Next-generation sequencing identifies contribution of both class I and II HLA genes on susceptibility of multiple sclerosis in Japanese
ECTRIMS Online Library. Ogawa K. 09/13/19; 278672; P1633
Kotaro Ogawa
Kotaro Ogawa
Contributions
Abstract

Abstract: P1633

Type: Poster Sessions

Abstract Category: Poster Session 3

K. Ogawa1,2, T. Okuno1, K. Hosomichi3, A. Hosokawa1,4, M. Kinoshita1, K. Miyamoto5, I. Inoue6, S. Kusunoki5, Y. Okada2, H. Mochizuki1

1Department of Neurology, 2Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, 3Department of Bioinformatics and Genomics, Graduate School of Advanced Preventive Medical Sciences, Kanazawa University, Kanazawa, 4Department of Neurology, Suita Municipal Hospital, Suita, 5Department of Neurology, Kindai University Faculty of Medicine, Osaka-Sayama, 6Division of Human Genetics, National Institute of Genetics, Mishima, Japan

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. We conducted a case-control analysis of 16 HLA genes.
Objectives: Previous Japanese studies reported the HLA alleles associated with MS(HLA-DRB1*15:01, HLA-DRB1*04:05, HLA-DPB1*03:01) and NMOSD(HLA-DRB1*16:02, HLA-DPB1*05:01). However, these studies used sequence-specific oligonucleotide hybridization, and only two classical HLA genes (HLA-DRB1, HLD-DPB1) were
genotyped. Thus, the classical and non-classical HLA genes affecting MS and NMOSD risk in Japanese people have not been studied in detail. In this research, we conducted NGS-based genotyping of 16 HLA genes with 4-digit-level allele resolution.
Aims: To explore the 4-digit HLA allele association with the susceptibility of MS and NMOSD in the Japanese population.
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 HLA-DQβ1 Phe9 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 was identified to be significantly associated with NMOSD susceptibility (P = 1.5 × 10−4, OR = 6.96, 95%CI = 2.55-19.0).
Conclusions: We newly identified the risk HLA alleles associated with MS (HLA-B*15:01,
HLA-B*39:01) and NMOSD risk (HLA-DQA1*05:03). We also identified that the amino acid polymorphisms at HLA-DQβ1 are more strongly associated with MS susceptibility than HLA alleles.
Disclosure: The authors declare that no conflicts exist.

Abstract: P1633

Type: Poster Sessions

Abstract Category: Poster Session 3

K. Ogawa1,2, T. Okuno1, K. Hosomichi3, A. Hosokawa1,4, M. Kinoshita1, K. Miyamoto5, I. Inoue6, S. Kusunoki5, Y. Okada2, H. Mochizuki1

1Department of Neurology, 2Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, 3Department of Bioinformatics and Genomics, Graduate School of Advanced Preventive Medical Sciences, Kanazawa University, Kanazawa, 4Department of Neurology, Suita Municipal Hospital, Suita, 5Department of Neurology, Kindai University Faculty of Medicine, Osaka-Sayama, 6Division of Human Genetics, National Institute of Genetics, Mishima, Japan

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. We conducted a case-control analysis of 16 HLA genes.
Objectives: Previous Japanese studies reported the HLA alleles associated with MS(HLA-DRB1*15:01, HLA-DRB1*04:05, HLA-DPB1*03:01) and NMOSD(HLA-DRB1*16:02, HLA-DPB1*05:01). However, these studies used sequence-specific oligonucleotide hybridization, and only two classical HLA genes (HLA-DRB1, HLD-DPB1) were
genotyped. Thus, the classical and non-classical HLA genes affecting MS and NMOSD risk in Japanese people have not been studied in detail. In this research, we conducted NGS-based genotyping of 16 HLA genes with 4-digit-level allele resolution.
Aims: To explore the 4-digit HLA allele association with the susceptibility of MS and NMOSD in the Japanese population.
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 HLA-DQβ1 Phe9 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 was identified to be significantly associated with NMOSD susceptibility (P = 1.5 × 10−4, OR = 6.96, 95%CI = 2.55-19.0).
Conclusions: We newly identified the risk HLA alleles associated with MS (HLA-B*15:01,
HLA-B*39:01) and NMOSD risk (HLA-DQA1*05:03). We also identified that the amino acid polymorphisms at HLA-DQβ1 are more strongly associated with MS susceptibility than HLA alleles.
Disclosure: The authors declare that no conflicts exist.

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