Unravelling the Role of Epigenetics and Cytokines in Type 2 Diabetes among African-ancestry Populations - PROJECT SUMMARY/ABSTRACT African-ancestry populations in the US and Europe are disproportionately 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 are 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. It also suggested that variations in circulating cytokines, partly driven by African-ancestry specific genetic variants, may play a role in the biology of T2D in Africans. The mentored phase of the Pathway to Independence award enabled the candidate to acquire the necessary knowledge and skills to build on this work. An outstanding mentoring committee guided her in mastering causal inference methods, including the application of Mendelian randomization approaches to epigenetic data, polygenic prediction, and mediation analysis, as well as multi-omics analysis. The Center for Research on Genomics and Global Health (CRGG H) at the National Human Genome Research Institute (NHGRI), renowned for its genetics and genomics research in diverse populations, especially African-ancestry populations, provided an ideal environment for the candidate's training du ring the K99 phase of the project. By inferring causality in the previously observed associations between DNA methylation, circulating cytokines, and diabetes, the candidate was able to identify specific DNA methylation sites causally associated with T2D in Africans through two-sample Mendelian randomization approaches. The candidate also identified three circulating cytokines causally associated with insulin sensitivity and beta-cell function, the hallmarks of T2D pathophysiology. To further improve our understanding of the etiology of T2D in Africans, it is imperative to better understand what drives variation in the circulating cytokines causally associated with T2D in Africans. Given the complex interplay of genetic and environmental factors in T2D etiology, the candidate aims to identify both lifestyle and genetic factors causing variability in these cytokines. To achieve this, the candidate will leverage data from two existing cohorts: sub-Saharan Africans living in Africa from the AADM study and sub-Saharan Africans living in Africa and Europe from the RODAM study. To test the hypothesis that both lifestyle factors and genetic regulatory mechanisms drive variation in circulating cytokines relevant forT2D in Africans, the candidate will accomplish two specific aims. Aim 1 is to infer causality in lifestyle-cytokine associations using Mendelian randomization approaches. Aim 2 will identify regulatory mechanisms of cytokines using multi-omics data. Mechanisms by which loci identified in the candidate's published GWAS analyses exert their effect will be studied using genotype, whole genome sequence, DNA methylation, RNA-seq data, and metabolic data. The training received during the mentored phase significantly enhanced the candidate's skill set, allowing the candidate to develop into an independent investigator and lead a lab at the University of Maryland aimed at studying cardiometabolic diseases among African-ancestry populations.
