Insights to the genetic etiology of a lifestyle-related disease with differential levels of severity using a hierarchy of common genetic variants

Abstract

Genome evolution in disparate species is synopsized to highlight the role of common genetic variants during their adaptation, and an evolutionary perspective is provided to infer lifestyle-related disease progression in humans. Cardiovascular disease (CVD) is a multi-factorial disease, where maladaptation due to a sedentary lifestyle and faulty diet can influence its prognosis, but the genetic basis for its differential severity remains unknown. As a healthy diet and lifestyle may restrict its prognosis, we hypothesize that a hierarchy of common genetic variants may differentially modulate that severity in a subpopulation. We suggest that the loss-of-function paradigm due to a genetic variant may give rise to a broad spectrum of CVD severity in conjunction with other variants. Here, we have inferred that CAD severity may be a consequence of the plasticity of common variants exclusive among patients with disparate disease severity. Most importantly, we have used a small and outbred subpopulation to demonstrate that common genetic variants can be exploited to trace this unique facet of CAD etiology. Moreover, we corroborate our hypothesis by reporting that a hierarchical plasticity of the LDLR gene, which has been implicated in a differential response to lipid metabolism, is associated with differential CVD severity.\n\nCan we gain insight to the genetic etiology of diseases using a limited number of genomes (few hundred)? Can small data sets lend insights that large data sets may subsequently confirm? Here, I show how common genetic variants, which were identified only from hundreds of individuals, may be used to gain unique insights regarding the disease etiology of a common lifestyle-related disease.