Statin Use and Genetically Predicted HMG-CoA Reductase Inhibition in Relation to Clonal Hematopoiesis

Abstract Background Clonal hematopoiesis (CH) is associated with increased risks of diverse cardiovascular diseases, hematologic malignancies and mortality, yet no preventive therapies are approved. As emerging data implicate lipid pathways in CH pathogenesis, we investigated the association of statin use and genetically proxied inhibition of HMG-CoA reductase (HMGCR) with CH risk, and validated findings using primary peripheral blood mononuclear cells (PBMCs). Methods We performed an observational analysis of 416,118 UK Biobank participants of European ancestry using multivariable logistic regression to compare CH prevalence among statin users and nonusers. Mendelian randomization (MR) analyses evaluated the causal association of genetically proxied lowering of low-density lipoprotein cholesterol (LDL-C) with risk of CH using two instruments; (i) the lead HMGCR variant (rs12916) which proxied LDL-C lowering by statins, and, (ii) 303 genome-wide LDL-C-lowering variants representing polygenic mechanisms. Summary statistics were obtained from the Global Lipid Genetics Consortium genome-wide association study (N = 842,634). Experimentally, primary PBMCs from a DNMT3A R882 hotspot mutation carrier were cultured in methylcellulose with pravastatin or vehicle control to evaluate colony-forming dynamics. Results Among 416,118 individuals, 20,488 had CH, including 11,550 with single DNMT3A -mutant and 4,375 with single TET2 -mutant CH. Pre-recruitment statin users had reduced odds of DNMT3A -mutant CH (OR=0.93; 95% CI:0.88-0.98; P =0.009), driven primarily by associations with DNMT3A R882 –mutant (OR=0.78; 95% CI:0.66-0.92; P =0.003), but not TET2 -mutant CH (OR=1.05; 95% CI:0.97-1.14; P =0.20). Similarly, genetically predicted HMG-CoA-reductase inhibition equivalent to a 1 SD reduction in circulating LDL-C levels was associated with lower odds of DNMT3A -mutant CH (OR=0.66; 95% CI:0.45-0.95; P =0.03) but not TET2 -mutant CH (OR=1.34; 95% CI:0.76-2.36; P = 0.31). By contrast, polygenic estimation of LDL-C lowering was not associated with DNMT3A -mutant CH (OR=1.05; 95% CI:0.97-1.14; P =0.20), suggesting protective effects were independent of LDL-C lowering per se. Genetically predicted HMG-CoA reductase inhibition had wide effects on blood cell counts and indices, suggesting effects on bone marrow cell dynamics. In vitro , pravastatin selectively suppressed colony formation of primary human DNMT3A R882 –mutant relative to wild-type cells (P=0.031). Conclusions Statin therapy and genetically predicted lifelong inhibition of HMG-CoA reductase were significantly associated with reduced risk of DNMT3A -mutant CH, likely via LDL-C-independent mechanisms, which may be specific to DNMT3A -mutant CH. This provides a strong rationale for prospective trials evaluating the effect of statins on risk of developing DNMT3A -mutant CH, subsequent clonal expansion, and associated clinical sequelae. Clinical Perspectives What is new? This study provides the first evidence that statins may protect against DNMT3A -mutant clonal hematopoiesis (CH), with convergent findings of observational analysis of statin users and genetic epidemiology utilizing Mendelian randomization to proxy lifelong HMG-CoA reductase inhibition. Observational analyses suggest the protective effect may be strongest against DNMT3A R882 –mutant CH. We provide evidence that pravastatin selectively suppresses colony formation of primary human DNMT3A R882 –mutant primary peripheral blood mononuclear cells in vitro , suggesting a possible effect on clonal expansion. What are the clinical implications? Although DNMT3A -mutant CH is associated with diverse cardiovascular diseases, hematological malignancies and mortality, no preventive treatments are currently established; this study provides a viable avenue for future interventional studies. These data establish a strong rationale for prospective trials evaluating whether statins prevent the development or expansion of DNMT3A -mutant CH and its cardiovascular consequences. Given that statins are widely used with established safety profiles, affordable and have proven cardiovascular benefit, such trials are readily implementable.