A genetic association study of circulating coagulation factor VIII and von Willebrand factor levels.
Paul S de VriesPaula ReventunMichael R BrownAdam S HeathJennifer E HuffmanNgoc-Quynh LeAllison BeboJennifer A BrodyGerard Temprano-SagreraLaura M RaffieldAyse Bilge OzelFlorian ThibordDeepti JainJoshua P LewisBenjamin A T RodriguezNathan PankratzKent D TaylorOzren PolasekMing-Huei ChenLisa R YanekGerman D CarrasquillaRiccardo E MarioniMarcus E KleberDavid-Alexandre TrégouëtJie YaoRuifang Li-GaoPeter K JoshiStella TrompetAngel Martinez-PerezMohsen GhanbariTom E HowardAlex P ReinerMarios ArvanitisKathleen A RyanTraci M BartzIgor RudanNauder FaradayAllan LinnebergLynette EkunweGail DaviesGraciela E DelgadoPierre SuchonXiuqing GuoFrits Richard RosendaalLucija KlarićRaymond NoordamFrank J A van RooijJoanne E CurranMarsha M WheelerWilliam O OsburnJeffrey R O'ConnellEric BoerwinkleAndrew David BeswickBruce M PsatyIvana KolčićJuan Carlos Carlos SoutoLewis C BeckerTorben HansenMargaret F DoyleSarah E HarrisAngela P MoisslJean-François DeleuzeStephen S RichAstrid van Hylckama VliegHarry CampbellDavid J StottJose Manuel SoriaMoniek P M de MaatLaura AlmasyLawrence C BrodyPaul L AuerBraxton D MitchellYoav Ben-ShlomoMyriam FornageCaroline HaywardRasika A MathiasTuomas O KilpeläinenLeslie A LangeSimon R CoxWinfried MärzPierre-Emmanuel MorangeJerome I RotterDennis O Mook-KanamoriJames F WilsonPim van der HarstJohan Wouter JukemaM Arfan IkramJohn BlangeroCharles KooperbergKarl C DeschAndrew Danner JohnsonMaria Sabater-LlealCharles J LowensteinNicholas L SmithAlanna C MorrisonPublished in: Blood (2024)
Coagulation factor VIII (FVIII) and its carrier protein von Willebrand factor (VWF) are critical to coagulation and platelet aggregation. We leveraged whole-genome sequence data from the Trans-Omics for Precision Medicine (TOPMed) program along with TOPMed-based imputation of genotypes in additional samples to identify genetic associations with circulating FVIII and VWF levels in a single-variant meta-analysis, including up to 45 289 participants. Gene-based aggregate tests were implemented in TOPMed. We identified 3 candidate causal genes and tested their functional effect on FVIII release from human liver endothelial cells (HLECs) and VWF release from human umbilical vein endothelial cells. Mendelian randomization was also performed to provide evidence for causal associations of FVIII and VWF with thrombotic outcomes. We identified associations (P < 5 × 10-9) at 7 new loci for FVIII (ST3GAL4, CLEC4M, B3GNT2, ASGR1, F12, KNG1, and TREM1/NCR2) and 1 for VWF (B3GNT2). VWF, ABO, and STAB2 were associated with FVIII and VWF in gene-based analyses. Multiphenotype analysis of FVIII and VWF identified another 3 new loci, including PDIA3. Silencing of B3GNT2 and the previously reported CD36 gene decreased release of FVIII by HLECs, whereas silencing of B3GNT2, CD36, and PDIA3 decreased release of VWF by HVECs. Mendelian randomization supports causal association of higher FVIII and VWF with increased risk of thrombotic outcomes. Seven new loci were identified for FVIII and 1 for VWF, with evidence supporting causal associations of FVIII and VWF with thrombotic outcomes. B3GNT2, CD36, and PDIA3 modulate the release of FVIII and/or VWF in vitro.
Keyphrases
- genome wide
- endothelial cells
- systematic review
- copy number
- dna methylation
- randomized controlled trial
- type diabetes
- genome wide identification
- metabolic syndrome
- machine learning
- gene expression
- electronic health record
- genome wide association study
- weight loss
- artificial intelligence
- protein protein
- glycemic control
- genome wide analysis