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

作者：Paul Carter, Malgorzata Gozdecka, Sean Wen, Pedro M. Quirós, Sam Lockhart, Monika Dudek, Laura Bond, George Richenberg, Susanna C. Larsson, Daniel I. Bromage, Jonathan S. Mitchell, Brian J.P. Huntly, Peter Libby, Murray Charles Henry Clarke, Margarete Fabre, George S. Vassiliou, Stephen Burgess, Siddhartha Kar · 发表于：medRxiv · 年份：2026 · DOI：10.64898/2026.07.08.26357595 · 研究领域：Genetic Associations and Epidemiology、Myeloproliferative Neoplasms: Diagnosis and Treatment、Acute Myeloid Leukemia Research

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...