DMMC Course POPULATION GENETICS & SNP ANALYSIS

Durkan Lecture Theatre, Institute of Molecular Medicine, TCD, St James's Hospital

1445-1540 Thursday 7 June 2007

PharmacoGenetics/Omics of Cardiovascular Disease
Dr Alice Stanton (RCSI)

Exhaustive efforts to relate common genetic variation to complex clinical outcomes such as hypertension and atherosclerotic vascular disease have yielded little in terms of reproducible factors with even modest influences on actual disease risk or outcome. Hence, despite recent advances in genotyping technology, bioinfomatics resources and statistical approaches, many pundits question the value of association studies addressing genetic determinants of such complex disorders. In this lecture the value of high quality intermediate phenotypic data in both candidate gene studies and whole genome association analyses of cardiovascular disease and of responses to therapy will be discussed.
A common SNP in a renin distal enhancer element has been reported to influence in vitro gene transcription in transfected human choriodecidual cells. Using ambulatory blood pressure (BP) monitoring rather than mere isolated office measurements of BP, we have recently provided the first evidence that renin –5312C/T has in vivo functional activity. We found carriage of the -5312T allele, a specific marker for a single renin haplotype, to be associated with elevated BP levels in healthy humans. The magnitude of the effect associated with carriage of the -5312T allele ranged from 2.7 mm Hg to 1.5 mm Hg. Furthermore we found evidence that the polymorphism predicts BP lowering responses to renin angiotensin system blockade in hypertensive patients, and that this prediction is additional to that of plasma renin activity. If these findings are confirmed by further epidemiological studies and clinical trials, genotyping for the renin -5312C/T polymorphism may have value in the early identification of those at risk of hypertension and cardiovascular events. Further, renin -5312C/T genotyping in combination with measurement of PRA, may improve the selection of optimal antihypertensive therapy in individual patients.
Finally, the strategy for a two-tiered, whole-genome association study of atherosclerosis and cardiovascular events, within a large clinical trial of BP lowering therapy, will be briefly discussed. In tier 1, ultrasonic common carotid intima-media thickness, a reliable measure of early atherosclerosis, will serve as the primary end-point, and in the tier 2 replication study, cardiovascular events, heart attacks and strokes, will be the primary endpoint. In this way we anticipate the creation of a genomic predisposition map for atherosclerosis, and the identification of a number of novel genetic variants associated with atherosclerotic events, and with responses to specific BP lowering regimens.