Hsu J, Smith JD
Purpose of Review
Genome-wide association studies have led to the discovery of many single nucleotide polymorphisms (SNPs) associated with coronary artery disease (CAD). However, many of these SNPs are in between genes (intergenic), and presumably function through the regulation of gene expression. Microarrays that measure the expression of thousands of mRNAs have allowed investigators to study how genetic variation alters gene expression at a genome-wide level. Combining these methods have led to progress in understanding the molecular basis for the genetic susceptibility to atherosclerosis.
Recent studies confirm that gene expression differences due to genetic variation play an underlying role in atherosclerosis. Expression levels of SORT1 are negatively correlated with an intergenic risk allele on chromosome 1p13.3 that was previously associated with CAD. Increased SORT1 expression leads to lower hepatic secretion of LDL providing a mechanistic link between a common risk variant and disease. In addition three out of thirteen newly identified CAD risk loci were found to strongly affect the expression of nearby genes. Another recent study detected variants adjacent to a newly identified atherosclerosis risk locus on chromosome 11q22 that were associated with the expression of PDGFD, a member of the platelet derived growth factor family.
Cataloging the genetics of gene expression provides a small but crucial molecular link between genetics and clinical phenotypes such as atherosclerosis. Thus, gene expression is an endophenotype that can lead to the discovery of the underlying genes responsible for increasing atherosclerosis risk and potential diagnostic and therapeutic targets.