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Mendelian randomization supports bidirectional causality between telomere length and clonal hematopoiesis of indeterminate potential.
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.
Affiliation
  • Nakao T; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Bick AG; Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.
  • Taub MA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • Zekavat SM; Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
  • Uddin MM; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Niroula A; Division of Genetic Medicine, Department of Medicine, Vanderbilt University, Nashville, TN, USA.
  • Carty CL; Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
  • Lane J; Yale University School of Medicine, New Haven, CT, USA.
  • Honigberg MC; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Weinstock JS; Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.
  • Pampana A; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Gibson CJ; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • Griffin GK; Department of Laboratory Medicine, Lund University, Lund, Sweden.
  • Clarke SL; Initiative for Research and Education to Advance Community Health, Washington State University, Seattle, WA, USA.
  • Bhattacharya R; Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, MN, USA.
  • Assimes TL; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Emery LS; Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.
  • Stilp AM; Department of Medicine, Harvard Medical School, Boston, MA, USA.
  • Wong Q; Center for Statistical Genetics, Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI, USA.
  • Broome J; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Laurie CA; Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.
  • Khan AT; Department of Medicine, Harvard Medical School, Boston, MA, USA.
  • Smith AV; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Blackwell TW; Department of Pathology, Harvard Medical School, Boston, MA, USA.
  • Codd V; Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.
  • Nelson CP; Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
  • Yoneda ZT; Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.
  • Peralta JM; Division of Cardiology, Massachusetts General Hospital, Boston, MA, USA.
  • Bowden DW; Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
  • Irvin MR; VA Palo Alto Health Care System, Palo Alto, CA, USA.
  • Boorgula M; Department of Biostatistics, University of Washington, Seattle, WA, USA.
  • Zhao W; Department of Biostatistics, University of Washington, Seattle, WA, USA.
  • Yanek LR; Department of Biostatistics, University of Washington, Seattle, WA, USA.
  • Wiggins KL; Department of Biostatistics, University of Washington, Seattle, WA, USA.
  • Hixson JE; Department of Biostatistics, University of Washington, Seattle, WA, USA.
  • Gu CC; Department of Biostatistics, University of Washington, Seattle, WA, USA.
  • Peloso GM; Center for Statistical Genetics, Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI, USA.
  • Roden DM; Center for Statistical Genetics, Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI, USA.
  • Reupena MS; Department of Cardiovascular Sciences, University of Leicester, Leicester, UK.
  • Hwu CM; National Institute for Health Research Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, UK.
  • DeMeo DL; Department of Cardiovascular Sciences, University of Leicester, Leicester, UK.
  • North KE; National Institute for Health Research Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, UK.
  • Kelly S; Division of Cardiology, Vanderbilt University Medical Center, Nashville, TN, USA.
  • Musani SK; Department of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX, USA.
  • Bis JC; Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, USA.
  • Lloyd-Jones DM; Department of Biostatistics, School of Public Health, University of Alabama, Birmingham, AL, USA.
  • Johnsen JM; Division of Biomedical Informatics and Personalized Medicine and the Colorado Center for Personalized Medicine, School of Medicine, University of Colorado, Aurora, CO, USA.
  • Preuss M; Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA.
  • Tracy RP; GeneSTAR Research Program, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Peyser PA; Department of Medicine, University of Washington, Seattle, WA, USA.
Sci Adv ; 8(14): eabl6579, 2022 Apr 08.
Article in En | MEDLINE | ID: mdl-35385311
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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Type of study: Clinical_trials / Etiology_studies Language: En Journal: Sci Adv Year: 2022 Document type: Article Affiliation country: United States
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Full text: 1 Collection: 01-internacional Database: MEDLINE Type of study: Clinical_trials / Etiology_studies Language: En Journal: Sci Adv Year: 2022 Document type: Article Affiliation country: United States