Assessing the Influence of the Human Lipidome on Risk of Diabetes in a Minority Population

PROJECT SUMMARY Type 2 diabetes is a major public health concern. Diabetes currently affects 25.8 million people in the US alone and 90-95% of all cases are type 2. There are many complications related to diabetes, including a significantly increased risk of heart disease and stroke, blindness, kidney failure and kidney disease, nonalcoholic fatty liver

disease, neuropathy, hearing loss and lower-limb amputations. There are several risk factors predisposing individuals to the development of this disease including demographic characteristics like sex, age and ethnicity; and behavioral and lifestyle-related modifications. In addition, metabolic determinants such as impaired glucose

tolerance and insulin resistance increase the risk of an individual progressing to type 2 diabetes. Significant diabetes health disparities exist in minority populations, including Hispanics and African Americans, where prevalence of diabetes is increased. Evidence from both epidemiological and lipidomic studies have shown that

specific lipoproteins and their constituent lipids are important factors in the development of type 2 diabetes, where, like many other metabolic diseases, lipid metabolism is disrupted. The classical lipid parameters most commonly examined in relation to disease risk are themselves complex entities composed of multiple lipid

species. We hypothesize that these basic lipid species represent intermediate phenotypes that lie closer to the genomic level in the interplay between phenotype and disease, and therefore may be better predictors of disease risk and increase the pace of discovery of genes causally involved in lipid variation and type 2 diabetes.

In this project, we will exploit whole genome sequence (WGS) information in powerful extended pedigrees of Mexican American individuals in combination with comprehensive measures of the human lipidome, to identify novel genes and functional variants influencing lipid variation and type 2 diabetes, in an effort to reduce the

diabetes health disparities evident in Hispanic populations. The combination of these precise biological lipid phenotypes and WGS gives us an unprecedented opportunity to identify novel genes and functional variants influencing human lipid variation and risk of diabetes. To achieve these objectives, we will (I) measure T2D risk

phenotypes including targeted lipid profiling of more than 800 lipid species; and multiple measures of metabolic function, and perform quantitative genetic analyses; (II) identify sequence variation influencing lipid variation and diabetes in all individuals using WGS; (Ill) perform hypothesis based replication in an independent Mexican

American population; and (IV) perform functional assessments of variants of interest in relevant iPSC-derived cells and analyze free and total fatty acid content in a subset of the cohort. The estimated economic burden of diabetes in the United States alone is approximately $245 billion per year, making this disease of major public health importance. The ability to identify genes that are causally involved in

disease risk provides an unparalleled opportunity to quickly determine biological pathways that are involved in disease pathology. A better understanding of the genetic contribution to lipid variation and diabetes development will provide novel approaches for the characterization, treatment and potential prevention of this costly disease.