A genetic association study of circulating coagulation factor VIII and von Willebrand factor levels
Por:
de Vries, PS, Reventun, P, Brown, MR, Heath, AS, Huffman, JE, Le, NQ, Bebo, A, Brody, JA, Temprano-Sagrera, G, Raffield, LM, Ozel, AB, Thibord, F, Jain, D, Lewis, JP, Rodriguez, BAT, Pankratz, N, Taylor, KD, Polasek, O, Chen, MH, Yanek, LR, Carrasquilla, GD, Marioni, RE, Kleber, ME, Trégouët, DA, Yao, J, Li-Gao, R, Joshi, PK, Trompet, S, Martinez-Perez, A, Ghanbari, M, Howard, TE, Reiner, AP, Arvanitis, M, Ryan, KA, Bartz, TM, Rudan, I, Faraday, N, Linneberg, A, Ekunwe, L, Davies, G, Delgado, GE, Suchon, P, Guo, XQ, Rosendaal, FR, Klaric, L, Noordam, R, van Rooij, F, Curran, JE, Wheeler, MM, Osburn, WO, O'Connell, JR, Boerwinkle, E, Beswick, A, Psaty, BM, Kolcic, I, Souto, JC, Becker, LC, Hansen, T, Doyle, MF, Harris, SE, Moissl, AP, Deleuze, JF, Rich, SS, Vlieg, AV, Campbell, H, Stott, DJ, Soria, JM, de Maat, MPM, Almasy, L, Brody, LC, Auer, PL, Mitchell, BD, Ben-Shlomo, Y, Fornage, M, Hayward, C, Mathias, RA, Kilpelaeinen, TO, Lange, LA, Cox, SR, März, W, Morange, PE, Rotter, JI, Mook-Kanamori, DO, Wilson, JF, van der Harst, P, Jukema, JW, Ikram, MA, Blangero, J, Kooperberg, C, Desch, KC, Johnson, AD, Sabater-Lleal, M, Lowenstein, CJ, Smith, NL, Morrison, AC
Publicada:
2 may 2024
Ahead of Print:
1 may 2024
Resumen:
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 fi ed 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 fi ed associations (P < 5 x 10(-9)) at 7 new loci for FVIII (ST3GAL4, CLEC4M, B3GNT2, ASGR1, F12, KNG1, and TREM1/NCR2) / 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 fi ed 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 fi ed 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.
Filiaciones:
de Vries, PS:
Univ Texas Hlth Sci Ctr Houston, Human Genet Ctr, Sch Publ Hlth, Dept Epidemiol Human Genet & Environm Sci, 1200 Pressler St,Ste E-429, Houston 77030, TX USA
Reventun, P:
Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD USA
Brown, MR:
Univ Texas Hlth Sci Ctr Houston, Human Genet Ctr, Sch Publ Hlth, Dept Epidemiol Human Genet & Environm Sci, 1200 Pressler St,Ste E-429, Houston 77030, TX USA
Heath, AS:
Univ Texas Hlth Sci Ctr Houston, Human Genet Ctr, Sch Publ Hlth, Dept Epidemiol Human Genet & Environm Sci, 1200 Pressler St,Ste E-429, Houston 77030, TX USA
Huffman, JE:
VA Boston Healthcare Syst, Massachusetts Vet Epidemiol Res & Informat Ctr, Boston, MA USA
Le, NQ:
Inst Recerca St Pau, Unit Genom Complex Dis, Barcelona, Spain
Bebo, A:
Univ Texas Hlth Sci Ctr Houston, Human Genet Ctr, Sch Publ Hlth, Dept Epidemiol Human Genet & Environm Sci, 1200 Pressler St,Ste E-429, Houston 77030, TX USA
Brody, JA:
Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA
Temprano-Sagrera, G:
Inst Recerca St Pau, Unit Genom Complex Dis, Barcelona, Spain
