Genetic and environmental risk factors in mestizos and indigenous populations of Peru: the role of Native component in Alzheimer's disease

秘鲁混血人和土著居民的遗传和环境风险因素：本土成分在阿尔茨海默病中的作用

• 批准号: 10228327
• 负责人: Giuseppe Tosto
• 金额: $ 107.07万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-10 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10228327
• 关键词: African American; Age; Alleles; Alzheimer' s Disease; Amerindian; Biological; Biological Markers; Blood; Cardiovascular system; Caribbean Hispanic; Censuses; Clinical; Clinical assessments; Cognitive; Cohort Studies; Collaborations; Collection; Communities; Complex; DNA; Data; Dementia; Diagnosis; Diet; Disease; Education; Elderly; Environmental Risk Factor; Ethnic group; Etiology; European; Fostering; Frequencies; Genes; Genetic; Genetic Risk; Genetic study; Grant; High Prevalence; Hispanics; Hypertension; Impaired cognition; Impairment; Incidence; Indigenous; Individual; Late Onset Alzheimer Disease; Life Style; Location; Low Prevalence; Meta-Analysis; Methods; Mexican; Native Americans; Native-Born; Neurocognitive; Neuropsychology; Not Hispanic or Latino; Peru; Peruvian; Physical activity; Population; Population Study; Prevalence; Quechua; Randomized; Research; Research Priority; Risk Factors; Role; Rural; Sampling; Surveys; Testing; Underrepresented Minority; Universities; Variant; admixture mapping; apolipoprotein E-4; biomarker panel; cardiovascular risk factor; cognitive testing; cohort; demographics; diabetic; experience; genetic risk factor; genome wide association study; health data; health disparity; high risk; illiterate; improved; interest; lifestyle data; lifestyle factors; mild cognitive impairment; non-genetic; pleiotropism; population based; protective factors; recruit; research clinical testing; screening; sociodemographics; tool

ABSTRACT Late-onset Alzheimer's disease (LOAD) is the main cause of dementia; its causes accumulating evidence supports a strong genetic component underpinning its etiology. are still unknown but Hispanics (genetically admixed of European, African and Native American ancestry) show higher prevalence and incidence of LOAD than in non-Hispanic Whites; ancestry may explain the different frequencies of LOAD and other diseases across ethnic groups. To this end, we aim to elucidate the contribution of Native American ancestry to LOAD. Previous studies showed that ancestry is associated with many complex diseases although not extensively studied in LOAD. We show strong preliminary results supporting this observation. This study will recruit two Indigenous Amerindian populations, the Quechuas and Aymaras, in southern Peruvian Andes in collaboration with Prof. Nilton Custodio at the Instituto Peruano de Neurociencia (IPN). These populations show unique genetic and clinical features. 1) They show predominant Native American ancestry and very low prevalence (<5%) of APOE-ɛ4 allele (LOAD's main genetic risk factors). 2) They have surprisingly low frequencies of cardiovascular risk factors and diseases (CVRF/CVD) and we earlier showed that those with high burden of CVRF/CVD are at high risk for LOAD (Tosto et al. 2015). These features provide an unprecedented opportunity to identify genetic and non-genetic risk as well as protective factors for LOAD. In addition, this proposal responds to high-priority topic of interest for PAR-19-070 by fostering increased inclusion of underrepresented minorities in studies of health disparities and LOAD. We aim to recruit ~1,000 Aymara and Quechua in Puno and Arequipa, respectively, in addition to further expand an ongoing cohort of ~1,000 Lima mestizos (500 have already been collected with extensive demographic, clinical assessment and cognitive data). We will conduct extensive cognitive, sociodemographic and lifestyle assessment, cardiovascular profiling and blood collection for DNA extraction and biomarkers. We will leverage ongoing cohort studies of other Hispanic populations available at Columbia University (Caribbean Hispanics, Mexicans) for comparison and meta-analysis. We aim to: AIM 1) Identify cases of MCI and LOAD by recruiting and collecting biological samples and performing extensive cognitive assessment in Quechuas, Aymaras and Lima mestizos. AIM 2) Elucidate the association between LOAD and established risk factors (CVRF/CVD, blood biomarkers, lifestyle factors) in Peruvian and other Hispanic populations available at Columbia University. AIM 3) Perform GWAS and admixture mapping to identify genetic and ancestral loci associated with LOAD and their interplay with cardiovascular conditions, biomarkers and lifestyle factors.

摘要 迟发性阿尔茨海默病(LOAD)是痴呆的主要原因；其原因 越来越多的证据支持其病因学的强大遗传成分。 仍然是未知的，但 拉美裔美国人(基因上 混杂着欧洲人、非洲人和美洲土著血统)显示出更高的负荷率和发病率 与非西班牙裔白人相比；祖先可能解释了不同的负载和其他疾病的频率 种族群体。为此，我们的目标是阐明美洲原住民祖先对Load的贡献。 以前的研究表明，祖先与许多复杂的疾病有关，尽管并不广泛 在负荷中学习。我们展示了支持这一观察的强有力的初步结果。 这项研究将招募秘鲁南部的两个土著美洲印第安人，Quechuas和Aymaras人 与佩鲁亚诺·德·神经科学研究所(IPN)的尼尔顿·库斯托迪奥教授合作。这些 人群表现出独特的遗传和临床特征。1)他们表现出主要的美洲原住民血统和 载脂蛋白E-ɛ4等位基因(LOAD的主要遗传危险因素)的患病率非常低(&lt；5%)。2)他们的支持率低得出奇 心血管危险因素和疾病(CVRF/CVD)的频率，我们早先发现，那些高风险因素和疾病 CVRF/CVD的负担是负荷的高风险(Tosto等人2015年)。这些功能提供了前所未有的 有机会确定遗传和非遗传风险以及负荷的保护因素。此外, 该提案响应了PAR-19-070感兴趣的高优先级主题，因为它促进了 在关于健康差距和负荷的研究中，少数群体的代表性不足。 我们的目标是在普诺和阿雷基帕分别招聘约1,000名艾马拉和盖丘亚人，并进一步扩大 正在进行的约1,000名利马混血儿(已收集到500名利马混血儿， 临床评估和认知数据)。我们将进行广泛的认知、社会人口和生活方式 用于DNA提取和生物标记物的评估、心血管状况分析和血液采集。我们将利用 哥伦比亚大学正在对其他拉美裔人口进行队列研究(加勒比海拉美裔， 墨西哥人)进行比较和荟萃分析。 我们的目标是：1)通过招募和收集生物样本并执行以下操作来识别MCI和LOAD病例 在Quechuas、Aymaras和Lima Mestizos进行广泛的认知评估。目的2)阐明两者之间的联系 在秘鲁和澳大利亚，负荷与已确定的危险因素(CVRF/CVD、血液生物标记物、生活方式因素)之间的关系 其他拉美裔人口可在哥伦比亚大学学习。目标3)执行GWAS和混合体映射以 确定与负荷相关的遗传和祖先基因及其与心血管疾病的相互作用， 生物标志物和生活方式因素。

项目成果

A benchmark study on current GWAS models in admixed populations.

• DOI: 10.1093/bib/bbad437
• 发表时间: 2023-11-22
• 期刊: Briefings in bioinformatics
• 影响因子: 9.5