Project 1: Longitudinal

项目1：遗传关联和比较队列研究 摘要 心脏代谢性疾病(CMD)在整个生命周期内发展，并由一系列复杂的相互作用引起 包括环境、行为选择、社会人口和社会经济因素，与 遗传易感性图谱。非洲有一个高度多样化的民族群体，每个民族都有自己独特的 随着时间的推移而演变的文化习俗、规范和独特的环境。因此，研究它是很重要的 多个群体和AWI-Gen的优势之一是我们在西非-东部-南非的存在，在农村和 城市环境正在经历复杂的健康和人口结构转型。AWI-Gen第一阶段是一个人口- 基于对约12,000名个体的横断面研究，以检查遗传和环境因素对CMD的影响； AWI-Gen第二阶段的续签申请将以这些基线为基础，并建立纵向队列 在阿金库尔、迪克盖尔、内罗毕、纳诺罗、纳夫隆戈和索韦托；在农村和 南非、肯尼亚、布基纳法索和加纳的城市。这将使评估遗传关联成为可能， 撒哈拉以南非洲人群的遗传易感性和基因-环境(G-E)相互作用， 特别要注意的是，在5年的时间里，研究与心脏代谢性疾病风险轨迹的关系。这将是 是撒哈拉以南非洲第一个解决在理解上的严重不足的多种族研究 当过渡的力量推动心脏代谢状况上升的时候。我们期待着调查结果 在我们的大陆背景下高度相关，并更广泛地贡献见解。这个项目 概述了我们对所有AWI-Gen参与者进行第二阶段数据和样本收集的计划。自从这项研究以来 嵌套在INDEPTH网络和健康发展路径的既定人群队列中 作为研究单位(DPHRU)，我们预计最初登记的参与者将有超过70%的后续行动。这 将提供一个机会来检查CMD相关生物标志物(包括血压、血脂)的变化 概况、空腹血糖和胰岛素水平)、身体成分(包括内脏脂肪和皮下脂肪) 以及与健康相关的行为(吸烟、饮酒和体育活动)。我们还将拥有 关于最初队列中发生的所有死亡及其可能原因的综合数据，以及 因此，在非洲环境中制定包含基因组的风险预测模型方面具有独特的地位 了解以及已建立的风险标记。全基因组SNP阵列数据将从阶段开始提供 1，并用于关联和G-E相互作用研究。从欧洲和欧洲转移的风险基因座的复制 对非洲人来说，其他人口将创造独特的潜力，利用较低水平的连锁不平衡 在非洲基因组中，用于将这些基因座精细定位到病因基因和变异体，并将指导精细定位和 候选区域的功能分析，包括区域捕获下一代测序。我们还将 对异常的CMD表型进行深入分析，例如具有持续的“代谢健康”的个体 肥胖“(MHO)表型和潜在的低频高影响等位基因。我们的总体目标是建立 基因组对心脏代谢性疾病的贡献和多重相互作用时的风险 在背景传染病流行较高的情况下，过渡正在推动 CMD在整个非洲大陆的升级。鉴于预期寿命的增加，其他问题和 将包括与衰老和认知相关的测量，以与NIH支持的健康相协调 非洲的老龄化：正在阿金库尔进行的INDEPTH社区纵向研究(HAALSI)项目。这个 AWI-Gen阶段2的方法将需要加强社区参与，我们设想了一个有效的 向个人和社区反馈结果的策略。

Project 1: Genetic association and comparative cohort studies Abstract Cardiometabolic diseases (CMD) develop across the lifespan and result from a complex set of interactions that include the environment, behavioral choices, socio-demographic and socio-economic factors, interacting with a genetic susceptibility profile. Africa has a highly diverse group of ethnic populations each with their specific cultural practices, norms and unique environments that have evolved over time. It is therefore important to study multiple groups and one of the strengths of AWI-Gen is our presence in west-east-south Africa, in both rural and urban settings undergoing complex health and demographic transitions. AWI-Gen Phase 1 was a population- based cross-sectional study of ~12,000 individuals to examine genetic and environmental contributions to CMD; the renewal application for AWI-Gen Phase 2 will build from these baselines and establish longitudinal cohorts in Agincourt, Dikgale, Nairobi, Nanoro, Navrongo and Soweto; well-established research settings in rural and urban South Africa, Kenya, Burkina Faso and Ghana. This will make it possible to evaluate genetic associations, genetic susceptibility and gene-environment (G-E) interactions in a diversity of sub-Saharan African populations, notably to look at associations with risk trajectories for cardiometabolic disease over a 5-year period. This will be the first multi-ethnic study in sub-Saharan Africa to address a critical shortfall in understanding at a time when the force of transitions is driving the rise in cardiometabolic conditions. We expect findings to be highly relevant in our continental context and contribute insights far more widely. This project outlines our plans for a second phase of data and sample collection on all AWI-Gen participants. Since the study is nested in established population cohorts of the INDEPTH Network and Developmental Pathways to Health Research Unit (DPHRU), we anticipate a greater than 70% follow-up of the original enrolled participants. This will provide an opportunity to examine changes in CMD relevant biomarkers (including blood pressure, lipid profiles, fasting blood glucose and insulin levels), body composition (including visceral and subcutaneous fat) and health-related behaviors (smoking, alcohol consumption and physical activity). We will also have comprehensive data on all deaths occurring and their probable cause among those in the original cohorts, and thus be in a unique position to formulate risk prediction models in African settings that incorporate genomic understanding as well as established risk markers. Genome-wide SNP array data will be available from Phase 1 and used for association and G-E interaction studies. Replication of risk loci which transfer from European and other populations to Africans will create a unique potential to harness the lower levels of linkage disequilibrium in African genomes for fine mapping of these loci to causal genes and variants, and will guide fine mapping and functional analysis in candidate regions, including regional capture next generation sequencing. We will also pursue in-depth analysis of outlier CMD phenotypes such as individuals with a persistent “Metabolically Healthy Obese” (MHO) phenotype and potential low frequency high impact alleles. Our overall goal is to establish the genomic contribution to cardiometabolic diseases and risk at a time when multiple interacting transitions, in the presence of high background infectious disease prevalence, are driving a rapid escalation in CMD across the African continent. Given rising life expectancy, additional questions and measurements related to aging and cognition will be included so as to harmonize with the NIH-supported Health & Aging in Africa: Longitudinal Studies of INDEPTH Communities (HAALSI) project underway at Agincourt. The approach for AWI-Gen Phase 2 will require enhanced community engagement and we envisage an effective strategy for feedback of results to individuals and communities.