Metformin, a biguanide, is used as first-line therapy to treat patients with type 2 diabetes (T2D), yet over 35% of patients on metformin monotherapy fail to achieve acceptable glycemic control. 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
Among the world’s most widely prescribed drugs, metformin is used by 120 million patients with T2D worldwide. Given how little we know about this enigmatic yet widely prescribed drug, even one unequivocal insight would be of immense value. The specific aims of our project are to:
Overview of MAPP approaches and goals.
Aim 1. Identify genetic variants that impact response to metformin in 28,000 participants from multiple ethnic groups in the U.S. and Europe. In particular, we will conduct the largest GWAS of metformin response (N ~ 18,000) in multiple ethnic groups and validate the findings in a large international metformin consortium (MetGen) (Total sample size = 28,000).
Aim 2. Identify the causal variants of genes discovered in Aim 1, using a multi-tier approach. In particular, we will discover and functionally analyze rare variants in genes identified in our GWAS; and associate functional variants with metformin response. Aim 3. Determine the pharmacologic mechanisms of functional variants in detailed endophenotypic clinical studies that include clinical measurements of metformin response. In particular, we will determine how functional SNPs identified in Aim 2 affect key metformin endophenotypes, e.g. insulin sensitivity, fasting glucose.