Mendelian randomization supports bidirectional causality between telomere length and clonal hematopoiesis of indeterminate potential.
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Authors
Taub, Margaret A
Gibson, Christopher J
Laurie, Cecelia A
Blackwell, Thomas W
Bowden, Donald W
Irvin, Marguerite R
Boorgula, Meher
Zhao, Wei
Hixson, James E
Reupena, Muagututi'a S
DeMeo, Dawn L
Kelly, Shannon
Musani, Solomon K
Desai, Pinkal
Tiwari, Hemant K
Smith, Nicholas L
Cupples, L Adrienne
Samoan Obesity, Lifestyle and Genetic Adaptations Study (OLaGA) Group
Deka, Ranjan
Naseri, Take T
Morrison, Alanna C
Vries, Paul S
Shoemaker, M Benjamin
Pace, Betty S
Blangero, John
Barnes, Kathleen C
Kardia, Sharon LR
Abecasis, Gonçalo R
Becker, Lewis C
Darbar, Dawood
de Andrade, Mariza
Chen, Yii-Der Ida
Kaplan, Robert C
Meyers, Deborah A
Psaty, Bruce M
Fornage, Myriam
Boerwinkle, Eric
Danesh, John
Reiner, Alexander P
NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium
Publication Date
2022-04-08Journal Title
Sci Adv
ISSN
2375-2548
Publisher
American Association for the Advancement of Science (AAAS)
Volume
8
Issue
14
Language
eng
Type
Article
This Version
VoR
Metadata
Show full item recordCitation
Nakao, T., Bick, A. G., Taub, M. A., Zekavat, S. M., Uddin, M. M., Niroula, A., Carty, C. L., et al. (2022). Mendelian randomization supports bidirectional causality between telomere length and clonal hematopoiesis of indeterminate potential.. Sci Adv, 8 (14) https://doi.org/10.1126/sciadv.abl6579
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.
Sponsorship
Medical Research Council (MR/M012816/1)
Identifiers
35385311, PMC8986098
External DOI: https://doi.org/10.1126/sciadv.abl6579
This record's URL: https://www.repository.cam.ac.uk/handle/1810/336929
Rights
Attribution-NonCommercial 4.0 International
Licence URL: https://creativecommons.org/licenses/by-nc/4.0/
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