction

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. Ogawa et al Journal of Neuroinflammation (2019) 16:162 and class I HLA genes independently confer susceptibility to MS [14] These researchers used an HLA imputation method, which computationally imputed HLA variants from single nucleotide polymorphisms (SNP) genotype data obtained from GWAS. They analyzed MS associations with eight classical HLA genes and found HLA-A*02:01 had an independent protective effect on MS. In 2016, Nakamura et al conducted HLA analysis and found that HLADRB1*04:05 and HLA-DRB1*15:01 were risk factors for MS in Japanese individuals [17]. They found that living at higher latitude and HLA-DRB1*04:05 independently affect the severity of MS

Methods

Results

Discussion

Conclusion