Mendelian randomization supports bidirectional causality between telomere length and clonal hematopoiesis of indeterminate potential
Authors: Nakao Tetsushi , Bick Alexander G. , Taub Margaret A. , Zekavat Seyedeh M. , Uddin Md M. , Niroula Abhishek , Carty Cara L. , Lane John , Honigberg Michael C. , Weinstock Joshua S. , Pampana Akhil , Gibson Christopher J. , Griffin Gabriel K. , Clarke Shoa L. , Bhattacharya Romit , Assimes Themistocles L. , Emery Leslie S. , Stilp Adrienne M. , Wong Quenna , Broome Jai , Laurie Cecelia A. , Khan Alyna T. , Smith Albert V. , Blackwell Thomas W. , Codd Veryan , Nelson Christopher P. , Yoneda Zachary T. , Peralta Juan M. , Bowden Donald W. , Irvin Marguerite R. , Boorgula Meher , Zhao Wei , Yanek Lisa R. , Wiggins Kerri L. , Hixson James E. , Gu C. Charles , Peloso Gina M. , Roden Dan M. , Reupena Muagututi’a S. , Hwu Chii-Min , DeMeo Dawn L. , North Kari E. , Kelly Shannon , Musani Solomon K. , Bis Joshua C. , Lloyd-Jones Donald M. , Johnsen Jill M. , Preuss Michael , Tracy Russell P. , Peyser Patricia A. , Qiao Dandi , Desai Pinkal , Curran Joanne E. , Freedman Barry I. , Tiwari Hemant K. , Chavan Sameer , Smith Jennifer A. , Smith Nicholas L. , Kelly Tanika N. , Hidalgo Bertha , Cupples L. Adrienne , Weeks Daniel E. , Hawley Nicola L. , Minster Ryan L. ,   The Samoan Obesity, Lifestyle and Genetic Adaptations Study (OLaGA) Group, Deka Ranjan , Naseri Take T. , de las Fuentes Lisa , Raffield Laura M. , Morrison Alanna C. , Vries Paul S. , Ballantyne Christie M. , Kenny Eimear E. , Rich Stephen S. , Whitsel Eric A. , Cho Michael H. , Shoemaker M. Benjamin , Pace Betty S. , Blangero John , Palmer Nicholette D. , Mitchell Braxton D. , Shuldiner Alan R. , Barnes Kathleen C. , Redline Susan , Kardia Sharon L.R. , Abecasis Gonçalo R. , Becker Lewis C. , Heckbert Susan R. , He Jiang , Post Wendy , Arnett Donna K. , Vasan Ramachandran S. , Darbar Dawood , Weiss Scott T. , McGarvey Stephen T. , de Andrade Mariza , Chen Yii-Der Ida , Kaplan Robert C. , Meyers Deborah A. , Custer Brian S. , Correa Adolfo , Psaty Bruce M. , Fornage Myriam , Manson JoAnn E. , Boerwinkle Eric , Konkle Barbara A. , Loos Ruth J.F. , Rotter Jerome I. , Silverman Edwin K. , Kooperberg Charles , Danesh John , Samani Nilesh J. , Jaiswal Siddhartha , Libby Peter , Ellinor Patrick T. , Pankratz Nathan , Ebert Benjamin L. , Reiner Alexander P. , Mathias Rasika A. , Do Ron ,   NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, Natarajan Pradeep 
Published: April 2022

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.