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.

项目总结/摘要 美国和欧洲的非洲血统人群受到2型糖尿病（T2 D）的严重影响， 在撒哈拉以南的非洲地区迅速增长。造成这种不成比例的负担的原因人们知之甚少， 是遗传和环境因素之间复杂的相互作用，如生活方式。候选人以前领导的工作 证明非洲人的T2 D可以部分追溯到DNA甲基化-一种重要的表观遗传机制 这是遗传因素和生活方式因素之间相互作用的关键媒介。候选人正在进行的工作表明， 循环细胞因子的变化，部分由非洲血统特异性遗传变异驱动，可能在生物学中发挥作用。 T2 D在非洲为了提高我们对非洲T2 D病因的理解，必须建立因果关系 在以前观察到的协会，并确定这些因素与T2 D相关的调节机制。到 为了实现这一目标，候选人将利用三个现有群体的数据： AADM研究，RODAM研究中生活在非洲和欧洲的撒哈拉以南非洲人，以及美国的非洲裔美国人 来自HUFS研究。检验由生活方式因素诱导的循环细胞因子变化增加T2 D的假设 通过表观遗传机制的风险，候选人将实现三个具体目标。为了实现目标1，候选人 将评估先前观察到的非洲人DNA甲基化与T2 D之间的因果关系， 两样本孟德尔随机化（MR）方法。目的2是确定是否细胞因子作为因果关系， 生活方式因素和T2 D之间的中介。这将分两步实现：第一步（目标2a），候选人 将使用多种多基因预测方法来计算一组12个多基因风险评分，例如多基因风险评分（PRS） 在AADM和HUFS中测量的糖尿病相关细胞因子。这些风险评分将用作MR中的工具变量 分析.对于第二步（目标2b），将计算饮酒、吸烟和BMI的风险评分，以推断 生活方式-细胞因子关联的因果关系。最后，目标3将确定调节机制，细胞因子与 使用多组学数据的T2 D。继承候选人最近对12个研究中确定的相关位点 对于感兴趣的细胞因子，这些基因座发挥其作用的机制将使用基因型、全基因组 序列、DNA甲基化和RNA-seq数据。候选人和主要导师已经建立了一个优秀的 指导委员会培训候选人的因果推理方法，包括MR方法的应用， 表观遗传学数据、多基因预测和介导分析以及多组学分析。问题研究中心 国家人类基因组研究所（NHGRI）的基因组学和全球健康（CRGGH）是世界知名的 用于不同人群，特别是非洲血统人群的遗传学和基因组学研究。因此 为候选人在项目K99阶段接受培训提供了理想的环境。拟议的培训将 补充候选人的流行病学背景和表观遗传学分析的经验，并将允许 候选人发展成为一个独立的研究者和领先的专家，在心脏代谢疾病领域， 非洲裔人口。