Mendelian randomization supports bidirectional causality between telomere length and clonal hematopoiesis of indeterminate potential
Tetsushi Nakao, Alexander G. Bick, Margaret A. Taub, Seyedeh M. Zekavat, Md Mesbah Uddin, Abhishek Niroula, Cara L. Carty, John Lane, Michael C. Honigberg, Joshua S. Weinstock, Akhil Pampana, Christopher J. Gibson, Gabriel K. Griffin, Shoa L. Clarke, Romit Bhattacharya, Themistocles L. Assimes, Leslie S. Emery, Adrienne M. Stilp, Quenna Wong, Jai Broome, Cecelia Laurie, Alyna Khan, Albert V. Smith, Thomas W. Blackwell, Veryan Codd, Christopher P. Nelson, Zachary T. Yoneda, Juan M. Peralta, Donald W. Bowden, Marguerite R. Irvin, Meher Preethi Boorgula, Wei Zhao, Lisa R. Yanek, Kerri L. Wiggins, James E. Hixson, C. Charles Gu, Gina M. Peloso, Dan M. Roden, Muagututi‘a Sefuiva Reupena, Chii‐Min Hwu, Dawn L. DeMeo, Kari E. North, Shannon Kelly, Solomon K. Musani, Joshua C. Bis, Donald M. Lloyd‐Jones, Jill M. Johnsen, Michael Preuß, Russell P. Tracy, Patricia A. Peyser, Dandi Qiao, Pinkal Desai, Joanne E. Curran, Barry I. Freedman, Hemant K. Tiwari, Sameer Chavan, Jennifer A. Smith, Nicholas L. Smith, Tanika N. Kelly, Bertha Hidalgo, L. Adrienne Cupples, Daniel E. Weeks, Nicola L. Hawley, Ryan L. Minster, The Samoan Obesity, Lifestyle and Genetic Adaptations Study (OLaGA) Group, Ranjan Deka, Take Naseri, Lisa de las Fuentes, Laura M. Raffield, Alanna C. Morrison, Paul S. de Vries, Christie M. Ballantyne, Eimear E. Kenny, Stephen S. Rich, Eric A. Whitsel, Michael H. Cho, M. Benjamin Shoemaker, Betty S. Pace, John Blangero, Nicholette D. Palmer, Braxton D. Mitchell, Alan R. Shuldiner, Kathleen C. Barnes, Susan Redline, Sharon L.R. Kardia, Gonçalo R. Abecasis, Lewis C. Becker, Susan R. Heckbert, Jiang He, Wendy S. Post, Donna K. Arnett, Ramachandran S. Vasan, Dawood Darbar, Scott T. Weiss, Stephen T. McGarvey, Mariza de Andrade, Yii‐Der Ida Chen, Robert C. Kaplan, Deborah A. Meyers, Brian Custer
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.