Mendelian randomization supports bidirectional causality between telomere length and clonal hematopoiesis of indeterminate potential.
Tetsushi NakaoAlexander G BickMargaret A TaubSeyedeh Maryam ZekavatM D Mesbah UddinAbhishek NiroulaCara L CartyJohn LaneMichael C HonigbergJoshua S WeinstockAkhil PampanaChristopher J GibsonGabriel K GriffinShoa L ClarkeRomit BhattacharyaThemistocles L AssimesLeslie S EmeryAdrienne M StilpQuenna WongJai G BroomeCecelia A LaurieAlyna T KhanAlbert Vernon SmithThomas W BlackwellVeryan CoddChristopher P NelsonZachary T YonedaJuan M PeraltaDonald W BowdenMarguerite R IrvinMeher BoorgulaWei ZhaoLisa R YanekKerri L WigginsJames E HixsonCharles C GuGina M PelosoDan M RodenMuagututi'a S ReupenaChii-Min HwaDawn L DeMeoKari E NorthShannon KellySolomon K MusaniJoshua C BisDonald M Lloyd-JonesJill M JohnsenMichael H PreussRussell P TracyPatricia A PeyserDandi QiaoPinkal DesaiJoanne E CurranBarry I FreedmanHemant K TiwariSameer ChavanJennifer A SmithNicholas L SmithTanika N KellyBertha A HidalgoL Adrienne CupplesDaniel E WeeksNicola L HawleyRyan L Minsternull nullRanjan DekaTake T NaseriLisa de Las FuentesLaura M RaffieldAlanna C MorrisonPaul S VriesChristie M BallantyneEimear E KennyStephen S RichEric A WhitselMichael H ChoM Benjamin ShoemakerBetty S PaceJohn BlangeroNicholette D D AllredBraxton D MitchellAlan R ShuldinerKathleen C BarnesSusan RedlineSharon L R KardiaGonçalo R AbecasisLewis C BeckerSusan R HeckbertJiang HeWendy S PostDonna K ArnettRamachandran S VasanDawood DarbarScott T WeissStephen T McGarveyMariza de AndradeYii-Der Ida ChenRobert C KaplanDeborah A MeyersBrian S CusterAdolfo CorreaBruce M PsatyMyriam FornageJo Ann E MansonEric BoerwinkleBarbara A KonkleRuth J F LoosJerome I RotterEdwin K SilvermanCharles KooperbergJohn DaneshNilesh J SamaniSiddhartha JaiswalPeter LibbyPatrick T EllinorNathan D PankratzBenjamin L EbertAlexander P ReinerRasika A MathiasRon Donull nullPradeep NatarajanPublished in: Science advances (2022)
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.
Keyphrases
- coronary artery disease
- high throughput
- circulating tumor cells
- cardiovascular events
- percutaneous coronary intervention
- coronary artery bypass grafting
- genome wide association
- induced apoptosis
- single cell
- gene expression
- case control
- dna methylation
- electronic health record
- depressive symptoms
- copy number
- climate change
- endoplasmic reticulum stress
- cell death
- quantum dots
- cell proliferation
- mass spectrometry
- peripheral blood
- deep learning
- induced pluripotent stem cells
- hematopoietic stem cell