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

Tetsushi Nakao^{1

2

3

4}, Alexander G Bick^{1

5}, Margaret A Taub⁶, Seyedeh M Zekavat⁷, Md M Uddin^{1

2}, Abhishek Niroula^{1

3

8}, Cara L Carty⁹, John Lane¹⁰, Michael C Honigberg^{1

2

11}, Joshua S Weinstock¹², Akhil Pampana^{1

2}, Christopher J Gibson¹¹, Gabriel K Griffin^{1

13

14}, Shoa L Clarke¹⁵, Romit Bhattacharya^{2

16}, Themistocles L Assimes^{15

17}, Leslie S Emery¹⁸, Adrienne M Stilp¹⁸, Quenna Wong¹⁸, Jai Broome¹⁸, Cecelia A Laurie¹⁸, Alyna T Khan¹⁸, Albert V Smith¹², Thomas W Blackwell¹², Veryan Codd^{19

20}, Christopher P Nelson^{19

20}, Zachary T Yoneda²¹, Juan M Peralta²², Donald W Bowden²³, Marguerite R Irvin²⁴, Meher Boorgula²⁵, Wei Zhao²⁶, Lisa R Yanek²⁷, Kerri L Wiggins²⁸, James E Hixson²⁹, C Charles Gu³⁰, Gina M Peloso³¹, Dan M Roden³², Muagututi'a S Reupena³³, Chii-Min Hwu^{34

35}, Dawn L DeMeo³⁶, Kari E North³⁷, Shannon Kelly^{38

39}, Solomon K Musani⁴⁰, Joshua C Bis⁴¹, Donald M Lloyd-Jones^{42

43}, Jill M Johnsen⁴⁴, Michael Preuss⁴⁵, Russell P Tracy^{46

47}, Patricia A Peyser²⁶, Dandi Qiao³⁶, Pinkal Desai⁴⁸, Joanne E Curran²², Barry I Freedman⁴⁹, Hemant K Tiwari⁵⁰, Sameer Chavan²⁵, Jennifer A Smith^{26

51}, Nicholas L Smith^{52

53

54}, Tanika N Kelly^{55

56}, Bertha Hidalgo⁵⁰, L Adrienne Cupples^{31

57}, Daniel E Weeks⁵⁸, Nicola L Hawley⁵⁹, Ryan L Minster⁶⁰; Samoan Obesity, Lifestyle and Genetic Adaptations Study (OLaGA) Group; Ranjan Deka^{61

62}, Take T Naseri⁶³, Lisa de las Fuentes^{30

64}, Laura M Raffield⁶⁵, Alanna C Morrison²⁹, Paul S Vries²⁹, Christie M Ballantyne⁶⁶, Eimear E Kenny^{67

68

69}, Stephen S Rich⁷⁰, Eric A Whitsel^{37

71}, Michael H Cho⁷², M Benjamin Shoemaker²¹, Betty S Pace⁷³, John Blangero²², Nicholette D Palmer²³, Braxton D Mitchell^{74

75}, Alan R Shuldiner⁷⁶, Kathleen C Barnes²⁵, Susan Redline^{11

77

78}, Sharon L R Kardia²⁶, Gonçalo R Abecasis^{12

79}, Lewis C Becker²⁷, Susan R Heckbert^{52

53}, Jiang He^{55

56}, Wendy Post⁸⁰, Donna K Arnett⁸¹, Ramachandran S Vasan^{31

57

82}, Dawood Darbar⁸³, Scott T Weiss^{11

36}, Stephen T McGarvey⁸⁴, Mariza de Andrade⁸⁵, Yii-Der Ida Chen⁸⁶, Robert C Kaplan^{87

