The Landscape of Pharmacogenetic Variants Associated with Noninsulin Antidiabetic Drugs in the Indian Population

Genetic variants contribute to differential responses to non-insulin antidiabetic drugs (NIADs), and consequently to variable plasma glucose control. India’s distinct genetic architecture and its exploding burden of Type 2 Diabetes (T2D) warrants a population-specific survey of NIAD-associated pharmacogenetic (PGx) variants. We mined 1029 Indian whole genomes for PGx variants, drug-drug (DDI) and drug-drug-gene interactions (DDGI) associated with 44 NIADs. Overall, we found 76 known and 52 predicted deleterious common PGx variants associated with response to T2D therapy among Indians. We report remarkable inter-ethnic differences in the relative cumulative counts of decreased and increased response-associated alleles across NIAD classes. Indians and South Asians showed a significant excess of decreased metformin response-associated alleles compared to other global populations. Network analysis of shared PGx genes predicts high DDI risk during co-administration of NIADs with other metabolic disease drugs. We also predict an increased CYP2C19-mediated DDGI risk for CYP3A4/3A5-metabolized NIADs, saxagliptin, linagliptin and glyburide when co-administered with PPIs. Our findings provide an actionable resource for accelerating future diabetes PGx studies in Indians and reconsidering NIAD dosing guidelines to ensure maximum efficacy and safety in the population. Disclosure A.Sivadas: None. A.Mishra: None. A.Mukhopadhyay: None. K.Narayan: None. S.Sivasubbu: None. V.Scaria: None. A.Kurpad: None. S.Sahana: None. B.Jolly: None. R.C.Bhoyar: None. A.Jain: None. D.Sharma: None. M.Imran: None. V.Senthivel: None. M.K.Divakar: None. Funding DBT/Wellcome Trust India Alliance (IA/E/19/1/504945)