A genome-wide association study identifies new loci for factor VII and implicates factor VII in ischemic stroke etiology
Por:
de Vries, PS, Sabater-Lleal, M, Huffman, JE, Marten, J, Song, C, Pankratz, N, Bartz, TM, de Haan, HG, Delgado, GE, Eicher, JD, Martinez-Perez, A, Ward-Caviness, CK, Brody, JA, Chen, MH, de Maat, MPM, Franberg, M, Gill, D, Kleber, ME, Rivadeneira, F, Soria, JM, Tang, WH, Tofler, GH, Uitterlinden, AG, Vlieg, AV, Seshadri, S, Boerwinkle, E, Davies, NM, Giese, AK, Ikram, MK, Kittner, SJ, McKnight, B, Psaty, BM, Reiner, AP, Sargurupremraj, M, Taylor, KD, Fornage, M, Hamsten, A, Marz, W, Rosendaal, FR, Souto, JC, Dehghan, A, Johnson, AD, Morrison, AC, O'Donnell, CJ, Smith, NL, INVENT Consortium, MEGASTROKE Consortium Intl
Publicada:
28 feb 2019
Resumen:
Factor VII (FVII) is an important component of the coagulation cascade. Few genetic loci regulating FVII activity and/or levels have been discovered to date. We conducted a meta-analysis of 9 genome-wide association studies of plasma FVII levels (7 FVII activity and 2 FVII antigen) among 27 495 participants of European and African ancestry. Each study performed ancestry-specific association analyses. Inverse variance weighted meta-analysis was performed within each ancestry group and then combined for a trans-ancestry meta-analysis. Our primary analysis included the 7 studies that measured FVII activity, and a secondary analysis included all 9 studies. We provided functional genomic validation for newly identified significant loci by silencing candidate genes in a human liver cell line (HuH7) using small-interfering RNA and then measuring F7 messenger RNA and FVII protein expression. Lastly, we used meta-analysis results to perform Mendelian randomization analysis to estimate the causal effect of FVII activity on coronary artery disease, ischemic stroke (IS), and venous thromboembolism. We identified 2 novel (REEP3 and JAZF1-AS1) and 6 known loci associated with FVII activity, explaining 19.0% of the phenotypic variance. Adding FVII antigen data to the meta-analysis did not result in the discovery of further loci. Silencing REEP3 in HuH7 cells upregulated FVII, whereas silencing JAZF1 downregulated FVII. Mendelian randomization analyses suggest that FVII activity has a positive causal effect on the risk of IS. Variants at REEP3 and JAZF1 contribute to FVII activity by regulating F7 expression levels. FVII activity appears to contribute to the etiology of IS in the general population.
Filiaciones:
de Vries, PS:
Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Dept Epidemiol Human Genet & Environm Sci, Human Genet Ctr, Houston, TX 77030 USA
Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands
Sabater-Lleal, M:
Inst Invest Biomed St Pau, Unit Genom Complex Dis, Barcelona, Spain
Karolinska Inst, Dept Med, Cardiovasc Med Unit, Stockholm, Sweden
Karolinska Univ Hosp, Ctr Mol Med, Stockholm, Sweden
Huffman, JE:
NHLBI, Populat Sci Branch, NIH, Framingham, MA USA
Framingham Heart Dis Epidemiol Study, Framingham, MA USA
Vet Affairs VA Boston Healthcare Syst, Ctr Populat Genom, Jamaica Plain, MA USA
Marten, J:
Univ Edinburgh, Western Gen Hosp, MRC, Human Genet Unit,Inst Genet & Mol Genet & Pathol, Edinburgh, Midlothian, Scotland
Song, C:
NHLBI, Populat Sci Branch, NIH, Framingham, MA USA
Framingham Heart Dis Epidemiol Study, Framingham, MA USA
Uppsala Univ, Dept Med Sci, Uppsala, Sweden
Uppsala Univ, Dept Immunol Genet & Pathol, Uppsala, Sweden
Pankratz, N:
Univ Minnesota, Sch Med, Dept Lab Med & Pathol, Minneapolis, MN 55455 USA
Bartz, TM:
Univ Washington, Dept Biostat, Seattle, WA 98195 USA
de Haan, HG:
Leiden Univ, Dept Clin Epidemiol, Med Ctr, Leiden, Netherlands
Delgado, GE:
Heidelberg Univ, Med Fac Mannheim, Dept Med 5, Mannheim, Germany