Raffield, LM:
Univ N Carolina, Dept Genet, Chapel Hill, NC USA
Ozel, AB:
Univ Michigan, Dept Human Genet, Ann Arbor, MI USA
Thibord, F:
NHLBI, Div Intramural Res, Populat Sci Branch, Framingham Heart Study, Framingham, MA USA
Jain, D:
Univ Washington, Genet Anal Ctr, Sch Publ Hlth, Dept Biostat, Seattle, WA USA
Lewis, JP:
Univ Maryland, Dept Med, Baltimore, MD USA
Rodriguez, BAT:
NHLBI, Div Intramural Res, Populat Sci Branch, Framingham Heart Study, Framingham, MA USA
Pankratz, N:
Univ Minnesota, Dept Lab Med & Pathol, Minneapolis, MN USA
Taylor, KD:
Harbor UCLA Med Ctr, Inst Translat Genom & Populat Sci, Lundquist Inst Biomed Innovat, Dept Pediat, Torrance, CA USA
Polasek, O:
Univ Split, Fac Med, Split, Croatia
Chen, MH:
NHLBI, Div Intramural Res, Populat Sci Branch, Framingham Heart Study, Framingham, MA USA
Yanek, LR:
Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD USA
Carrasquilla, GD:
Univ Copenhagen, Novo Nordisk Fdn, Ctr Basic Metab Res, Copenhagen, Denmark
Karolinska Inst, Inst Environm Med, Stockholm, Sweden
Marioni, RE:
Univ Edinburgh, Inst Genet & Canc, Ctr Genom & Expt Med, Edinburgh, Scotland
Kleber, ME:
Synlab MVZ Humangenet Mannheim, Mannheim, Germany
Heidelberg Univ, Med Fac Mannheim, Dept Med 5, Mannheim, Germany
Trégouët, DA:
Bordeaux Populat Hlth Res Ctr, INSERM, UMR 1219, Bordeaux, France
Yao, J:
Harbor UCLA Med Ctr, Inst Translat Genom & Populat Sci, Lundquist Inst Biomed Innovat, Dept Pediat, Torrance, CA USA
Li-Gao, R:
Leiden Univ, Med Ctr, Dept Clin Epidemiol, Leiden, Netherlands
Joshi, PK:
Univ Edinburgh, Usher Inst, Ctr Global Hlth Res, Edinburgh, Scotland
Trompet, S:
Leiden Univ, Med Ctr, Dept Internal Med, Sect Gerontol & Geriatr, Leiden, Netherlands
Martinez-Perez, A:
Inst Recerca St Pau, Unit Genom Complex Dis, Barcelona, Spain
Ghanbari, M:
Erasmus MC Univ, Dept Epidemiol, Med Ctr, Rotterdam, Netherlands
Howard, TE:
Univ Texas Rio Grande Valley, Sch Med, Dept Human Genet, Brownsville, TX USA
Reiner, AP:
Fred Hutchinson Canc Ctr, Publ Hlth Sci, Seattle, WA USA
Arvanitis, M:
Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD USA
Fred Hutchinson Canc Ctr, Publ Hlth Sci, Seattle, WA USA
Ryan, KA:
Univ Maryland, Dept Med, Baltimore, MD USA
Bartz, TM:
Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA
Univ Washington, Dept Biostat, Cardiovasc Hlth Res Unit, Seattle, WA USA
Rudan, I:
Univ Edinburgh, Usher Inst, Ctr Global Hlth Res, Edinburgh, Scotland
Faraday, N:
Johns Hopkins Univ, Sch Med, Dept Anesthesiol & Crit Care Med, Baltimore, MD USA
Linneberg, A:
Bispebjerg & Frederiksberg Hosp, Ctr Clin Res & Prevent, Copenhagen, Denmark
Univ Copenhagen, Fac Hlth & Med Sci, Dept Clin Med, Copenhagen, Denmark
Ekunwe, L:
Univ Mississippi, Med Ctr, Dept Med, Jackson, MS USA
Davies, G:
Univ Edinburgh, Dept Psychol, Lothian Birth Cohorts, Edinburgh, Scotland
