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

doi:10.1126/sciadv.abl6579

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

,

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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.

Original language	English
Article number	eabl6579
Journal	Science advances
Volume	8
Issue number	14
DOIs	https://doi.org/10.1126/sciadv.abl6579
State	Published - Apr 2022

Bibliographical note

Funding Information:
This work was supported by the following: NHLBI 3R01HL-117626-02S1, contract no. HHSN268201800002I (core support including centralized genomic read mapping and genotype calling, along with variant quality metrics and filtering were provided by the TOPMed Informatics Research Center); NHLBI R01HL-120393, U01HL-120393, contract HHSN268201800001I (core support including phenotype harmonization, data management, sample-identity QC, and general program coordination were provided by the TOPMed Data Coordinating Center); NHLBI R01HL146860 (phenotype harmonization for coronary artery disease in TOPMed) (the funding supports for each study in TOPMed are listed in table S4); Biotechnology and Biological Sciences Research Council and British Heart Foundation (BHF) through UK Medical Research Council (MRC) grant MR/M012816/1 (UK Biobank telomere measurement); the Uehara Memorial Foundation Overseas Research Fellowship R-C12, 201740153 (to T.N.); British Heart Foundation (BHF) SP/16/4/32697 (to C.P.N.); National Institutes for Health Research (NIHR) Leicester Cardiovascular Biomedical Research Centre BRC-1215-20010 (to V.C., C.P.N., and N.J.S.); Hassenfeld Scholar Award from the Massachusetts General Hospital (to P.N.); NHLBI R01HL1427, R01HL148565, and R01HL148050 (to P.N.); Fondation Leducq TNE-18CVD04 (to T.N., P.N., and B.L.E.); NHLBI 1R01HL134892, the American Heart Association 18CSA34080399 (to P.L.); NHLBI R01HL046380, R01HL113338, and R35HL135818 (to S.R.); National Center for Advancing Translational Sciences KL2TR002490 (to L.M.R.); National Institute of Diabetes and Digestive and Kidney Disease R01DK110113, R01DK107786, R01DK124097, and R01HL142302 (to R.J.F.L.); and NHLBI PO1 HL132825 (to S.T.W.).

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Copyright © 2022 The Authors, some rights reserved;

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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@article{d58bcfc9734c49fc873c4fbcb16fbe3a,

title = "Mendelian randomization supports bidirectional causality between telomere length and clonal hematopoiesis of indeterminate potential",

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.",

author = "Tetsushi Nakao and Bick, {Alexander G.} and Taub, {Margaret A.} and Zekavat, {Seyedeh M.} and Uddin, {Md M.} and Abhishek Niroula and Carty, {Cara L.} and John Lane and Honigberg, {Michael C.} and Weinstock, {Joshua S.} and Akhil Pampana and Gibson, {Christopher J.} and Griffin, {Gabriel K.} and Clarke, {Shoa L.} and Romit Bhattacharya and Assimes, {Themistocles L.} and Emery, {Leslie S.} and Stilp, {Adrienne M.} and Quenna Wong and Jai Broome and Laurie, {Cecelia A.} and Khan, {Alyna T.} and Smith, {Albert V.} and Blackwell, {Thomas W.} and Veryan Codd and Nelson, {Christopher P.} and Yoneda, {Zachary T.} and Peralta, {Juan M.} and Bowden, {Donald W.} and Irvin, {Marguerite R.} and Meher Boorgula and Wei Zhao and Yanek, {Lisa R.} and Wiggins, {Kerri L.} and Hixson, {James E.} and {Charles Gu}, C. and Peloso, {Gina M.} and Roden, {Dan M.} and Reupena, {Muagututi'a S.} and Hwu, {Chii Min} and DeMeo, {Dawn L.} and North, {Kari E.} and Shannon Kelly and Musani, {Solomon K.} and Bis, {Joshua C.} and Lloyd-Jones, {Donald M.} and Johnsen, {Jill M.} and Michael Preuss and Tracy, {Russell P.} and Arnett, {Donna K.}",

