The HLA-DRB1*09:01-DQB1*03:03 haplotype is associated with the risk for late-onset Alzheimer’s disease in APOE $${{\varepsilon }}$$ 4–negative Japanese adults

IF 5.4 Q1 GERIATRICS & GERONTOLOGY
Daichi Shigemizu, Koya Fukunaga, Akiko Yamakawa, Mutsumi Suganuma, Kosuke Fujita, Tetsuaki Kimura, Ken Watanabe, Taisei Mushiroda, Takashi Sakurai, Shumpei Niida, Kouichi Ozaki
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引用次数: 0

Abstract

Late-onset Alzheimer’s disease (LOAD) is the most common cause of dementia among those older than 65 years. The onset of LOAD is influenced by neuroinflammation. The human leukocyte antigen (HLA) system is involved in regulating inflammatory responses. Numerous HLA alleles and their haplotypes have shown varying associations with LOAD in diverse populations, yet their impact on the Japanese population remains to be elucidated. Here, we conducted a comprehensive investigation into the associations between LOAD and HLA alleles within the Japanese population. Using whole-genome sequencing (WGS) data from 303 LOAD patients and 1717 cognitively normal (CN) controls, we identified four-digit HLA class I alleles (A, B, and C) and class II alleles (DRB1, DQB1, and DPB1). We found a significant association between the HLA-DRB1*09:01-DQB1*03:03 haplotype and LOAD risk in APOE \({\rm{\varepsilon }}\)4–negative samples (odds ratio = 1.81, 95% confidence interval = 1.38–2.38, P = 2.03\({\times 10}^{-5}\)). These alleles not only showed distinctive frequencies specific to East Asians but demonstrated a high degree of linkage disequilibrium in APOE \({\rm{\varepsilon }}\)4–negative samples (r2 = 0.88). Because HLA class II molecules interact with T-cell receptors (TCRs), we explored potential disparities in the diversities of TCR α chain (TRA) and β chain (TRB) repertoires between APOE \({\rm{\varepsilon }}\)4–negative LOAD and CN samples. Lower diversity of TRA repertoires was associated with LOAD in APOE \({\rm{\varepsilon }}\)4-negative samples, irrespective of the HLA DRB1*09:01-DQB1*03:03 haplotype. Our study enhances the understanding of the etiology of LOAD in the Japanese population and provides new insights into the underlying mechanisms of its pathogenesis.

Abstract Image

HLA-DRB1*09:01-DQB1*03:03 单倍型与 APOE $${{{varepsilon }}$ 4 阴性日本成年人罹患晚发性阿尔茨海默病的风险有关
晚发性阿尔茨海默病(LOAD)是 65 岁以上人群中最常见的痴呆症病因。阿尔茨海默病的发病受神经炎症的影响。人类白细胞抗原(HLA)系统参与调节炎症反应。在不同人群中,许多 HLA 等位基因及其单倍型与 LOAD 有着不同的关联,但它们对日本人群的影响仍有待阐明。在此,我们对日本人群中 LOAD 与 HLA 等位基因之间的关系进行了全面调查。利用 303 名 LOAD 患者和 1717 名认知正常(CN)对照的全基因组测序(WGS)数据,我们确定了四位数的 HLA I 类等位基因(A、B 和 C)和 II 类等位基因(DRB1、DQB1 和 DPB1)。我们发现,在APOE({\rm{\varepsilon }}\)4阴性样本中,HLA-DRB1*09:01-DQB1*03:03单倍型与LOAD风险之间存在明显关联(几率比=1.81,95%置信区间=1.38-2.38,P=2.03({\times 10}^{-5}\))。这些等位基因不仅显示出东亚人特有的频率,而且在 APOE ({\rm{\varepsilon}}\)4 阴性样本中显示出高度的连锁不平衡(r2 = 0.88)。由于HLA II类分子与T细胞受体(TCRs)相互作用,我们探讨了APOE ({\rm{\varepsilon }})4阴性LOAD样本和CN样本之间TCR α链(TRA)和β链(TRB)复合物多样性的潜在差异。无论HLA DRB1*09:01-DQB1*03:03单倍型如何,APOE({\rm{\varepsilon}})4阴性样本中较低的TRA序列多样性与LOAD相关。我们的研究加深了对日本人群中 LOAD 病因的了解,并对其发病机制提供了新的见解。
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来源期刊
NPJ Aging and Mechanisms of Disease
NPJ Aging and Mechanisms of Disease Medicine-Geriatrics and Gerontology
自引率
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0
审稿时长
8 weeks
期刊介绍: npj Aging and Mechanisms of Disease is an online open access journal that provides a forum for the world’s most important research in the fields of aging and aging-related disease. The journal publishes papers from all relevant disciplines, encouraging those that shed light on the mechanisms behind aging and the associated diseases. The journal’s scope includes, but is not restricted to, the following areas (not listed in order of preference): • cellular and molecular mechanisms of aging and aging-related diseases • interventions to affect the process of aging and longevity • homeostatic regulation and aging • age-associated complications • translational research into prevention and treatment of aging-related diseases • mechanistic bases for epidemiological aspects of aging-related disease.
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