RNA profiling and the genetics of myocardial infarction

Abstract

Notwithstanding our increase in knowledge on the events that lead to atherosclerosis and myocardial infarction, the literature on the genetic determinants of these related diseases is ridden with conflicting results. In this study a novel RNA profiling technique was applied in a case-control setting including 524 men with a history of myocardial infarction and 628 control subjects. The relationship between a selection of polymorphisms, RNA expression and other intermediate phenotypes, and disease outcome was investigated. Patients had higher levels of inflammatory molecules and Toll-like receptors (TLRs) than controls. Macrophage migration inhibitory factor (MlF) and the intracellular regulator proteinase inhibitor 9 (PI9) gave the highest odds ratios for myocardial infarction. Analysis of genetic data with the RNA data revealed that DNA changes in inflammation-related genes can influence several disease-related intermediate phenotypes. The underlying levels of expression of genes of related function were shown to have considerable impact on the effect of a particular gene on disease outcome. The overall effect of polymorphisms on risk outcome tended to be small, but additive, and was frequently modified by smoking. Aberrant RNA profiles acted as sentinels for particularly deleterious or protective outcomes. Bioinformatics tools were applied to detect a new MlF splice variant and to determine different roles of alternative transcripts of TLR4. To date, this is the largest RNA profiling study on myocardial infarction. This innovative approach highlights a degree of complexity in the expression and regulation of inflammatory molecules that needs to be accounted for to improve our understanding of the mechanism of genetic risk in atherosclerosis and myocardial infarction.