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bioRxiv · 10.1101/213124

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

Fatakia, S. N.
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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.

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Fatakia, S. N.. 2017-11-02. Insights to the genetic etiology of a lifestyle-related disease with differential levels of severity using a hierarchy of common genetic variants. https://doi.org/10.1101/213124

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