Alexander M Kulminski, Ethan Jain-Washburn, Ian Philipp, Yury Loika, Elena Loiko, Irina Culminskaya
{"title":"TOMM40 和 APOC1 变体可区分 APOE ε4 等位基因对不同性别、年龄和血统的阿尔茨海默病风险的影响。","authors":"Alexander M Kulminski, Ethan Jain-Washburn, Ian Philipp, Yury Loika, Elena Loiko, Irina Culminskaya","doi":"10.1002/dad2.12600","DOIUrl":null,"url":null,"abstract":"<p><strong>Introduction: </strong>The variability in apolipoprotein E (<i>APOE</i>) <i>ε</i>4-attributed susceptibility to Alzheimer's disease (AD) across ancestries, sexes, and ages may stem from the modulating effects of other genetic variants.</p><p><strong>Methods: </strong>We examined associations of compound genotypes (CompGs) comprising the <i>ε</i>4-encoding rs429358, <i>TOMM40</i> rs2075650, and <i>APOC1</i> rs12721046 polymorphisms with AD in White (7181/16,356 AD-affected/unaffected), Hispanic/Latino (2305/2921), and Black American (547/1753) participants across sexes and ages.</p><p><strong>Results: </strong>The absence and presence of the rs2075650 and/or rs12721046 minor alleles in the <i>ε</i>4-bearing CompGs define lower- and higher-AD-risk profiles, respectively, in White participants. They differentially impact AD risks in men and women of different ancestries, exhibiting an increasing, decreasing, flat, and nonlinear-with lower risks at ages younger than 65/70 years and older than 85 years compared to the ages in between-patterns across ages.</p><p><strong>Discussion: </strong>The <i>ε</i>4-bearing CompGs have a potential to differentiate biological mechanisms of sex-, age-, and ancestry-specific AD risks and serve as AD biomarkers.</p><p><strong>Highlights: </strong>Younger White women carrying the lower-risk (LR) CompG are at small risk of AD.Black carriers of the LR CompG are at negligible risk of AD at 85 years and older.The higher-risk (HR) CompGs confer high AD risk in Whites and Blacks at 70 to 85 years.AD risk decreases with age for Hispanic/Lation women carrying the HR CompGs.Hispanic/Lation carriers of the LR CompG but not HR CompGs have higher AD risk than Blacks.</p>","PeriodicalId":53226,"journal":{"name":"Alzheimer''s and Dementia: Diagnosis, Assessment and Disease Monitoring","volume":"16 2","pages":"e12600"},"PeriodicalIF":4.0000,"publicationDate":"2024-06-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11193136/pdf/","citationCount":"0","resultStr":"{\"title\":\"<i>TOMM40</i> and <i>APOC1</i> variants differentiate the impacts of the <i>APOE ε</i>4 allele on Alzheimer's disease risk across sexes, ages, and ancestries.\",\"authors\":\"Alexander M Kulminski, Ethan Jain-Washburn, Ian Philipp, Yury Loika, Elena Loiko, Irina Culminskaya\",\"doi\":\"10.1002/dad2.12600\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Introduction: </strong>The variability in apolipoprotein E (<i>APOE</i>) <i>ε</i>4-attributed susceptibility to Alzheimer's disease (AD) across ancestries, sexes, and ages may stem from the modulating effects of other genetic variants.</p><p><strong>Methods: </strong>We examined associations of compound genotypes (CompGs) comprising the <i>ε</i>4-encoding rs429358, <i>TOMM40</i> rs2075650, and <i>APOC1</i> rs12721046 polymorphisms with AD in White (7181/16,356 AD-affected/unaffected), Hispanic/Latino (2305/2921), and Black American (547/1753) participants across sexes and ages.</p><p><strong>Results: </strong>The absence and presence of the rs2075650 and/or rs12721046 minor alleles in the <i>ε</i>4-bearing CompGs define lower- and higher-AD-risk profiles, respectively, in White participants. They differentially impact AD risks in men and women of different ancestries, exhibiting an increasing, decreasing, flat, and nonlinear-with lower risks at ages younger than 65/70 years and older than 85 years compared to the ages in between-patterns across ages.</p><p><strong>Discussion: </strong>The <i>ε</i>4-bearing CompGs have a potential to differentiate biological mechanisms of sex-, age-, and ancestry-specific AD risks and serve as AD biomarkers.</p><p><strong>Highlights: </strong>Younger White women carrying the lower-risk (LR) CompG are at small risk of AD.Black carriers of the LR CompG are at negligible risk of AD at 85 years and older.The higher-risk (HR) CompGs confer high AD risk in Whites and Blacks at 70 to 85 years.AD risk decreases with age for Hispanic/Lation women carrying the HR CompGs.Hispanic/Lation carriers of the LR CompG but not HR CompGs have higher AD risk than Blacks.