Genetics of Plasminogen Activator Inhibitor – 1: a potent biological effector of cardiovascular disease risk

Abstract

Cardiovascular disease (CVD) is an inclusive term encompassing several disorders of the circulatory system that together account for the majority of global non-communicable disease (NCD) mortality. Major thrombotic events, due in part to impaired fibrinolysis, are a unifying characteristic of several CVDs. Plasminogen activator inhibitor-1 (PAI-1) is a major regulator of fibrinolysis, and PAI-1 levels associate with CVD susceptibility and severity in several populations. The main objectives of this dissertation were to evaluate the genetic impact of common single nucleotide polymorphisms (SNPs) on inter-individual variation in PAI-1 levels in a Ghanaian population, and present a novel method to identify candidate genes for prioritization in future studies. We discovered novel associations between single variants in the arylsulfatase b (ARSB), carboxypeptidase A2 (CPA2), and leukocyte receptor cluster member 9 (LENG9) and median PAI-1 levels. Quantile regression analyses directed at the upper quartile of the PAI-1 distribution was performed to uncover novel variants with significant impact on this clinically relevant portion of the PAI-1 distribution. Upper quartile regression analyses revealed significant associations between single variants in period circadian clock 3 (PER3), a discovery that supports previous evidence of the involvement of the circadian pathway in regulation of PAI-1 levels in Caucasian populations as well as model organisms. This finding suggests that the significance of the circadian pathway as a whole may be generalizable across populations, even though gene effects may be population specific. We present a novel approach; Multi-lOcus based selection of Candidate genes (MOCA), which incorporates multi-variant association signals into the prioritization of genes for further evaluation. MOCA identified four significantly associated loci; these loci included 28 novel candidate genes for PAI-1 levels. Each MOCA identified locus was located within previously identified CVD and/or PAI-1 related quantitative trait loci (QTL).