note = "Funding Information: This work was supported by the following: NHLBI 3R01HL-117626-02S1, contract no. HHSN268201800002I (core support including centralized genomic read mapping and genotype calling, along with variant quality metrics and filtering were provided by the TOPMed Informatics Research Center); NHLBI R01HL-120393, U01HL-120393, contract HHSN268201800001I (core support including phenotype harmonization, data management, sample-identity QC, and general program coordination were provided by the TOPMed Data Coordinating Center); NHLBI R01HL146860 (phenotype harmonization for coronary artery disease in TOPMed) (the funding supports for each study in TOPMed are listed in table S4); Biotechnology and Biological Sciences Research Council and British Heart Foundation (BHF) through UK Medical Research Council (MRC) grant MR/M012816/1 (UK Biobank telomere measurement); the Uehara Memorial Foundation Overseas Research Fellowship R-C12, 201740153 (to T.N.); British Heart Foundation (BHF) SP/16/4/32697 (to C.P.N.); National Institutes for Health Research (NIHR) Leicester Cardiovascular Biomedical Research Centre BRC-1215-20010 (to V.C., C.P.N., and N.J.S.); Hassenfeld Scholar Award from the Massachusetts General Hospital (to P.N.); NHLBI R01HL1427, R01HL148565, and R01HL148050 (to P.N.); Fondation Leducq TNE-18CVD04 (to T.N., P.N., and B.L.E.); NHLBI 1R01HL134892, the American Heart Association 18CSA34080399 (to P.L.); NHLBI R01HL046380, R01HL113338, and R35HL135818 (to S.R.); National Center for Advancing Translational Sciences KL2TR002490 (to L.M.R.); National Institute of Diabetes and Digestive and Kidney Disease R01DK110113, R01DK107786, R01DK124097, and R01HL142302 (to R.J.F.L.); and NHLBI PO1 HL132825 (to S.T.W.). Publisher Copyright: Copyright {\textcopyright} 2022 The Authors, some rights reserved;",

year = "2022",

month = apr,

doi = "10.1126/sciadv.abl6579",

language = "English",

volume = "8",

number = "14",

}

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 - Funding Information: This work was supported by the following: NHLBI 3R01HL-117626-02S1, contract no. HHSN268201800002I (core support including centralized genomic read mapping and genotype calling, along with variant quality metrics and filtering were provided by the TOPMed Informatics Research Center); NHLBI R01HL-120393, U01HL-120393, contract HHSN268201800001I (core support including phenotype harmonization, data management, sample-identity QC, and general program coordination were provided by the TOPMed Data Coordinating Center); NHLBI R01HL146860 (phenotype harmonization for coronary artery disease in TOPMed) (the funding supports for each study in TOPMed are listed in table S4); Biotechnology and Biological Sciences Research Council and British Heart Foundation (BHF) through UK Medical Research Council (MRC) grant MR/M012816/1 (UK Biobank telomere measurement); the Uehara Memorial Foundation Overseas Research Fellowship R-C12, 201740153 (to T.N.); British Heart Foundation (BHF) SP/16/4/32697 (to C.P.N.); National Institutes for Health Research (NIHR) Leicester Cardiovascular Biomedical Research Centre BRC-1215-20010 (to V.C., C.P.N., and N.J.S.); Hassenfeld Scholar Award from the Massachusetts General Hospital (to P.N.); NHLBI R01HL1427, R01HL148565, and R01HL148050 (to P.N.); Fondation Leducq TNE-18CVD04 (to T.N., P.N., and B.L.E.); NHLBI 1R01HL134892, the American Heart Association 18CSA34080399 (to P.L.); NHLBI R01HL046380, R01HL113338, and R35HL135818 (to S.R.); National Center for Advancing Translational Sciences KL2TR002490 (to L.M.R.); National Institute of Diabetes and Digestive and Kidney Disease R01DK110113, R01DK107786, R01DK124097, and R01HL142302 (to R.J.F.L.); and NHLBI PO1 HL132825 (to S.T.W.). 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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UR - http://www.scopus.com/inward/citedby.url?scp=85127658648&partnerID=8YFLogxK

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 -

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

Abstract

Bibliographical note

ASJC Scopus subject areas

UN SDGs

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