TY - JOUR
T1 - Mendelian randomization supports bidirectional causality between telomere length and clonal hematopoiesis of indeterminate potential
AU - Nakao, Tetsushi
AU - Bick, Alexander G.
AU - Taub, Margaret A.
AU - Zekavat, Seyedeh M.
AU - Uddin, Md M.
AU - Niroula, Abhishek
AU - Carty, Cara L.
AU - Lane, John
AU - Honigberg, Michael C.
AU - Weinstock, Joshua S.
AU - Pampana, Akhil
AU - Gibson, Christopher J.
AU - Griffin, Gabriel K.
AU - Clarke, Shoa L.
AU - Bhattacharya, Romit
AU - Assimes, Themistocles L.
AU - Emery, Leslie S.
AU - Stilp, Adrienne M.
AU - Wong, Quenna
AU - Broome, Jai
AU - Laurie, Cecelia A.
AU - Khan, Alyna T.
AU - Smith, Albert V.
AU - Blackwell, Thomas W.
AU - Codd, Veryan
AU - Nelson, Christopher P.
AU - Yoneda, Zachary T.
AU - Peralta, Juan M.
AU - Bowden, Donald W.
AU - Irvin, Marguerite R.
AU - Boorgula, Meher
AU - Zhao, Wei
AU - Yanek, Lisa R.
AU - Wiggins, Kerri L.
AU - Hixson, James E.
AU - Charles Gu, C.
AU - Peloso, Gina M.
AU - Roden, Dan M.
AU - Reupena, Muagututi'a S.
AU - Hwu, Chii Min
AU - DeMeo, Dawn L.
AU - North, Kari E.
AU - Kelly, Shannon
AU - Musani, Solomon K.
AU - Bis, Joshua C.
AU - Lloyd-Jones, Donald M.
AU - Johnsen, Jill M.
AU - Preuss, Michael
AU - Tracy, Russell P.
AU - Arnett, Donna K.
N1 - Publisher Copyright:
Copyright © 2022 The Authors, some rights reserved;
PY - 2022/4
Y1 - 2022/4
N2 - 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.
AB - 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.
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U2 - 10.1126/sciadv.abl6579
DO - 10.1126/sciadv.abl6579
M3 - Article
C2 - 35385311
AN - SCOPUS:85127658648
VL - 8
JO - Science advances
JF - Science advances
IS - 14
M1 - eabl6579
ER -
