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
{"title":"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","authors":"Daichi Shigemizu, Koya Fukunaga, Akiko Yamakawa, Mutsumi Suganuma, Kosuke Fujita, Tetsuaki Kimura, Ken Watanabe, Taisei Mushiroda, Takashi Sakurai, Shumpei Niida, Kouichi Ozaki","doi":"10.1038/s41514-023-00131-3","DOIUrl":null,"url":null,"abstract":"<p>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 <i>APOE</i> <span>\\({\\rm{\\varepsilon }}\\)</span>4–negative samples (odds ratio = 1.81, 95% confidence interval = 1.38–2.38, <i>P</i> = 2.03<span>\\({\\times 10}^{-5}\\)</span>). These alleles not only showed distinctive frequencies specific to East Asians but demonstrated a high degree of linkage disequilibrium in <i>APOE</i> <span>\\({\\rm{\\varepsilon }}\\)</span>4–negative samples (<i>r</i><sup>2</sup> = 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 <i>APOE</i> <span>\\({\\rm{\\varepsilon }}\\)</span>4–negative LOAD and CN samples. Lower diversity of TRA repertoires was associated with LOAD in <i>APOE</i> <span>\\({\\rm{\\varepsilon }}\\)</span>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.</p>","PeriodicalId":19334,"journal":{"name":"NPJ Aging and Mechanisms of Disease","volume":null,"pages":null},"PeriodicalIF":5.4000,"publicationDate":"2024-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"NPJ Aging and Mechanisms of Disease","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1038/s41514-023-00131-3","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"GERIATRICS & GERONTOLOGY","Score":null,"Total":0}
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.
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.