Delgado, GE:
Heidelberg Univ, Med Fac Mannheim, Dept Med 5, Mannheim, Germany
Suchon, P:
Aix Marseille Univ, INSERM, INRAE, C2VN, Marseille, France
La Timone Hosp, Lab Haematol, Marseille, France
Guo, XQ:
Harbor UCLA Med Ctr, Inst Translat Genom & Populat Sci, Lundquist Inst Biomed Innovat, Dept Pediat, Torrance, CA USA
Rosendaal, FR:
Leiden Univ, Med Ctr, Dept Clin Epidemiol, Leiden, Netherlands
Klaric, L:
Univ Edinburgh, Inst Genet & Canc, MRC Human Genet Unit, Edinburgh, Scotland
Noordam, R:
Leiden Univ, Med Ctr, Dept Internal Med, Sect Gerontol & Geriatr, Leiden, Netherlands
van Rooij, F:
Erasmus MC Univ, Dept Epidemiol, Med Ctr, Rotterdam, Netherlands
Curran, JE:
Univ Texas Rio Grande Valley, Sch Med, Dept Human Genet, Brownsville, TX USA
Wheeler, MM:
Univ Washington, Dept Genome Sci, Seattle, WA USA
Osburn, WO:
Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD USA
O'Connell, JR:
Univ Maryland, Dept Med, Baltimore, MD USA
Boerwinkle, E:
Univ Texas Hlth Sci Ctr Houston, Human Genet Ctr, Sch Publ Hlth, Dept Epidemiol Human Genet & Environm Sci, 1200 Pressler St,Ste E-429, Houston 77030, TX USA
Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX USA
Beswick, A:
Univ Bristol, Translat Hlth Sci, Bristol, England
Psaty, BM:
Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA
Dept Epidemiol & Hlth Syst, Seattle, WA USA
Dept Populat Hlth, Seattle, WA USA
Kolcic, I:
Univ Split, Fac Med, Split, Croatia
Souto, JC:
Hosp Santa Creu i St Pau, Unit Thrombosis & Hemostasis, Barcelona, Spain
Becker, LC:
Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD USA
Hansen, T:
Univ Copenhagen, Novo Nordisk Fdn, Ctr Basic Metab Res, Copenhagen, Denmark
Doyle, MF:
Univ Vermont, Larner Coll Med, Dept Pathol & Lab Med, Colchester, VT USA
Harris, SE:
Univ Mississippi, Med Ctr, Dept Med, Jackson, MS USA
Moissl, AP:
Friedrich Schiller Univ Jena, Inst Nutr Sci, Jena, Germany
Competence Cluster Nutr & Cardiovasc Hlth Halle Je, Jena, Germany
Deleuze, JF:
Univ Paris Saclay, Ctr Natl Rech Genom Humaine, CEA, Evry, France
Fdn Jean Dausset, Ctr Etud Polymorphisme Humain, Paris, France
Rich, SS:
Univ Virginia, Ctr Publ Hlth Genom, Dept Publ Hlth Sci, Charlottesville, VA USA
Vlieg, AV:
Leiden Univ, Med Ctr, Dept Clin Epidemiol, Leiden, Netherlands
Campbell, H:
Univ Edinburgh, Usher Inst, Ctr Global Hlth Res, Edinburgh, Scotland
Stott, DJ:
Univ Glasgow, Inst Cardiovasc & Med Sci, Coll Med Vet & Life Sci, Glasgow, Scotland
Soria, JM:
Inst Recerca St Pau, Unit Genom Complex Dis, Barcelona, Spain
de Maat, MPM:
Erasmus MC Univ, Dept Hematol, Med Ctr, Rotterdam, Netherlands
Almasy, L:
Univ Penn, Perelman Sch Med, Dept Genet, Philadelphia, PA USA
Childrens Hosp Philadelphia, Dept Biomed & Hlth Informat, Philadelphia, PA USA
Brody, LC:
Natl Human Genome Res Inst, NIH, Bethesda, MD USA
