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. 2019 Aug 5;16(1):162.
doi: 10.1186/s12974-019-1551-z.

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

Kotaro Ogawa  1   2 , Tatsusada Okuno  2 , Kazuyoshi Hosomichi  3 , Akiko Hosokawa  2   4 , Jun Hirata  1   5 , Ken Suzuki  1 , Saori Sakaue  1 , Makoto Kinoshita  2 , Yoshihiro Asano  6 , Katsuichi Miyamoto  7 , Ituro Inoue  8 , Susumu Kusunoki  7 , Yukinori Okada  9   10 , Hideki Mochizuki  2
Affiliations

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

Kotaro Ogawa et al. J Neuroinflammation. .

Abstract

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 × 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).

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.

Keywords: HLA; Multiple sclerosis; Neuromyelitis optica spectrum disorder; Next-generation sequencing.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Multiple sclerosis risk-associated amino acid positions of the HLA genes in three-dimensional structure models. HLA amino acid positions with significant MS risk in HLA-DQ molecules. The protein structure is based on Protein Data Bank (PDB) entries 1jk8 and prepared using UCSF Chimera (version 1.7). Residues at the amino acid positions with significant MS risk is highlighted in red
Fig. 2
Fig. 2
Multiple sclerosis risk-associated amino acid positions of the HLA genes. Diamonds represent the –log10(P) of the amino acid positions of the tested HLA genes. Labeled red diamonds represent the –log10(P) values of the amino acid positions significantly associated with MS. The horizontal lines represent the association P value of HLA-DRB1*15:01. a No amino acid polymorphisms of HLA-B was significantly associated with MS. b No amino acid polymorphisms of HLA-DRB1 is significantly associated with MS. c The HLA-DQβ1 position 9 and 70 were associated with MS more significantly than HLA-DRB1*15:01
See this image and copyright information in PMC

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