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Background: Clonal hematopoiesis of indeterminate potential (CHIP), the expansion of leukemogenic mutations in hematopoietic stem cells in asymptomatic individuals, is an emerging age-related risk factor for blood cancers and myriad cardio-metabolic diseases. The spectrum of metabolites that may protect from or predispose to development of CHIP remains unknown. Methods: We obtained CHIP genotypes and measured serum metabolites among UK Biobank, a population-based study of United Kingdom residents aged 40-70 years. CHIP was also categorized by driver genes DNMT3A and TET2 and presence of large CHIP clones (variant allele fraction or VAF > 10%). 152 lipid and lipoprotein metabolites were performed using NMR from blood samples. The relationship of CHIP to metabolites was assessed by multivariate linear regression adjusting for covariates of age, sex, smoking and principal components 1-10. Results: Among the 12,186 included UK Biobank participants with mean (SD) age 57.1 (8.0), we identified CHIP in 701 (5.75%). 313 participants with CHIP had large clones (VAF>10%), and of these, 169 had DNMT3A mutations and 75 had TET2 mutations. Presence of CHIP was nominally associated with multiple measures of HDL and apolipoprotein B-containing lipoprotein metabolites. Among HDL metabolites, CHIP was associated with reductions in the percentage of HDL total cholesterol (ß = -0.09, P = 0.01), free cholesterol (ß = -0.072, P = 0.01) and cholesteryl ester (ß = -0.087, P = 0.01) and increased HDL triglyceride percentage (ß = 0.09, P = 0.01). Similar findings were observed for small, medium and large HDL particles. CHIP was also associated with decreased percentage of small LDL free cholesterol (ß = -0.089, P = 0.016) and phospholipid (ß = -0.106, P = 0.0057) and increased cholesterol ester (ß = 0.105, P = 0.0061). For VLDL, CHIP was associated with increased VLDL particle number (ß = 0.077, P = 0.035) and VLDL phospholipid percentage (ß = 0.085, P = 0.025) in the largest VLDL particles. Similar findings among HDL and VLDL metabolites were seen in those with large CHIP clones due to TET2 mutations but not with large clones due to DNMT3A mutations. Conclusions: These results reveal novel relationships of CHIP with lipid and lipoprotein metabolites in a population-based cohort.

A 73-year–old man with a history of hypertension and a family history of coronary artery disease (CAD) was seen in an outpatient clinic for stable angina. Physical examination showed bilateral earlobe creases, known as Frank’s sign (Figure 1), and no other relevant cardiac findings. Figure 1. Bilateral earlobe crease (Frank’s sign). ECG showed normal sinus rhythm with no signs of ischemia. He was evaluated with a nuclear stress test, which revealed moderate reversible perfusion defects localized to the …