Genetic Variants in CPA6 and PRPF31 Are Associated With Variation in Response to Metformin in Individuals With Type 2 Diabetes
| Autor: | Sook Wah Yee, Skylar W. Marvel, Hetal Shah, Tammy M. Havener, Michiaki Kubo, MetGen Investigators, John B. Buse, Accord, He Gao, Alessandro Doria, Kaixin Zhou, Monique M. Hedderson, Ewan R. Pearson, Mark A. Herman, ACCORDion Investigators, John Jack, Josyf C. Mychaleckyi, Kathleen M. Giacomini, Howard L. McLeod, Michael J. Wagner, Alison A. Motsinger-Reif, Daniel M. Rotroff |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty PRPF31 endocrine system diseases Endocrinology Diabetes and Metabolism Type 2 diabetes 03 medical and health sciences 0302 clinical medicine Internal medicine Diabetes mellitus Internal Medicine Medicine business.industry Genetic variants nutritional and metabolic diseases Total body medicine.disease 3. Good health Metformin Clinical trial 030104 developmental biology Endocrinology 030220 oncology & carcinogenesis Knockout mouse business medicine.drug |
| Zdroj: | Diabetes. 67:1428-1440 |
| ISSN: | 1939-327X 0012-1797 |
| DOI: | 10.2337/db17-1164 |
| Popis: | Metformin is the first-line treatment for type 2 diabetes (T2D). Although widely prescribed, the glucose-lowering mechanism for metformin is incompletely understood. Here, we used a genome-wide association approach in a diverse group of individuals with T2D from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) clinical trial to identify common and rare variants associated with HbA1c response to metformin treatment and followed up these findings in four replication cohorts. Common variants in PRPF31 and CPA6 were associated with worse and better metformin response, respectively (P < 5 × 10−6), and meta-analysis in independent cohorts displayed similar associations with metformin response (P = 1.2 × 10−8 and P = 0.005, respectively). Previous studies have shown that PRPF31(+/−) knockout mice have increased total body fat (P = 1.78 × 10−6) and increased fasted circulating glucose (P = 5.73 × 10−6). Furthermore, rare variants in STAT3 associated with worse metformin response (q |
| Databáze: | OpenAIRE |
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