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

Nakao, T. ; Niroula, A. LU and Do, Ron (2022) In Science Advances 8(14).
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... (More)
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; (Less)
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author
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Contribution to journal
publication status
published
subject
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
in
Science Advances
volume
8
issue
14
article number
eabl6579
publisher
American Association for the Advancement of Science (AAAS)
external identifiers
  • scopus:85127658648
  • pmid:35385311
ISSN
2375-2548
DOI
10.1126/sciadv.abl6579
language
English
LU publication?
yes
id
78149dc6-fe09-432f-8690-39a394a83d27
date added to LUP
2022-09-12 08:59:45
date last changed
2023-05-15 11:23:05
@article{78149dc6-fe09-432f-8690-39a394a83d27,
  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;}},
  author       = {{Nakao, T. and Niroula, A. and Do, Ron}},
  issn         = {{2375-2548}},
  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}},
  language     = {{eng}},
  number       = {{14}},
  publisher    = {{American Association for the Advancement of Science (AAAS)}},
  series       = {{Science Advances}},
  title        = {{Mendelian randomization supports bidirectional causality between telomere length and clonal hematopoiesis of indeterminate potential}},
  url          = {{http://dx.doi.org/10.1126/sciadv.abl6579}},
  doi          = {{10.1126/sciadv.abl6579}},
  volume       = {{8}},
  year         = {{2022}},
}