Extended Data Fig. 10: Lack of association of sulphonylureas and insulin administration or genetically predicted glycemic-related traits with DNMT3A-R882 CH.
From: Mitochondrial metabolism sustains DNMT3A-R882-mutant clonal haematopoiesis
(a) Association between metformin and overall CH or gene-specific CH risk. CH split by small clone (VAF ≤ 10%) and large clone (VAF > 10%). In total, 11,190 individuals taking metformin or metformin in combination with other antidiabetic medications and 401,044 individuals not on metformin were included in the analysis. (b) Distribution of large DNMT3A-R882 clones (VAF > 10%) among 15 individuals taking metformin or metformin in combination with other anti-diabetic medications and 650 individuals not on metformin. The P value was derived using linear regression with VAF as outcome and metformin as predictor, adjusted for age, sex, smoking status, and first four genetic principal components (PCs). Boxplots represent the median, first and third quartiles, with whiskers representing 1.5 times the interquartile range. (c) Association between sulphonylureas (glibenclamide, gliclazide, glipizide, glimepiride, tolbutamide) and overall CH or gene-specific CH risk. Only individuals taking sulphonylureas as the only form of anti-diabetic medication were included in the analysis. In total, 571 individuals on sulphonylureas only and 398,712 individuals not on anti-diabetic medications were included for analysis. We observed significant association for PPM1D CH: OR = 4.49 [95 CI% = 1.99-10.12], P = 0.00029. (d) Association between insulin and overall CH or gene-specific CH risk. Only individuals taking insulin as the only form of anti-diabetic medication were included in the analysis. In total, 1,488 individuals on insulin only and 398,712 individuals not on anti-diabetic were included for analysis. For (a,c,d) odds ratios 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. Measures of centre represent the odds ratios, and the error bars represent the lower and upper bound of the 95% confidence interval of the odds ratios. Significant P values (<0.05) are indicated with full circles. (e-h) MR analyses of the effect of HbA1c, BMI, T2D, BMI-adjusted WTHR (exposure) on overall CH and gene-specific CH risk (outcome). In total, 392,186 individuals not on metformin at recruitment and passed sample-level QC for genotyping array (excluded samples with genotype missingness > 5%, samples with non-XX or -XY chromosome configuration, and samples with high heterozygosity) were included for analysis here. Measures of centre represent the beta coefficients, and the error bars represent the lower and upper bound of the 95% confidence interval of the beta coefficients. Beta coefficients and unadjusted P values were derived from inverse variance weighting method. Significant P values (<0.05) are indicated with full circles. Schematics in c,d were created using BioRender (https://biorender.com).
