Unravelling the Role of Epigenetics and Cytokines in Type 2 Diabetes among African-ancestry Populations

揭示表观遗传学和细胞因子在非洲血统人群 2 型糖尿病中的作用

• 批准号: 10709197
• 负责人: Karlijn Anna Catharina Meeks
• 金额: --
• 依托单位: NATIONAL HUMAN GENOME RESEARCH INST
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10709197
• 关键词: Affect; Africa; Africa South of the Sahara; African; African American population; African ancestry; Alcohol consumption; American; Back; Binding; Biology; Body mass index; Cardiometabolic Disease; Cell physiology; Clinical; Complement; Complex; CpG dinucleotide; DNA; DNA Methylation; Data; Development; Diabetes Mellitus; Disease; Educational workshop; Environment; Environmental Risk Factor; Epidemiology; Epigenetic Process; Ethnic Origin; Etiology; Europe; European; European ancestry; Family Study; Gene Expression; Genetic; Genetic Variation; Genetic study; Genome; Genomics; Genotype; Goals; High Prevalence; Immunoassay; Individual; Least-Squares Analysis; Life Style; Maps; Measures; Mediating; Mediation; Mediator; Medicine; Mendelian randomization; Mentors; Methods; Migrant; Multiomic Data; National Human Genome Research Institute; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Observational Study; Outcome; Pathogenesis; Pathway interactions; Phase; Population; Population Heterogeneity; Prevalence; Prevention; Proteins; Publishing; Quantitative Trait Loci; Reporting; Research; Research Personnel; Resources; Risk; Role; Rural; Sampling; Smoking; System; Testing; Training; Universities; Variant; Work; career development; chromatin remodeling; cohort; cytokine; diabetes risk; epidemiology study; epigenetic marker; epigenome-wide association studies; experience; genetic epidemiology; genetic variant; genome sequencing; genome wide association study; global health; health equity; histone modification; improved; interest; large datasets; learning strategy; lifestyle factors; methyl group; multiple omics; novel; polygenic risk score; public health intervention; rare variant; tool; transcriptome sequencing; whole genome

PROJECT SUMMARY/ABSTRACT African-ancestry populations in the US and Europe are disproportionally affected by type 2 diabetes (T2D), while rates are rapidly increasing in sub-Saharan Africa. The reasons for this disproportionate burden are poorly understood but thought to be a complex interplay between genetic and environmental factors, such as lifestyle. Previous work led by the candidate demonstrated that T2D in Africans can partly be traced back to DNA methylation – an important epigenetic mechanism that is a key mediator in the interplay between genetics and lifestyle factors. The candidate’s ongoing work suggests that variations in circulating cytokines, partly driven by African-ancestry specific genetic variants, may play a role in the biology of T2D in Africans. To improve our understanding of the etiology of T2D in Africans, it is imperative to establish causality in previously observed associations and to identify regulatory mechanisms by which these factors are related to T2D. To achieve this, the candidate will leverage data from three existing cohorts: sub-Saharan Africans living in Africa from the AADM study, sub-Saharan Africans living in Africa and Europe from the RODAM study, and African Americans in the US from the HUFS study. To test the hypothesis that changes in circulating cytokines induced by lifestyle factors increase T2D risk through epigenetic mechanisms, the candidate will accomplish three specific aims. To achieve Aim 1, the candidate will assess the causality in the previously observed association between DNA methylation and T2D in Africans by means of two-sample Mendelian randomization (MR) approaches. Aim 2 is to determine whether cytokines act as a causal mediator between lifestyle factors and T2D. This will be achieved in two steps: For the first step (Aim 2a), the candidate will use multiple polygenic prediction methods to compute risk scores, such as polygenic risk scores (PRS), for a set of 12 diabetes-related cytokines measured in AADM and HUFS. These risk scores will be used as instrumental variables in MR analysis. For the second step (Aim 2b), risk scores for alcohol consumption, smoking, and BMI will be computed to infer causality in lifestyle-cytokine associations. Lastly, Aim 3 will identify regulatory mechanisms by which cytokines relate to T2D by using multi-omics data. Carrying forward relevant loci identified in the candidate’s recent research on the 12 cytokines of interest, mechanisms by which these loci exert their effect will be studied using genotype, whole genome sequence, DNA methylation, and RNA-seq data. The candidate and primary mentor have established an excellent mentoring committee to train the candidate in causal inference methods, including the application of MR approaches to epigenetic data, polygenic prediction, and mediation analysis, as well as in multi-omics analysis. The Center for Research on Genomics and Global Health (CRGGH) at the National Human Genome Research Institute (NHGRI) is world-renowned for genetics and genomics research in diverse populations, and in African-ancestry populations in particular. It is therefore the ideal environment for the candidate to receive training during the K99 phase of the project. The proposed training will complement the candidate’s background in epidemiology and experience with epigenetics analysis and will allow the candidate to develop into an independent investigator and leading expert in the field of cardiometabolic diseases among African-ancestry populations.