Auer, PL:
Med Coll Wisconsin, Dept Biostat, Milwaukee, WI USA
Mitchell, BD:
Baltimore Vet Adm Med Ctr, Geriatr Res & Educ Clin Ctr, Baltimore, MD USA
Ben-Shlomo, Y:
Univ Bristol, Populat Hlth Sci, Bristol, England
Fornage, M:
Univ Texas Hlth Sci Ctr Houston, Human Genet Ctr, Sch Publ Hlth, Dept Epidemiol Human Genet & Environm Sci, 1200 Pressler St,Ste E-429, Houston 77030, TX USA
Univ Texas Hlth Sci Ctr Houston, Brown Fdn, Inst Mol Med, McGovern Med Sch, Houston, TX USA
Hayward, C:
Univ Edinburgh, Inst Genet & Canc, MRC Human Genet Unit, Edinburgh, Scotland
Mathias, RA:
Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD USA
Kilpelaeinen, TO:
Univ Copenhagen, Novo Nordisk Fdn, Ctr Basic Metab Res, Copenhagen, Denmark
Lange, LA:
Univ Colorado, Dept Biomed Informat, Anschutz Med Campus, Aurora, CO USA
Cox, SR:
Univ Mississippi, Med Ctr, Dept Med, Jackson, MS USA
März, W:
Heidelberg Univ, Med Fac Mannheim, Dept Med 5, Mannheim, Germany
Synlab Holding Deutschland GmbH, Synlab Acad, Mannheim, Germany
Morange, PE:
Aix Marseille Univ, INSERM, INRAE, C2VN, Marseille, France
La Timone Hosp, Lab Haematol, Marseille, France
Rotter, JI:
Harbor UCLA Med Ctr, Inst Translat Genom & Populat Sci, Lundquist Inst Biomed Innovat, Dept Pediat, Torrance, CA USA
Mook-Kanamori, DO:
Leiden Univ, Med Ctr, Dept Clin Epidemiol, Leiden, Netherlands
Leiden Univ, Med Ctr, Dept Publ Hlth & Primary Care, Leiden, Netherlands
Wilson, JF:
Univ Edinburgh, Usher Inst, Ctr Global Hlth Res, Edinburgh, Scotland
van der Harst, P:
Univ Utrecht, Univ Med Ctr Utrecht, Dept Cardiol, Div Heart & Lungs, Utrecht, Netherlands
Jukema, JW:
Leiden Univ, Med Ctr, Dept Cardiol, Leiden, Netherlands
Netherlands Heart Inst, Utrecht, Netherlands
Ikram, MA:
Erasmus MC Univ, Dept Epidemiol, Med Ctr, Rotterdam, Netherlands
Blangero, J:
Univ Texas Rio Grande Valley, Sch Med, Dept Human Genet, Brownsville, TX USA
Kooperberg, C:
Fred Hutchinson Canc Ctr, Publ Hlth Sci, Seattle, WA USA
Desch, KC:
Univ Michigan, Dept Pediat, CS Mott Childrens Hosp, Ann Arbor, MI USA
Johnson, AD:
NHLBI, Div Intramural Res, Populat Sci Branch, Framingham Heart Study, Framingham, MA USA
Sabater-Lleal, M:
Inst Recerca St Pau, Unit Genom Complex Dis, Barcelona, Spain
Ctr Mol Med, Karolinska Inst, Dept Med, Cardiovasc Med Unit, Stockholm, Sweden
Lowenstein, CJ:
Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD USA
Smith, NL:
Univ Washington, Dept Epidemiol, Seattle, WA USA
Kaiser Permanente Washington, Kaiser Permanente Washington Hlth Res Inst, Seattle, WA USA
Seattle Epidemiol & Informat Ctr, Dept Vet Affairs Off Res & Dev, Seattle, WA USA
Morrison, AC:
Univ Texas Hlth Sci Ctr Houston, Human Genet Ctr, Sch Publ Hlth, Dept Epidemiol Human Genet & Environm Sci, 1200 Pressler St,Ste E-429, Houston 77030, TX USA
Green Submitted
|