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 M 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 A Laurie; Alyna T 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 Boorgula; Wei Zhao; Lisa R Yanek; Kerri L Wiggins; James E Hixson; C Charles Gu; Gina M Peloso; Dan M Roden; Muagututi'a S 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; Samoan Obesity, Lifestyle and Genetic Adaptations Study (OLaGA) Group; Ranjan Deka; Take T Naseri; Lisa de las Fuentes; Laura M Raffield; Alanna C Morrison; Paul S 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 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 S Custer; Adolfo Correa; Bruce M Psaty; Myriam Fornage; JoAnn E Manson; Eric Boerwinkle; Barbara A Konkle; Ruth J F Loos; Jerome I Rotter; Edwin K Silverman; Charles Kooperberg; John Danesh; Nilesh J Samani; Siddhartha Jaiswal; Peter Libby; Patrick T Ellinor; Nathan Pankratz; Benjamin L Ebert; Alexander P Reiner; Rasika A Mathias; Ron Do; NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium; Pradeep Natarajan

doi:10.1126/sciadv.abl6579

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

Sci Adv. 2022 Apr 8;8(14):eabl6579. doi: 10.1126/sciadv.abl6579. Epub 2022 Apr 6.

Authors

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.

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.

Abstract

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