American Diabetes Association
Metformin_GWAS_supplement_20230801Sb.pdf (2.28 MB)

Genome-wide association study identifies pharmacogenomic variants associated with metformin glycemic response in African American patients with type-2 diabetes

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posted on 2023-08-28, 20:38 authored by Baojun Wu, Sook Wah Yee, Shujie Xiao, Fei Xu, Sneha B. Sridhar, Mao Yang, Samantha Hochstadt, Whitney Cabra, David E. Lanfear, Monique M Hedderson, Kathleen M. Giacomini, L. Keoki Williams

OBJECTIVE: Metformin is the most common treatment for type-2 diabetes (T2D). However, there have been no pharmacogenomic studies for T2D in which a population of color was used in the discovery analysis. This study sought to identify genomic variants associated with metformin response in African American patients with diabetes.

RESEARCH DESIGN AND METHODS: Patients in the discovery set were adult, African American participants from the Diabetes Mult-omic Investigation of Drug Response (DIAMOND), a cohort study of T2D patients from a health system serving southeast Michigan. DIAMOND participants had genome-wide genotype data and longitudinal electronic records of laboratory results and medication fills. The genome-wide discovery analysis identified polymorphisms correlated to changes in hemoglobin A1c (HbA1c) levels among individuals on metformin monotherapy. Lead associations were assessed for replication in an independent cohort of African American participants from Kaiser Permanente Northern California (KPNC) and in European American participants from DIAMOND.

RESULTS: The discovery set consisted of 447 African American individuals, whereas the replication sets included 353 African American KPNC participants and 466 European American DIAMOND participants. The primary analysis identified a variant, rs143276236, in the gene ARFGEF3, which met the threshold for genome-wide significance, replicated in KPNC African Americans, and was still significant in the meta-analysis (P=1.17x10-9). None of the significant discovery variants replicated in European Americans DIAMOND participants.

CONCLUSIONS: We identified a novel and biologically plausible genetic variant associated with a change in HbA1c levels among African American patients on metformin monotherapy. These results highlight the importance of diversity in pharmacogenomic studies.


This project was supported by grant funding from the Fund for Henry Ford Hospital and multiple institutes from the National Institutes of Health: the Diabetes, Digestive, and Kidney Disorders (R01DK064695 and R01DK113003 to LKW), the National Heart Lung and Blood Institute (R01HL079055, R01HL118267, and R01HL141845 to LKW), the National Institute of Allergy and Infectious Diseases (R01AI079139 and R56AI165903 to LKW) and the National Institute of General Medical Sciences (U01GM061390 and R01GM117163 to SWY, KMG, MMH). SWY and KMG would like to acknowledge Dr. Michiaki Kubo, Dr. Atsushi Takahashi, Dr. Shiro Maeda, Dr. Yukihide Momozawa and Dr. Yoichiro Kamatani at RIKEN Institute, Japan for performing genotyping of the KPNC cohort on the Illumina Infinium OmniExpress-24 v1.2 array.


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