88}, Deborah A Meyers⁸⁹, Brian S Custer³⁸, Adolfo Correa⁹⁰, Bruce M Psaty^{41

52

91}, Myriam Fornage^{29

92}, JoAnn E Manson^{11

93

94}, Eric Boerwinkle¹², Barbara A Konkle^{28

95}, Ruth J F Loos^{45

96}, Jerome I Rotter⁸⁶, Edwin K Silverman³⁶, Charles Kooperberg⁹⁷, John Danesh^{98

99

100}, Nilesh J Samani^{19

20}, Siddhartha Jaiswal¹⁰¹, Peter Libby^{4

11}, Patrick T Ellinor^{1

102}, Nathan Pankratz¹⁰, Benjamin L Ebert^{1

3

103}, Alexander P Reiner⁹⁷, Rasika A Mathias²⁷, Ron Do^{45

69

104}; NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium; Pradeep Natarajan^{1

2

11}

Affiliations

¹ Broad Institute of MIT and Harvard, Cambridge, MA, USA.
² Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.
³ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
⁴ Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
⁵ Division of Genetic Medicine, Department of Medicine, Vanderbilt University, Nashville, TN, USA.
⁶ Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
⁷ Yale University School of Medicine, New Haven, CT, USA.
⁸ Department of Laboratory Medicine, Lund University, Lund, Sweden.
⁹ Initiative for Research and Education to Advance Community Health, Washington State University, Seattle, WA, USA.
¹⁰ Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, MN, USA.
¹¹ Department of Medicine, Harvard Medical School, Boston, MA, USA.
¹² Center for Statistical Genetics, Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI, USA.
¹³ Department of Pathology, Harvard Medical School, Boston, MA, USA.
¹⁴ Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.
¹⁵ Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
¹⁶ Division of Cardiology, Massachusetts General Hospital, Boston, MA, USA.
¹⁷ VA Palo Alto Health Care System, Palo Alto, CA, USA.
¹⁸ Department of Biostatistics, University of Washington, Seattle, WA, USA.
¹⁹ Department of Cardiovascular Sciences, University of Leicester, Leicester, UK.
²⁰ National Institute for Health Research Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, UK.
²¹ Division of Cardiology, Vanderbilt University Medical Center, Nashville, TN, USA.
²² Department of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX, USA.
²³ Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, USA.
²⁴ Department of Biostatistics, School of Public Health, University of Alabama, Birmingham, AL, USA.
²⁵ Division of Biomedical Informatics and Personalized Medicine and the Colorado Center for Personalized Medicine, School of Medicine, University of Colorado, Aurora, CO, USA.
²⁶ Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA.
²⁷ GeneSTAR Research Program, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
²⁸ Department of Medicine, University of Washington, Seattle, WA, USA.
²⁹ Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA.
³⁰ Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, USA.
³¹ Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
³² Departments of Medicine, Pharmacology, and Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA.
³³ Ministry of Health, Government of Samoa, Apia, Samoa.
³⁴ Section of Endocrinology and Metabolism, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
³⁵ School of Medicine, National Yang-Ming University, Taipei, Taiwan.
³⁶ Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
³⁷ Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, USA.
³⁸ Vitalant Research Institute, San Francisco, CA, USA.
³⁹ UCSF, Benioff Children's Hospital Oakland, Oakland, CA, USA.
⁴⁰ Jackson Heart Study, Department of Medicine, University of Mississippi Medical Center, Jackson, MS, USA.
⁴¹ Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
⁴² Division of Cardiology Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
⁴³ Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
⁴⁴ Bloodworks Northwest Research Institute, Seattle, WA, USA.
⁴⁵ The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁴⁶ Department of Pathology and Laboratory Medicine, Larner College of Medicine, University of Vermont, Burlington, VT, USA.
⁴⁷ Department of Pathology and Biochemistry, University of Vermont College of Medicine, Burlington, VT, USA.
⁴⁸ Division of Hematology and Oncology, Weill Cornell Medical College, New York, NY, USA.
⁴⁹ Internal Medicine-Nephrology, Wake Forest School of Medicine, Winston-Salem, NC, USA.
⁵⁰ Department of Epidemiology, School of Public Health, University of Alabama, Birmingham, AL, USA.
⁵¹ Survey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, MI, USA.
