Mendelian randomization supports bidirectional causality between telomere length and clonal hematopoiesis of indeterminate potential.
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Nakao T, Bick AG, Taub MA, Zekavat SM, Uddin MM, Niroula A, Carty CL, Lane J, Honigberg MC, Weinstock JS, Pampana A, Gibson CJ, Griffin GK, Clarke SL, Bhattacharya R, Assimes TL, Emery LS, Stilp AM, Wong Q, Broome J, Laurie CA, Khan AT, Smith AV, Blackwell TW, Codd V, Nelson CP, Yoneda ZT, Peralta JM, Bowden DW, Irvin MR, Boorgula M, Zhao W, Yanek LR, Wiggins KL, Hixson JE, Gu CC, Peloso GM, Roden DM, Reupena MS, Hwu CM, DeMeo DL, North KE, Kelly S, Musani SK, Bis JC, Lloyd-Jones DM, Johnsen JM, Preuss M, Tracy RP, Peyser PA, Qiao D, Desai P, Curran JE, Freedman BI, Tiwari HK, Chavan S, Smith JA, Smith NL, Kelly TN, Hidalgo B, Cupples LA, Weeks DE, Hawley NL, Minster RL, Samoan Obesity, Lifestyle and Genetic Adaptations Study (OLaGA) Group , Deka R, Naseri TT, de Las Fuentes L, Raffield LM, Morrison AC, Vries PS, Ballantyne CM, Kenny EE, Rich SS, Whitsel EA, Cho MH, Shoemaker MB, Pace BS, Blangero J, Palmer ND, Mitchell BD, Shuldiner AR, Barnes KC, Redline S, Kardia SLR, Abecasis GR, Becker LC, Heckbert SR, He J, Post W, Arnett DK, Vasan RS, Darbar D, Weiss ST, McGarvey ST, de Andrade M, Chen YI, Kaplan RC, Meyers DA, Custer BS, Correa A, Psaty BM, Fornage M, Manson JE, Boerwinkle E, Konkle BA, Loos RJF, Rotter JI, Silverman EK, Kooperberg C, Danesh J, Samani NJ, Jaiswal S, Libby P, Ellinor PT, Pankratz N, Ebert BL, Reiner AP, Mathias RA, Do R, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium , Natarajan P
Sci Adv 8 (14) eabl6579 [2022-04-08; online 2022-04-06]
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 35385311
DOI 10.1126/sciadv.abl6579
Crossref 10.1126/sciadv.abl6579