Next-generation sequencing identifies contribution of both class I and II HLA genes on susceptibility of multiple sclerosis in Japanese
Next-generation sequencing identifies contribution of both class I and II HLA genes on susceptibility of multiple sclerosis in Japanese
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DOI：
10.1186/s12974-019-1551-z
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发表时间：
2019-08-05
影响因子：
9.3
通讯作者：
Mochizuki, Hideki
中科院分区：
文献类型：
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作者：
Ogawa, Kotaro;Okuno, Tatsusada;Mochizuki, Hideki
背景
在日本人群中，与多发性硬化症（MS）和视神经脊髓炎谱系疾病（NMOSD）风险相关的经典和非经典人类白细胞抗原（HLA）基因谱尚未得到详细研究。我们对经典和非经典HLA基因进行了病例对照分析。
方法
我们使用基于新一代测序（NGS）的HLA基因分型方法，对45例MS患者、31例NMOSD患者和429名健康对照进行风险定位。我们使用逻辑回归分析和费舍尔精确检验评估了HLA变异与MS和NMOSD风险的关联。
结果
我们证实HLA - DRB1*15:01与MS的关联性最强（P = 2.1×10⁻⁵；优势比[OR] = 3.44，95%置信区间[95%CI] = 1.95 - 6.07）。逐步条件分析确定HLA - DRB1*04:05、HLA - B*39:01和HLA - B*15:01与独立的MS易感性相关（P - 条件 < 8.3×10⁻⁴）。关于HLA基因中的氨基酸多态性，我们发现HLA - DQβ1第9位的苯丙氨酸对MS易感性影响最大（P = 3.7×10⁻⁸，OR = 3.48，95%CI = 2.23 - 5.43）。HLA - DQβ1 Phe9的MS风险独立于HLA - DRB1*15:01（P - 条件 = 1.5×10⁻⁵，OR = 2.91，95%CI = 1.79 - 4.72），而当以HLA - DQβ1 Phe9为条件时，HLA - DRB1*15:01才有显著意义（P - 条件 = 0.037）。关于NMOSD的病例对照分析，HLA - DQA1*05:03与NMOSD有显著关联（P = 1.5×10⁻⁴，OR = 6.96，95%CI = 2.55 - 19.0）。
结论
我们确定了与MS和NMOSD风险相关的HLA变异。我们的研究有助于理解日本人群中MS和NMOSD的遗传结构。
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.