Multi-ancestry genome-wide study identifies effector genes and druggable pathways for coronary artery calcification.
Maryam KavousiMaxime M BosHanna J BarnesChristian L Lino CardenasDoris WongHaojie LuChani J HodonskyLennart P L LandsmeerAdam W TurnerMinjung KhoNatalie R HasbaniPaul S de VriesDonald W BowdenSandesh ChopadeJoris DeelenErnest Diez BenaventeXiuqing GuoEdith HoferShih-Jen HwangSharon M LutzLeo-Pekka LyytikainenLotte SlendersAlbert Vernon SmithMaggie A StanislawskiJessica van SettenQuenna WongLisa R YanekDiane M BeckerMarian BeekmanMatthew J BudoffMary F FeitosaChristopher FinanAustin T HilliardSharon L R KardiaJason C KovacicBrian G KralCarl D LangefeldLenore J LaunerShaista MalikFirdaus A A Mohamed HoeseinMichal MokryReinhold SchmidtJennifer A SmithKent D TaylorJames G TerryJeroen van der GrondJoyce van MeursRozemarijn VliegenthartJianzhao XuKendra A YoungNuno R ZilhãoRobert ZweikerThemistocles L AssimesLewis C BeckerDaniel BosJohn Jeffrey CarrL Adrienne CupplesDominique P V de KleijnMenno de WintherHester M den RuijterMyriam FornageBarry I FreedmanVilmundur G GudnasonAroon D HingoraniJohn E HokansonMohammad Arfan IkramIvana IšgumDavid R JacobsMika KähönenLeslie A LangeTerho LehtimäkiGerard PasterkampOlli T RaitakariHelena SchmidtPieternella Eline SlagboomAndre G UitterlindenMeike W VernooijJoshua C BisNora FranceschiniBruce M PsatyWendy S PostJerome I RotterJohan L M BjorkegrenChristopher J O'DonnellLawrence F BielakPatricia A PeyserRajeev MalhotraSander W van der LaanClint T MillerPublished in: Nature genetics (2023)
Coronary artery calcification (CAC), a measure of subclinical atherosclerosis, predicts future symptomatic coronary artery disease (CAD). Identifying genetic risk factors for CAC may point to new therapeutic avenues for prevention. Currently, there are only four known risk loci for CAC identified from genome-wide association studies (GWAS) in the general population. Here we conducted the largest multi-ancestry GWAS meta-analysis of CAC to date, which comprised 26,909 individuals of European ancestry and 8,867 individuals of African ancestry. We identified 11 independent risk loci, of which eight were new for CAC and five had not been reported for CAD. These new CAC loci are related to bone mineralization, phosphate catabolism and hormone metabolic pathways. Several new loci harbor candidate causal genes supported by multiple lines of functional evidence and are regulators of smooth muscle cell-mediated calcification ex vivo and in vitro. Together, these findings help refine the genetic architecture of CAC and extend our understanding of the biological and potential druggable pathways underlying CAC.
Keyphrases
- genome wide
- genome wide association study
- dna methylation
- coronary artery
- coronary artery disease
- genome wide association
- copy number
- smooth muscle
- chronic kidney disease
- pulmonary artery
- gene expression
- risk assessment
- cell therapy
- coronary artery bypass grafting
- regulatory t cells
- pulmonary hypertension
- soft tissue
- left ventricular
- bone marrow