Fig. 5: Metformin curtails DNMT3A-R882 CH in humans.
From: Mitochondrial metabolism sustains DNMT3A-R882-mutant clonal haematopoiesis
a, Schematic representation of the UKB analysis. b, Association between metformin and CH risk. In total, 11,190 individuals taking metformin or metformin in combination with other antidiabetic medications and 401,044 individuals not on metformin were analysed. c, Association between metformin and CH risk. Only individuals taking metformin were included in the analysis. In total, 5,644 individuals on metformin only and 398,712 individuals not on any form of antidiabetic medications were analysed. d, Association between undiagnosed/untreated diabetes and overall CH or gene-specific CH risk. HbA1c > 7% (equivalent of 53 mmol mol−1) was used to identify individuals with undiagnosed/untreated diabetes. Diabetic individuals and individuals taking metformin or other antidiabetic medications at recruitment were excluded. In total, 374,873 individuals with HbA1c data available were included (1,195 individuals with HbA1c > 7% and 373,642 with HbA1c ≤ 7%). e, Association between post-recruitment metformin intake and CH risk. Diabetic individuals and individuals taking metformin or other antidiabetic medications at recruitment were excluded. In total, 3,568 individuals who started on metformin at some time after recruitment (post-recruitment metformin) and 389,153 controls were included for analysis. In b–e, measures of centre represent the ORs, and the error bars represent the lower and upper bound of the 95% CI of the ORs. ORs and two-sided unadjusted P values were derived from logistic regression model with all CH or gene-specific CH as outcome, and with age, sex, smoking and the first four genetic principal components as covariates. Significant P values (<0.05) are indicated with full blue circles. f, Experimental strategy for testing the effect of metformin on DNMT3A-R882 clonal growth (versus WT). g,h, Sanger sequencing (g) and next-generation sequencing (h) of DNA collected from bulk colonies. i, Comparison of the proportion of WT versus DNMT3A-R882 colonies in metformin- versus vehicle-treated cells (P by two-sided Chi-square test). Schematics in a,d,e,f were created using BioRender (https://biorender.com).