</p>\",\"PeriodicalId\":53226,\"journal\":{\"name\":\"Alzheimer''s and Dementia: Diagnosis, Assessment and Disease Monitoring\",\"volume\":\"16 2\",\"pages\":\"e12600\"},\"PeriodicalIF\":4.0000,\"publicationDate\":\"2024-06-22\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11193136/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Alzheimer''s and Dementia: Diagnosis, Assessment and Disease Monitoring\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1002/dad2.12600\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/4/1 0:00:00\",\"PubModel\":\"eCollection\",\"JCR\":\"Q1\",\"JCRName\":\"CLINICAL NEUROLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Alzheimer''s and Dementia: Diagnosis, Assessment and Disease Monitoring","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1002/dad2.12600","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/4/1 0:00:00","PubModel":"eCollection","JCR":"Q1","JCRName":"CLINICAL NEUROLOGY","Score":null,"Total":0}
引用次数: 0
摘要
导言：不同血统、性别和年龄的载脂蛋白 E（APOE）ε4 对阿尔茨海默病（AD）易感性的差异可能源于其他遗传变异的调节作用：我们研究了白人（7181/16356 名受 AD 影响/未受 AD 影响者）、西班牙裔/拉美裔（2305/2921 名）和美国黑人（547/1753 名）参与者中不同性别和年龄的ε4编码 rs429358、TOMM40 rs2075650 和 APOC1 rs12721046 多态性组成的复合基因型（CompGs）与 AD 的关联：在白人参与者中，ε4-轴承CompGs中rs2075650和/或rs12721046小等位基因的缺失和存在分别定义了较低和较高的AD风险特征。它们对不同血统的男性和女性的AD风险有不同的影响，在不同年龄段表现出递增、递减、持平和非线性--与介于两者之间的年龄相比，年龄小于65/70岁和年龄大于85岁的风险较低：讨论：携带ε4的CompGs有可能区分性别、年龄和祖先特异性AD风险的生物学机制，并可作为AD生物标志物：携带低风险（LR）CompGs的年轻白人女性罹患AD的风险较小；携带LR CompGs的黑人在85岁及以上时罹患AD的风险可忽略不计；携带高风险（HR）CompGs的白人和黑人在70至85岁时罹患AD的风险较高；携带HR CompGs的西班牙裔/拉丁裔女性罹患AD的风险随年龄增长而降低；携带LR CompGs而非HR CompGs的西班牙裔/拉丁裔女性罹患AD的风险高于黑人。
TOMM40 and APOC1 variants differentiate the impacts of the APOE ε4 allele on Alzheimer's disease risk across sexes, ages, and ancestries.
Introduction: The variability in apolipoprotein E (APOE) ε4-attributed susceptibility to Alzheimer's disease (AD) across ancestries, sexes, and ages may stem from the modulating effects of other genetic variants.
Methods: We examined associations of compound genotypes (CompGs) comprising the ε4-encoding rs429358, TOMM40 rs2075650, and APOC1 rs12721046 polymorphisms with AD in White (7181/16,356 AD-affected/unaffected), Hispanic/Latino (2305/2921), and Black American (547/1753) participants across sexes and ages.
Results: The absence and presence of the rs2075650 and/or rs12721046 minor alleles in the ε4-bearing CompGs define lower- and higher-AD-risk profiles, respectively, in White participants. They differentially impact AD risks in men and women of different ancestries, exhibiting an increasing, decreasing, flat, and nonlinear-with lower risks at ages younger than 65/70 years and older than 85 years compared to the ages in between-patterns across ages.
Discussion: The ε4-bearing CompGs have a potential to differentiate biological mechanisms of sex-, age-, and ancestry-specific AD risks and serve as AD biomarkers.
Highlights: Younger White women carrying the lower-risk (LR) CompG are at small risk of AD.Black carriers of the LR CompG are at negligible risk of AD at 85 years and older.The higher-risk (HR) CompGs confer high AD risk in Whites and Blacks at 70 to 85 years.AD risk decreases with age for Hispanic/Lation women carrying the HR CompGs.Hispanic/Lation carriers of the LR CompG but not HR CompGs have higher AD risk than Blacks.
期刊介绍：
Alzheimer''s & Dementia: Diagnosis, Assessment & Disease Monitoring (DADM) is an open access, peer-reviewed, journal from the Alzheimer''s Association® that will publish new research that reports the discovery, development and validation of instruments, technologies, algorithms, and innovative processes. Papers will cover a range of topics interested in the early and accurate detection of individuals with memory complaints and/or among asymptomatic individuals at elevated risk for various forms of memory disorders. The expectation for published papers will be to translate fundamental knowledge about the neurobiology of the disease into practical reports that describe both the conceptual and methodological aspects of the submitted scientific inquiry. Published topics will explore the development of biomarkers, surrogate markers, and conceptual/methodological challenges. Publication priority will be given to papers that 1) describe putative surrogate markers that accurately track disease progression, 2) biomarkers that fulfill international regulatory requirements, 3) reports from large, well-characterized population-based cohorts that comprise the heterogeneity and diversity of asymptomatic individuals and 4) algorithmic development that considers multi-marker arrays (e.g., integrated-omics, genetics, biofluids, imaging, etc.) and advanced computational analytics and technologies.
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号