⁵² Department of Epidemiology, University of Washington, Seattle, WA, USA.
⁵³ Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA.
⁵⁴ Seattle Epidemiologic Research and Information Center, Department of Veterans Affairs Office of Research and Development, Seattle, WA, USA.
⁵⁵ Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA, USA.
⁵⁶ Tulane University Translational Science Institute, New Orleans, LA, USA.
⁵⁷ National Heart Lung and Blood Institute, Boston University's Framingham Heart Study, Framingham, MA, USA.
⁵⁸ Department of Human Genetics and Biostatistics, University of Pittsburgh, Pittsburgh, PA, USA.
⁵⁹ Department of Chronic Disease Epidemiology, Yale University, New Haven, CT, USA.
⁶⁰ Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA.
⁶¹ Department of Environmental Health, University of Cincinnati, Cincinnati, OH, USA.
⁶² Department of Environmental and Public Health Sciences, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
⁶³ Department of Health, American Samoa Government, Pago Pago, American Samoa, USA.
⁶⁴ Cardiovascular Division, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
⁶⁵ Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.
⁶⁶ Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
⁶⁷ Institute for Genomic Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁶⁸ Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁶⁹ Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁷⁰ Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
⁷¹ Department of Medicine, School of Medicine, University of North Carolina, Chapel Hill, NC, USA.
⁷² Channing Division of Network Medicine and Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
⁷³ Division of Hematology/Oncology, Department of Pediatrics, Augusta University, Augusta, GA, USA.
⁷⁴ Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
⁷⁵ Geriatrics Research and Education Clinical Center, Baltimore Veterans Administration Medical Center, Baltimore, MD, USA.
⁷⁶ Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, MD, USA.
⁷⁷ Division of Sleep and Circadian Disorders, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
⁷⁸ Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA.
⁷⁹ Regeneron Pharmaceuticals, Tarrytown, NY, USA.
⁸⁰ Department of Medicine, Division of Cardiology, Johns Hopkins University, Baltimore, MD, USA.
⁸¹ Dean's Office, College of Public Health, University of Kentucky, Lexington, KY, USA.
⁸² Departments of Cardiology and Preventive Medicine, Department of Medicine, Boston University School of Medicine, Boston, MA, USA.
⁸³ Division of Cardiology, University of Illinois at Chicago, Chicago, IL, USA.
⁸⁴ Department of Epidemiology and International Health Institute, Brown University School of Public Health, Providence, RI, USA.
⁸⁵ Mayo Clinic, Department of Health Sciences Research, Rochester, MN, USA.
⁸⁶ The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.
⁸⁷ Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA.
⁸⁸ Fred Hutchinson Cancer Research Center, Division of Public Health Sciences, Seattle, WA, USA.
⁸⁹ Division of Genetics, Genomics and Precision Medicine, University of Arizona, Tucson, AZ, USA.
⁹⁰ Departments of Medicine and Population Health Science, University of Mississippi Medical Center, Jackson, MS, USA.
⁹¹ Department of Health Services, University of Washington, Seattle, WA, USA.
⁹² Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA.
⁹³ Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
⁹⁴ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁹⁵ Bloodworks Northwest, Seattle, WA, USA.
⁹⁶ Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Science, University of Copenhagen, Copenhagen, Denmark.
⁹⁷ Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
⁹⁸ British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
⁹⁹ Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge, Cambridge, UK.
¹⁰⁰ National Institute for Health Research Cambridge Biomedical Research Centre, University of Cambridge and Cambridge University Hospitals, Cambridge, UK.
¹⁰¹ Department of Pathology, Stanford University, Stanford, CA, USA.
¹⁰² Cardiac Arrhythmia Service and Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.
¹⁰³ Howard Hughes Medical Institute, Boston, MA, USA.
¹⁰⁴ Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

PMID: 35385311
PMCID: PMC8986098
DOI: 10.1126/sciadv.abl6579

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

Tetsushi Nakao et al. Sci Adv. 2022.

