UNIVERSITY OF MALTA
LIFE SCIENCE RESEARCH SEMINARS
Web: http://events.um.edu.mt/scisem/
Email: scisem@um.edu.mt
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RNA Profiling and the Genetics of Myocardial Infarction.
Dr Stephanie Bezzina Wettinger
stephanie.bezzina-wettinger@um.edu.mt
Monday, 11 May 2009
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 (MIF) 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 diseaserelated 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 MIF 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.