UCSF

Gene-environment interactions are increasingly understood to be a primary contributing factor in the etiology of cardiovascular disease. Environmental factors include person and societal-level variables. Genome factors include sequence variation and mechanisms controlling genome expression. These regulatory mechanisms are the nexus of gene-environment interactions, and can be transient or adaptive; the latter are termed epigenetics. Some genetic characteristics are highly homogeneous within ethnic groups, due to a combination of geographically derived natural selection and environmental factors. South Asians are a population with disproportionately high cardiovascular disease burden. A prevalence study of cardiovascular risk factors in this population provides evidence that common risk factors are alterations in cholesterol metabolism; specifically low high-density lipoprotein cholesterol with elevated triglycerides. These initial observations led to a second study yielding evidence that abdominal adiposity is not a necessary precursor to the development of this dyslipidemia, challenging previous assumptions. A third study found pro-atherogenic risk profiles in South Asians are present decades earlier than in other populations. While these risk factors have genetic underpinnings, the added effects of a changing environment (i.e., Westernization of South Asians) are not known. MicroRNA are an epigenetic post-transcriptional regulatory mechanism of messenger RNA translation, and are potential biomarkers of pathophysiology and response to interventions. MicroRNA in human blood are differentially expressed in numerous disease conditions, and in vitro studies indicate that microRNA play a role in regulation of cholesterol metabolism in response to the extracellular environment. Methods to quantify microRNA include microarray, in which a large number of microRNA targets are screened. Microarray results are then validated with the more sensitive quantitative polymerase chain reaction method. Using microRNA arrays and a case-control design of pooled bio-specimens, a fourth study identified 16 candidate microRNA biomarkers of this atherogenic profile, which were then verified by quantitative polymerase chain reaction. Several of these are known to target messenger RNA involved in cholesterol metabolism. These results are promising evidence for translational application of microRNA as clinical biomarkers elucidating underlying genetic determinants of atherogenic risk in South Asians. Further research is needed to determine whether microRNA expression in blood is sensitive to cardiovascular risk reduction interventions.