Landscape of pharmacogenetic variants associated with non-insulin antidiabetic drugs in the Indian population

作者：Ambily Sivadas, Soumitra Sahana, Bani Jolly, Rahul C. Bhoyar, Abhinav Jain, Disha Sharma, Mohamed Imran, Vigneshwar Senthivel, Mohit Kumar Divakar, Anushree Mishra, Arpita Mukhopadhyay, Greg Gibson, KM Venkat Narayan, Sridhar Sivasubbu, Vinod Scaria, Anura V. Kurpad · 发表于：BMJ Open Diabetes Research & Care · 年份：2024 · DOI：10.1136/bmjdrc-2023-003769 · 被引用次数：17 · 研究领域：Pharmacogenetics and Drug Metabolism、Genetic Associations and Epidemiology、Genomics and Rare Diseases

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 ...