Abstract 401: Functional Analysis of Coronary Artery Disease-associated PLPP3 Gene Variants

Abstract

Heritable variants of the PLPP3 gene are associated with human coronary artery disease risk. Expression of the PLPP3 gene product, lipid phosphate phosphatase 3 (LPP3) is strongly increased in blood and vascular cells by pro-atherogenic, pro-inflammatory stimuli including oxidized LDL. PLPP3 is essential for vascular development in mice but animals with inducible post-natal or tissue specific inactivation of the gene exhibit accelerated development of aortic atherosclerosis. These observations suggest the hypothesis that PLPP3 normally functions to suppress the development and progression of atherosclerosis. The coronary artery disease-associated PPAP2B haplotype block is in the final intron of the gene. Recently published analysis of chromatin remodeling in oxidized LDL stimulated human monocytes identifies dynamic changes in these coronary artery disease associated loci. We show that several of these loci correspond to potential or identified regulatory genomic elements. Functional analysis of these elements identifies multiple cFos/AP1 and cEBP regulated transcriptional enhancer sequences that exhibit allelic variation that could impact on their function as regulators of PLPP3 gene expression. Some of these enhancer sequences bind their transcription factor targets in an allele specific manner and are functional activators of transcription from the PLPP3 promoter. Because haplotypes containing the coronary artery disease associated enchancer sequence variants are also associated with attenuated increases in PPAP2B expression in oxidized LDL treated human monocytes our observations support the hypothesis that heritable cardiovascular disease risk is associated with attenuation of cis acting enhancer sequences that normally promote LPP3 expression. These observations also raise the possibility that these intronic enhancers have longer distance or trans-acting effects on other genes that also contribute to coronary artery disease risk