. 2022 Apr 8;8(14):eabl6579.

doi: 10.1126/sciadv.abl6579. Epub 2022 Apr 6.

Authors

Affiliations

¹ Broad Institute of MIT and Harvard, Cambridge, MA, USA.
² Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.
³ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
⁴ Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
⁵ Division of Genetic Medicine, Department of Medicine, Vanderbilt University, Nashville, TN, USA.
⁶ Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
⁷ Yale University School of Medicine, New Haven, CT, USA.
⁸ Department of Laboratory Medicine, Lund University, Lund, Sweden.
⁹ Initiative for Research and Education to Advance Community Health, Washington State University, Seattle, WA, USA.
¹⁰ Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, MN, USA.
¹¹ Department of Medicine, Harvard Medical School, Boston, MA, USA.
¹² Center for Statistical Genetics, Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI, USA.
¹³ Department of Pathology, Harvard Medical School, Boston, MA, USA.
¹⁴ Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.
¹⁵ Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
¹⁶ Division of Cardiology, Massachusetts General Hospital, Boston, MA, USA.
¹⁷ VA Palo Alto Health Care System, Palo Alto, CA, USA.
¹⁸ Department of Biostatistics, University of Washington, Seattle, WA, USA.
¹⁹ Department of Cardiovascular Sciences, University of Leicester, Leicester, UK.
²⁰ National Institute for Health Research Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, UK.
²¹ Division of Cardiology, Vanderbilt University Medical Center, Nashville, TN, USA.
²² Department of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX, USA.
²³ Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, USA.
²⁴ Department of Biostatistics, School of Public Health, University of Alabama, Birmingham, AL, USA.
²⁵ Division of Biomedical Informatics and Personalized Medicine and the Colorado Center for Personalized Medicine, School of Medicine, University of Colorado, Aurora, CO, USA.
²⁶ Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA.
²⁷ GeneSTAR Research Program, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
²⁸ Department of Medicine, University of Washington, Seattle, WA, USA.
²⁹ Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA.
³⁰ Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, USA.
³¹ Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
³² Departments of Medicine, Pharmacology, and Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA.
³³ Ministry of Health, Government of Samoa, Apia, Samoa.
³⁴ Section of Endocrinology and Metabolism, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
³⁵ School of Medicine, National Yang-Ming University, Taipei, Taiwan.
³⁶ Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
³⁷ Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, USA.
³⁸ Vitalant Research Institute, San Francisco, CA, USA.
³⁹ UCSF, Benioff Children's Hospital Oakland, Oakland, CA, USA.
⁴⁰ Jackson Heart Study, Department of Medicine, University of Mississippi Medical Center, Jackson, MS, USA.
⁴¹ Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
⁴² Division of Cardiology Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
⁴³ Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
⁴⁴ Bloodworks Northwest Research Institute, Seattle, WA, USA.
⁴⁵ The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁴⁶ Department of Pathology and Laboratory Medicine, Larner College of Medicine, University of Vermont, Burlington, VT, USA.
⁴⁷ Department of Pathology and Biochemistry, University of Vermont College of Medicine, Burlington, VT, USA.
⁴⁸ Division of Hematology and Oncology, Weill Cornell Medical College, New York, NY, USA.
⁴⁹ Internal Medicine-Nephrology, Wake Forest School of Medicine, Winston-Salem, NC, USA.
⁵⁰ Department of Epidemiology, School of Public Health, University of Alabama, Birmingham, AL, USA.
⁵¹ Survey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, MI, USA.
⁵² Department of Epidemiology, University of Washington, Seattle, WA, USA.
⁵³ Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA.
