Landscape of pharmacogenetic variants associated with non-insulin antidiabetic drugs in the Indian population
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 ar...
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BMJ Publishing Group
2024-04-01
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| Series: | BMJ Open Diabetes Research & Care |
| Online Access: | https://drc.bmj.com/content/12/2/e003769.full |
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| author | Anura V Kurpad Disha Sharma KM Venkat Narayan Ambily Sivadas Arpita Mukhopadhyay Greg Gibson Abhinav Jain S Sahana Bani Jolly Rahul C Bhoyar Mohamed Imran Vigneshwar Senthivel Mohit Kumar Divakar Anushree Mishra Sridhar Sivasubbu Vinod Scaria |
| author_facet | Anura V Kurpad Disha Sharma KM Venkat Narayan Ambily Sivadas Arpita Mukhopadhyay Greg Gibson Abhinav Jain S Sahana Bani Jolly Rahul C Bhoyar Mohamed Imran Vigneshwar Senthivel Mohit Kumar Divakar Anushree Mishra Sridhar Sivasubbu Vinod Scaria |
| author_sort | Anura V Kurpad |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-5f63fe82d3b64dc390f49848b985ce41 |
| institution | DOAJ |
| issn | 2052-4897 |
| language | English |
| publishDate | 2024-04-01 |
| publisher | BMJ Publishing Group |
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| series | BMJ Open Diabetes Research & Care |
| spelling | doaj-art-5f63fe82d3b64dc390f49848b985ce412025-08-20T02:39:40ZengBMJ Publishing GroupBMJ Open Diabetes Research & Care2052-48972024-04-0112210.1136/bmjdrc-2023-003769Landscape of pharmacogenetic variants associated with non-insulin antidiabetic drugs in the Indian populationAnura V Kurpad0Disha Sharma1KM Venkat Narayan2Ambily Sivadas3Arpita Mukhopadhyay4Greg Gibson5Abhinav Jain6S Sahana7Bani Jolly8Rahul C Bhoyar9Mohamed Imran10Vigneshwar Senthivel11Mohit Kumar Divakar12Anushree Mishra13Sridhar Sivasubbu14Vinod Scaria15St John`s Medical College, Bangalore, Karnataka, IndiaCSIR Institute of Genomics and Integrative Biology, New Delhi, IndiaRollins School of Public Health, Atlanta, Georgia, USASt John`s Research Institute, Bangalore, Karnataka, IndiaSt John`s Research Institute, Bangalore, Karnataka, IndiaGeorgia Institute of Technology, Atlanta, Georgia, USACSIR Institute of Genomics and Integrative Biology, New Delhi, IndiaCSIR Institute of Genomics and Integrative Biology, New Delhi, IndiaAcademy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh, IndiaCSIR Institute of Genomics and Integrative Biology, New Delhi, IndiaCSIR Institute of Genomics and Integrative Biology, New Delhi, IndiaCSIR Institute of Genomics and Integrative Biology, New Delhi, IndiaCSIR Institute of Genomics and Integrative Biology, New Delhi, IndiaCSIR Institute of Genomics and Integrative Biology, New Delhi, IndiaCSIR Institute of Genomics and Integrative Biology, New Delhi, IndiaCSIR Institute of Genomics and Integrative Biology, New Delhi, IndiaIntroduction 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.https://drc.bmj.com/content/12/2/e003769.full |
| spellingShingle | Anura V Kurpad Disha Sharma KM Venkat Narayan Ambily Sivadas Arpita Mukhopadhyay Greg Gibson Abhinav Jain S Sahana Bani Jolly Rahul C Bhoyar Mohamed Imran Vigneshwar Senthivel Mohit Kumar Divakar Anushree Mishra Sridhar Sivasubbu Vinod Scaria Landscape of pharmacogenetic variants associated with non-insulin antidiabetic drugs in the Indian population BMJ Open Diabetes Research & Care |
| title | Landscape of pharmacogenetic variants associated with non-insulin antidiabetic drugs in the Indian population |
| title_full | Landscape of pharmacogenetic variants associated with non-insulin antidiabetic drugs in the Indian population |
| title_fullStr | Landscape of pharmacogenetic variants associated with non-insulin antidiabetic drugs in the Indian population |
| title_full_unstemmed | Landscape of pharmacogenetic variants associated with non-insulin antidiabetic drugs in the Indian population |
| title_short | Landscape of pharmacogenetic variants associated with non-insulin antidiabetic drugs in the Indian population |
| title_sort | landscape of pharmacogenetic variants associated with non insulin antidiabetic drugs in the indian population |
| url | https://drc.bmj.com/content/12/2/e003769.full |
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