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.
|State||Published - Apr 2022|
Bibliographical noteFunding 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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