?DESCRIPTION (provided by applicant): Our program, developed over 25 years of NHLBI support, has identified and continues to identify gene variants that interact with psychosocial stressors to influence, via central nervous system and peripheral mechanisms, expression of behavioral and physiological endophenotypes in pathways to cardiometabolic disease and adverse clinical course. During the renewal period, using current PPG samples (N=26,010) and public-access samples (N=51,651), Project 1 will continue this work by using traditional and novel high throughput bioinformatics approaches to identify and validate new and previously identified gene variants and gene-by stress interactions that influence disease pathways, adapting novel statistical approaches to evaluate effects on multiple cardiometabolic endophenotypes in the pathways to disease outcomes as a system, including multiple genes and mediating biological pathways. We will evaluate race as a moderator of these GxStr effects on disease pathways and outcomes. We will also use multiple, multimethod discovery techniques to converge on additional variants in the genetic architecture of GxStr. Project 1 will pass previously and newly identified gene variants associated, both directly and via interaction with stress, with cardiometabolic endophenotypes to Project 2 to test for effects on endophenotypes in pathways to type 2 diabetes, to Project 3 to test for effects on epigenetic, transcriptomic and metabolomics pathways that mediate effects on endophenotypes and disease endpoints, and to Project 4 to test for effects on response of endophenotypes to behavioral and drug interventions. Project 3 will also evaluate effects of gene variants associated with cardiometabolic responses to behavioral and pharmacologic interventions in Project 4 for effects on molecular epigenetic, transcriptomics and metabolomics mechanisms. Project 3 will use whole exome sequencing and who genome methylation to identify genetic and epigenetic variants associated with mental stress-induced myocardial ischemia and Takasubo's cardiomyopathy. Project 4 will also test agonists and antagonists of the 5HTR2C receptor to see if they increase and decrease, respectively, the enhanced cortisol response to mental stress we have found associated with the rs6318 Ser23C allele. Successful completion of the proposed research in Projects 1-4 will increase our understanding of GxStr interactions on the multiple pathways that influence the development and course of cardiometabolic disease - knowledge that will be critical for the ultimate development of effective preventive and treatment interventions.