Mendelian randomization supports bidirectional causality between telomere length and clonal hematopoiesis of indeterminate potential

T. Nakao, A. Niroula, Ron Do, The Samoan Obesity, Lifestyle and Genetic Adaptations Study (OLaGA) Group, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium

Research output: Contribution to journalArticlepeer-review

Abstract

Human genetic studies support an inverse causal relationship between leukocyte telomere length (LTL) and coronary artery disease (CAD), but directionally mixed effects for LTL and diverse malignancies. Clonal hematopoiesis of indeterminate potential (CHIP), characterized by expansion of hematopoietic cells bearing leukemogenic mutations, predisposes both hematologic malignancy and CAD. TERT (which encodes telomerase reverse transcriptase) is the most significantly associated germline locus for CHIP in genome-wide association studies. Here, we investigated the relationship between CHIP, LTL, and CAD in the Trans-Omics for Precision Medicine (TOPMed) program (n = 63,302) and UK Biobank (n = 47,080). Bidirectional Mendelian randomization studies were consistent with longer genetically imputed LTL increasing propensity to develop CHIP, but CHIP then, in turn, hastens to shorten measured LTL (mLTL). We also demonstrated evidence of modest mediation between CHIP and CAD by mLTL. Our data promote an understanding of potential causal relationships across CHIP and LTL toward prevention of CAD. Copyright © 2022 The Authors, some rights reserved;
Original languageEnglish
Article numbereabl6579
JournalScience Advances
Volume8
Issue number14
DOIs
Publication statusPublished - 2022

Subject classification (UKÄ)

  • Medical Genetics

Free keywords

  • Blood
  • Chromosomes
  • Computer aided design
  • Random processes
  • Causal relationships
  • Coronary artery disease
  • Genetic studies
  • Haematopoiesis
  • Hematopoietic cell
  • Human genetics
  • Leucocytes
  • Mixed effects
  • Randomisation
  • Telomere length
  • Diseases

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