⁵⁴ Seattle Epidemiologic Research and Information Center, Department of Veterans Affairs Office of Research and Development, Seattle, WA, USA.
⁵⁵ Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA, USA.
⁵⁶ Tulane University Translational Science Institute, New Orleans, LA, USA.
⁵⁷ National Heart Lung and Blood Institute, Boston University's Framingham Heart Study, Framingham, MA, USA.
⁵⁸ Department of Human Genetics and Biostatistics, University of Pittsburgh, Pittsburgh, PA, USA.
⁵⁹ Department of Chronic Disease Epidemiology, Yale University, New Haven, CT, USA.
⁶⁰ Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA.
⁶¹ Department of Environmental Health, University of Cincinnati, Cincinnati, OH, USA.
⁶² Department of Environmental and Public Health Sciences, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
⁶³ Department of Health, American Samoa Government, Pago Pago, American Samoa, USA.
⁶⁴ Cardiovascular Division, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
⁶⁵ Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.
⁶⁶ Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
⁶⁷ Institute for Genomic Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁶⁸ Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁶⁹ Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁷⁰ Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
⁷¹ Department of Medicine, School of Medicine, University of North Carolina, Chapel Hill, NC, USA.
⁷² Channing Division of Network Medicine and Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
⁷³ Division of Hematology/Oncology, Department of Pediatrics, Augusta University, Augusta, GA, USA.
⁷⁴ Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
⁷⁵ Geriatrics Research and Education Clinical Center, Baltimore Veterans Administration Medical Center, Baltimore, MD, USA.
⁷⁶ Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, MD, USA.
⁷⁷ Division of Sleep and Circadian Disorders, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
⁷⁸ Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA.
⁷⁹ Regeneron Pharmaceuticals, Tarrytown, NY, USA.
⁸⁰ Department of Medicine, Division of Cardiology, Johns Hopkins University, Baltimore, MD, USA.
⁸¹ Dean's Office, College of Public Health, University of Kentucky, Lexington, KY, USA.
⁸² Departments of Cardiology and Preventive Medicine, Department of Medicine, Boston University School of Medicine, Boston, MA, USA.
⁸³ Division of Cardiology, University of Illinois at Chicago, Chicago, IL, USA.
⁸⁴ Department of Epidemiology and International Health Institute, Brown University School of Public Health, Providence, RI, USA.
⁸⁵ Mayo Clinic, Department of Health Sciences Research, Rochester, MN, USA.
⁸⁶ The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.
⁸⁷ Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA.
⁸⁸ Fred Hutchinson Cancer Research Center, Division of Public Health Sciences, Seattle, WA, USA.
⁸⁹ Division of Genetics, Genomics and Precision Medicine, University of Arizona, Tucson, AZ, USA.
⁹⁰ Departments of Medicine and Population Health Science, University of Mississippi Medical Center, Jackson, MS, USA.
⁹¹ Department of Health Services, University of Washington, Seattle, WA, USA.
⁹² Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA.
⁹³ Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
⁹⁴ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁹⁵ Bloodworks Northwest, Seattle, WA, USA.
⁹⁶ Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Science, University of Copenhagen, Copenhagen, Denmark.
⁹⁷ Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
⁹⁸ British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
⁹⁹ Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge, Cambridge, UK.
¹⁰⁰ National Institute for Health Research Cambridge Biomedical Research Centre, University of Cambridge and Cambridge University Hospitals, Cambridge, UK.
¹⁰¹ Department of Pathology, Stanford University, Stanford, CA, USA.
¹⁰² Cardiac Arrhythmia Service and Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.
¹⁰³ Howard Hughes Medical Institute, Boston, MA, USA.
¹⁰⁴ Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

PMID: 35385311
PMCID: PMC8986098
DOI: 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.

