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

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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.