Tracing the genetic etiology of cardiovascular disease using a hierarchy of common genetic variants derived from patient subgroups stratified by differential levels in severity

Abstract

AbstractA pedagogical review in informatics based on computational molecular evolution is synopsized to illustrate the role of common genetic variants during adaptation to diverse habitat and physiological functions across disparate species. With that background, an evolutionary perspective is motivated to trace lifestyle-related disease progression in humans. Cardiovascular disease (CVD) is a multi-factorial disease, where maladaptation due to a sedentary lifestyle and faulty diet may influence its prognosis, but a healthy diet and lifestyle may as well restrict it. However, a comprehensive genetic basis for the differential severity in CVD remains unreported. Here, we have computed that CVD severity may be associated with the hierarchical plasticity of genes whose common genetic variants are exclusive among those patients having disparate levels of disease severity. Most importantly, we have used a small and outbred subpopulation to demonstrate that constellation of common variants can be exploited to trace the disease etiology. Taken together, we report a novel perspective to identify a hierarchy of common variants associated with differential CVD severity and subsequently hypothesize how the constellations of common variants may collectively modulate disease severity, which in turn may result in a relatively broad and complex spectrum of severity at the population-level. To corroborate our findings, we report a hierarchical plasticity of LDLR gene, which has been previously implicated in the differential response to lipid metabolism, is associated with differential CVD severity in the subpopulation under consideration.