PubMed Disclaimer

Figures

**Fig. 1.. Analytical procedure in this study.**
TOPMed (N = 63,302) and UK Biobank (N = 47,054) are the study cohorts. Mutect2 detected CHIP-associated mutations. Telomere length was estimated by TelSeq in TOPMed and qPCR (T/S ratio) in UK Biobank. We performed observational study and causal inference by bidirectional MR between LTL and CHIP. CHIP was associated with shorter LTL in the observational study. Germline genetic factors that increase CHIP development were associated with shorter LTL, whereas germline genetic factors that increase LTL were associated with developing CHIP. Mediation analysis adjusted for the measurable confounders detected the mediation effect of LTL on CHIP. CHIP, clonal hematopoiesis of indeterminate potential; LTL, leukocyte telomere length; TOPMed, Trans-Omics for Precision Medicine; UKBB, UK Biobank.

**Fig. 2.. CHIP prevalence and VAF are associated with shorter LTL.**
The associations of CHIP with LTL were assessed by linear regression model in both TOPMed and UK Biobank and then meta-analyzed by fixed-effect model. Both models were adjusted with age, sex, ever smoking, BMI, the first 11 genetic PCs, study within TOPMed, and sequencing center or batch (study was only applicable to TOPMed). The prevalence of CHIP with greater than 10% VAF associations was evaluated for overall and each mutated gene (A) and for each number of mutated genes in the same individuals (B). (C) The correlation between LTL and VAF among the population with CHIP from both TOPMed and UK Biobank pooled analysis is displayed. A subset in TOPMed with age 40 to 70 was included in the analysis to align with the age distribution in UK Biobank. As we could not include the population without CHIP in the analysis of (C), we added a red dashed line representing the average LTL in the population without CHIP. ***P < 0.001, after Bonferroni’s correction if applicable. DDR, DNA damage repair; VAF, variant allele frequency.

**Fig. 3.. Bidirectional one-sample MR studies indicated the positive causal effect of LTL on CHIP and the inverse causal effect of CHIP on LTL.**
Bidirectional one-sample MR was performed to assess the causal effect of both LTL on CHIP and CHIP on LTL. The summary statistics for LTL GWAS in Li *et al.* (11) was used for IV discovery for LTL on CHIP and TOPMed for CHIP on LTL. IVs were clumped if <10 Mb apart and in linkage disequilibrium (R² > 0.001 calculated in European ancestry from the 1000 Genome Project). IVs were further assessed by Steiger test to mitigate the effect of reverse causation resulting in 16 and 2 IVs, respectively. TOPMed and UK Biobank were used as the test cohort for both CHIP on LTL and LTL on CHIP and meta-analyzed. Used IVs and cohorts for each analysis are summarized in tables S4, S8, and S9. CI, confidence interval; IV, instrumental variable; MR: Mendelian randomization.

**Fig. 4.. Effect of mLTL and gLTL for mutation occurrence.**
Effect estimates of (A) measured LTL (mLTL) and (B) gLTL (one-sample MR using 14 IVs) on singleton mutation occurrence. The vcf files were generated by Mutect2 from 56,266 CRAM files in TOPMed with appropriate filters and single-base substitutions were extracted, stratified by trinucleotide context. IVs were selected as two-sample MR for LTL (Fig. 3) with outlier exclusion. Effect estimates with P < 0.05 are colored. * denotes false discovery rate < 0.05.

**Fig. 5.. Proposed model to explain “telomere paradox” in CHIP.**
People with longer gLTL have a higher incidence of mutagenesis and, thus, have a higher chance to acquire CHIP-associated mutations (middle). The cells that acquired CHIP have a shorter telomere such that mean mLTL decreases as the clone expands (bottom). This model can explain the “paradox” that genetically longer LTL is associated with higher incidence of CHIP, which has measured shorter LTL on average. HSPC, hematopoietic stem cell.

**Fig. 6.. Estimated change of mean LTL in each scenario.**
Schematic representation of estimated change of mLTL in each scenario speculated from our study. The slope after CHIP acquisition may differ by CHIP-related gene and mutation.

See this image and copyright information in PMC

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

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

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