Publications

INTRODUCTION: Genetic variants contribute to differential responses to non-insulin antidiabetic drugs (NIADs), and consequently to variable plasma  glucose control. Optimal control of plasma glucose is paramount to minimizing  type 2 diabetes-related long-term complications. India's distinct genetic  architecture and its exploding burden of type 2 diabetes warrants a  population-specific survey of NIAD-associated pharmacogenetic (PGx) variants. The  recent availability of large-scale whole genomes from the Indian population  provides a unique opportunity to generate a population-specific map of  NIAD-associated PGx variants. RESEARCH DESIGN AND METHODS: We mined 1029 Indian  whole genomes for PGx variants, drug-drug interaction (DDI) and drug-drug-gene  interactions (DDGI) associated with 44 NIADs. Population-wise allele frequencies  were estimated and compared using Fisher's exact test. RESULTS: Overall, we found  76 known and 52 predicted deleterious common PGx variants associated with  response to type 2 diabetes therapy among Indians. We report remarkable  interethnic 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 with other global populations. Network analysis of shared PGx  genes predicts high DDI risk during coadministration 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  coadministered with proton-pump inhibitors (PPIs). CONCLUSIONS: Indians and South  Asians have a distinct PGx profile for antidiabetes drugs, marked by an excess of  poor treatment response-associated alleles for various NIAD classes. This  suggests the possibility of a population-specific reduced drug response in  atleast some NIADs. In addition, our findings provide an actionable resource for  accelerating future diabetes PGx studies in Indians and South Asians and  reconsidering NIAD dosing guidelines to ensure maximum efficacy and safety in the  population.