Genetics of Cardiometabolic Diseases in the VA Population

Cardiometabolic disorders including obesity, insulin resistance, related dyslipidemia, and type 2 diabetes (T2DM)
are highly prevalent among U.S. Veterans and serve as major factors in the development of heart, vascular and
liver diseases. We have assembled a multi-disciplinary research team from multiple VA and academic medical
centers with expertise in cardiovascular and metabolic disease, clinical and epidemiological research, EHR
based research methods, genetic epidemiology, and statistical genetics, to participate in the Million Veteran
Program (MVP) through the Beta-test award entitled “Genetics of Cardiometabolic Diseases in the VA
Population”. In addition, we have helped establish a highly synergistic network of trait- and methodology-based
Working Groups that have facilitated collaborative projects among several funded Beta-test teams. Since first
gaining access to MVP genetic and phenotypic data in GenISIS less than 18 months ago, we have contributed
substantially to or led studies that have confirmed and/or identified >500 susceptibility loci for body mass index,
height, prediabetes, T2D, dyslipidemia, non-alcoholic fatty liver disease (NAFLD), coronary artery disease
(CAD), and peripheral artery disease (PAD). We have disseminated our findings to the scientific community
through >20 presentations at national meetings and have submitted or are preparing to submit multiple
manuscripts related to these initial efforts. For the current renewal application, we propose to continue this line
of investigation with particular focus in leveraging longitudinal information related to time course of disease. In
Aim 1, we will build on our momentum of our initial genome wide association studies (GWAS) of prevalent
disease and single time point measures of quantitative traits by expanding our efforts to examine the genetic
basis of the longitudinal progression of cardiometabolic traits including increasing BMI; pre-diabetes to type 2
diabetes, manifestation of micro- and macro-vascular complications in T2D, NAFLD to liver cirrhosis and cancer,
pre-clinical conditions to CHD, PAD, and abdominal aortic aneurysm (AAA) disease. In Aim 2, we will explore
the pleiotropic relationships between multiple cardiometabolic traits as well as with non-cardiometabolic traits in
the MVP and the UK Biobank. Moreover, we will conduct participant-level Mendelian Randomization studies to
more robustly document causal links between highly correlated pairs of traits identified through our pleiotropy
analyses. Finally, in Aim 3, we will assess the discriminatory power of derived polygenic risk scores for
cardiometabolic diseases in the VA population, with specific emphasis upon evaluating their value in different
minority populations. Our overarching hypothesis is that elucidating the genetic underpinnings of cardiometabolic
conditions and their interactions with environmental and/or lifestyle factors will provide a more precise
understanding of disease progression over time, thereby informing more targeted genomic medicine-based
disease management throughout the course of Veterans' lives.

Grant Number: 5I01BX003362-09
NIH Institute/Center: VA
Principal Investigator: Kyong-Mi Chang