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）是痴呆症的主要原因;其原因 越来越多的证据表明，其病因有很强的遗传因素。 仍然未知， 西班牙裔（遗传学） 欧洲、非洲和美洲原住民血统的混合）显示LOAD的患病率和发病率较高 比非西班牙裔白人;血统可以解释LOAD和其他疾病的不同频率， 种族群体。为此，我们的目标是阐明美洲原住民血统对负载的贡献。 以前的研究表明，祖先与许多复杂的疾病有关，尽管不是广泛的 在加载中学习我们显示了强有力的初步结果支持这一观察。 这项研究将招募秘鲁南部的两个土著美洲印第安人群体，克丘亚人和艾马拉人， 安第斯山脉与秘鲁神经科学研究所（IPN）的Nilton Custodio教授合作。这些 人群显示出独特的遗传和临床特征。1)他们显示出主要的美洲原住民血统， APOE-104等位基因（LOAD的主要遗传危险因素）的患病率非常低（<5%）。2)他们有惊人的低 心血管危险因素和疾病（CVRF/CVD）的频率，我们早些时候表明， CVRF/CVD负荷对LOAD的风险较高（Tosto等人，2015）。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LOAD的保护因素。此外，本发明还提供了一种方法， 本提案通过促进更多地包括以下内容，对PAR-19-070中的高优先级主题做出了响应 在健康差距和负载研究中代表性不足的少数群体。 我们的目标是在普诺和阿雷基帕分别招募约1,000名艾马拉人和盖丘亚人， 一个正在进行的约1,000名利马混血儿的队列（已经收集了500名广泛的人口统计资料， 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 评估、心血管分析和血液收集用于DNA提取和生物标志物。我们将利用 在哥伦比亚大学（Caribbean Hispanics， 墨西哥人）进行比较和荟萃分析。 我们的目标是：目的1）通过招募和收集生物样本并进行 对克丘亚人、艾马拉人和利马混血儿进行广泛的认知评估。目的2）阐明关联 秘鲁人的LOAD与已确定的风险因素（CVRF/CVD、血液生物标志物、生活方式因素）之间的关系， 哥伦比亚大学提供的其他西班牙裔人口。目的3）执行GWAS和混合物映射， 鉴定与LOAD相关的遗传和祖先基因座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