项目摘要/摘要 美国和欧洲的非洲官员人口受2型糖尿病（T2D）的影响不成比例 撒哈拉以南非洲迅速增加。这种不成比例的伯恩的原因知之甚少，但认为 成为遗传因素和环境因素（例如生活方式）之间的复杂相互作用。由候选人领导的先前工作 证明非洲人中的T2D可以部分地追溯到DNA甲基化 - 重要的表观遗传机制 这是遗传学和生活方式因素之间相互作用的关键调解人。候选人正在进行的工作表明 循环细胞因子的变化部分是由非洲 - 官能特定的特定遗传变异驱动的，可能在生物学中起作用 非洲人的T2D。为了提高我们对非洲人T2D病因的理解，必须建立因果关系 在先前观察到的关联中，并确定这些因素与T2D相关的调节机制。到 实现这一目标，候选人将利用三个现有队列的数据：居住在非洲的撒哈拉以南非洲人 AADM研究，居住在非洲和欧洲的撒哈拉以南非洲人以及美国的非裔美国人 来自HUFS研究。为了测试以下假设：生活方式因素引起的循环细胞因子的变化增加了T2D 通过表观遗传机制的风险，候选人将实现三个具体目标。为了达到目标1，候选人 将通过手段评估先前观察到的DNA甲基化与T2D之间的因果关系 两样本的孟德尔随机化方法（MR）方法。 AIM 2是确定细胞因子是否起因果的作用 生活方式因素与T2D之间的中介。这将分为两个步骤：第一步（AIM 2A），候选人 将使用多种多基因预测方法计算一组12 在AADM和HUFS中测得的与糖尿病相关的细胞因子。这些风险分数将用作MR的工具变量 分析。在第二步（AIM 2B）中，将计算出饮酒，吸烟和BMI的风险评分以推断 生活方式 - 伴侣协会的因果关系。最后，AIM 3将确定细胞因子与 T2D通过使用多媒体数据。进行相关的相关性，该候选人最近对12的研究进行了本地化 感兴趣的细胞因子，这些基因座执行其作用的机制将使用基因组进行研究 序列，DNA甲基化和RNA-seq数据。候选人和主要的精神已经建立了出色的 指导委员会以因果推理方法培训候选人，包括将MR方法应用于 表观遗传学数据，多基因预测和中介分析以及多词分析。研究中心 国家人类基因组研究所（NHGRI）的基因组和全球健康（CRGGH）是世界知名的 对于在潜水人群中，尤其是非洲人种群中的遗传学和基因组学研究。因此是 候选人在项目的K99阶段接受培训的理想环境。拟议的培训将 补充候选人在流行病学和表观遗传学分析中的经验背景，并将允许 候选人发展成为独立研究者和领先的心脏代谢疾病领域的领先专家 非洲人的人口。