Metformin, a biguanide, is used as first-line therapy to treat type 2 diabetes (T2D), yet over 35% of patients on metformin monotherapy fail to achieve acceptable glycemic control. In addition, studies indicate that there are profound inter-ethnic differences in the pharmacokinetics and pharmacodynamics of metformin, and that genetic factors contribute to metformin response. To date, there has been only a single published genomewide association study (GWAS) of metformin response in Europeans, and no GWAS in other ethnic The major goal of our study is to identify the genetic loci and pathways that confer nonresponse to metformin in a large multi-ethnic cohort of T2D patients on metformin. Our second goal is to identify rare causal variants that underlie variation in response to metformin through detailed cellular and clinical studies. To this end, we have assembled rich and diverse clinical cohorts including two groups. large multi-ethnic cohorts of patients with T2D on metformin who have provided DNA samples and clinical information (N = 15,000) made available largely through partnerships with the Kaiser Permanente Northern California (KPNC) Research Program on Genes, Environment and Health (RPGEH) and MetGen, an international consortium, which includes multiple cohorts from Europe and the U.S. of patients on metformin (N ~ 10,000). Our overall aims are to:
Aim 1. Identify genetic variants that impact response to metformin in 28,000 participants from multiple ethnic groups in the U.S. and Europe;
and Aim 2. Identify the causal variants of genes discovered in Aim 1, using a multi-tier approach. In particular, we will first use genomewide approaches with meta analyses to discover variants that underlie variation in response to metformin. Next targeted resequencing will be used to associate rare variants in genes that are identified in our GWAS with metformin response. Functional genomic studies in cells will be performed to identify functional variants, which will then be associated with metformin response in our clinical cohorts. Finally, in Aim 3, we will conduct endophenotypic clinical studies to determine clinical measurements of insulin sensitivity and glucose tolerance to understand the mechanisms through which the variants modulate metformin response. Collectively, this research proposal provides a robust multi-tier approach beginning with the largest cohort of patients with T2D on metformin to identify rare and common genetic variants that underlie variation in response to metformin and importantly, to understand their mechanisms. Data generated in this project will contribute enormously to predictive models that ultimately will be used for data-driven prescribing and precision medicine for anti- diabetic drug therapy.

Public Health Relevance

Metformin is a major medication used to treat diabetes, a health problem worldwide, which is associated with heart disease and obesity. How metformin works and why some patients respond poorly are not understood. This research will advance our understanding of the mechanisms responsible for metformin's beneficial effects in multiple ethnic groups using computational and experimental studies in cells and in people.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Xenobiotic and Nutrient Disposition and Action Study Section (XNDA)
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Okita, Richard T
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University of California San Francisco
Schools of Pharmacy
San Francisco
United States
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Rotroff, Daniel M; Yee, Sook Wah; Zhou, Kaixin et al. (2018) Genetic Variants in CPA6 and PRPF31 Are Associated With Variation in Response to Metformin in Individuals With Type 2 Diabetes. Diabetes 67:1428-1440
Yee, Sook Wah; Brackman, Deanna J; Ennis, Elizabeth A et al. (2018) Influence of Transporter Polymorphisms on Drug Disposition and Response: A Perspective From the International Transporter Consortium. Clin Pharmacol Ther 104:803-817
Liang, Xiaomin; Yee, Sook Wah; Chien, Huan-Chieh et al. (2018) Organic cation transporter 1 (OCT1) modulates multiple cardiometabolic traits through effects on hepatic thiamine content. PLoS Biol 16:e2002907
Fitipaldi, Hugo; McCarthy, Mark I; Florez, Jose C et al. (2018) A Global Overview of Precision Medicine in Type 2 Diabetes. Diabetes 67:1911-1922
Giacomini, Kathleen M; Yee, Sook Wah; Mushiroda, Taisei et al. (2017) Genome-wide association studies of drug response and toxicity: an opportunity for genome medicine. Nat Rev Drug Discov 16:1
Khuri, Natalia; Zur, Arik A; Wittwer, Matthias B et al. (2017) Computational Discovery and Experimental Validation of Inhibitors of the Human Intestinal Transporter OATP2B1. J Chem Inf Model 57:1402-1413
Florez, Jose C (2017) Mining the Genome for Therapeutic Targets. Diabetes 66:1770-1778
Florez, Jose C (2017) The pharmacogenetics of metformin. Diabetologia 60:1648-1655
Florez, Jose C (2017) Pharmacogenetics in type 2 diabetes: precision medicine or discovery tool? Diabetologia 60:800-807
Dujic, T; Zhou, K; Yee, S W et al. (2017) Variants in Pharmacokinetic Transporters and Glycemic Response to Metformin: A Metgen Meta-Analysis. Clin Pharmacol Ther 101:763-772

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