Functional and Pharmacogenomic Characterization of Hallmark Genetic Risk variants for Metabolic Traits in The Kuwaiti Population: Enrichening KADEM and The Kuwait Variome Database

The post-oil rich era of Kuwait brought a drastic shift from nomadic style of living to more sedentary lifestyle and a rapid nutrition transition, resulting in a dramatic increase in the prevalence of metabolic disorders. We at Dasman Diabetes Institute have been conducting genetic association studies and deciphered several genetic risk variants associated with the four classes of metabolic traits (namely anthropometry, lipid, glycemic, and blood pressure) in the Kuwaiti population. By way of imputing the genome-wide genetic variants, we increased the genome coverage of the tested genetic variants for associations with metabolic traits. We characterized the pleiotropy in genetic risk variants associated with metabolic traits. We further carried out functional variant prioritization by way of examining such association signals for several features, which includeduniqueness to the Kuwaiti population, replicability in other global ethnic populations, fine mapping for causal variants, and annotation for functional roles in key metabolic pathways. A list of 85 hallmark genetic risk variants from 64 genes was derived. We now aim, in the proposed project, to (a) delineate the metabolic protein biomarkers that are impacted by the genetic variation at these risk variants under the hypothesis that a risk variant influences the associated trait through regulating interactions with/among a set of metabolic proteins related to the trait; (b) enlarge the list of hallmark risk variants by way of evaluating the known T2D pharmacogenomic loci/variants in the context of the genetic profile of the Kuwaiti population; and (c) evaluate the pharmacogenomics of these hallmark genetic risk variants.