Eicher, JD:
NHLBI, Populat Sci Branch, NIH, Framingham, MA USA
Framingham Heart Dis Epidemiol Study, Framingham, MA USA
Martinez-Perez, A:
Inst Invest Biomed St Pau, Unit Genom Complex Dis, Barcelona, Spain
Ward-Caviness, CK:
US EPA, Natl Hlth & Environm Effects Res Lab, Chapel Hill, NC USA
Brody, JA:
Univ Washington, Dept Med, Seattle, WA USA
Chen, MH:
NHLBI, Populat Sci Branch, NIH, Framingham, MA USA
Framingham Heart Dis Epidemiol Study, Framingham, MA USA
de Maat, MPM:
Erasmus MC, Dept Hematol, Rotterdam, Netherlands
Franberg, M:
Karolinska Inst, Dept Med, Cardiovasc Med Unit, Stockholm, Sweden
Karolinska Univ Hosp, Ctr Mol Med, Stockholm, Sweden
Gill, D:
Imperial Coll London, Dept Epidemiol & Biostat, London, England
Imperial Coll London, Dept Stroke Med, London, England
Kleber, ME:
Heidelberg Univ, Med Fac Mannheim, Dept Med 5, Mannheim, Germany
Friedrich Schiller Univ Jena, Inst Nutr, Mannheim, Germany
Rivadeneira, F:
Erasmus MC, Dept Internal Med, Rotterdam, Netherlands
Soria, JM:
Inst Invest Biomed St Pau, Unit Genom Complex Dis, Barcelona, Spain
Tang, WH:
Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA
Tofler, GH:
Univ Sydney, Royal North Shore Hosp, Sydney, NSW, Australia
Uitterlinden, AG:
Erasmus MC, Dept Internal Med, Rotterdam, Netherlands
Vlieg, AV:
Leiden Univ, Dept Clin Epidemiol, Med Ctr, Leiden, Netherlands
Seshadri, S:
Framingham Heart Dis Epidemiol Study, Framingham, MA USA
Boston Univ, Dept Neurol, Boston, MA 02215 USA
Univ Texas Hlth Sci Ctr San Antonio, Glenn Biggs Inst Alzheimers & Neurodegenerat Dis, San Antonio, TX 78229 USA
Boerwinkle, E:
Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Dept Epidemiol Human Genet & Environm Sci, Human Genet Ctr, Houston, TX 77030 USA
Baylor Univ, Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA
Davies, NM:
Univ Bristol, Bristol Med Sch, MRC, Integrat Epidemiol Unit, Bristol, Avon, England
Giese, AK:
Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02115 USA
Ikram, MK:
Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands
Erasmus MC, Dept Neurol, Rotterdam, Netherlands
Kittner, SJ:
Univ Maryland, Sch Med, Dept Neurol, Baltimore, MD 21201 USA
Baltimore VA Med Ctr, Baltimore, MD USA
McKnight, B:
Univ Washington, Dept Biostat, Seattle, WA 98195 USA
Psaty, BM:
Univ Washington, Dept Med, Seattle, WA USA
Univ Washington, Dept Epidemiol, 1730 Minor Ave,Suite 1360, Seattle, WA 98101 USA
Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA
Kaiser Permanente Washington, Kaiser Permanente Washington Res Inst, Seattle, WA USA
Reiner, AP:
Univ Washington, Dept Epidemiol, 1730 Minor Ave,Suite 1360, Seattle, WA 98101 USA
Kaiser Permanente Washington, Kaiser Permanente Washington Res Inst, Seattle, WA USA
Fred Hutchinson Canc Res Ctr, 1124 Columbia St, Seattle, WA 98104 USA
Sargurupremraj, M:
Univ Bordeaux, INSERM, U1219, Bordeaux Populat Hlth Res Ctr, Bordeaux, France
Taylor, KD:
Harbor UCLA Med Ctr, Los Angeles BioMed Res Inst, Dept Pediat, Inst Translat Genom & Populat Sci, Torrance, CA 90509 USA
Fornage, M:
Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Dept Epidemiol Human Genet & Environm Sci, Human Genet Ctr, Houston, TX 77030 USA
Univ Texas Hlth Sci Ctr Houston, Brown Fdn, Inst Mol Med, Houston, TX 77030 USA
Hamsten, A:
Karolinska Inst, Dept Med, Cardiovasc Med Unit, Stockholm, Sweden
Karolinska Univ Hosp, Ctr Mol Med, Stockholm, Sweden
Marz, W:
Heidelberg Univ, Med Fac Mannheim, Dept Med 5, Mannheim, Germany
Synlab Holding Deutschland GmbH, Synlab Acad, Mannheim, Germany
Med Univ Graz, Clin Inst Med & Chem Lab Diagnost, Graz, Austria
Rosendaal, FR:
Leiden Univ, Dept Clin Epidemiol, Med Ctr, Leiden, Netherlands
Leiden Univ, Med Ctr, Einthoven Lab Expt Vasc Med, Leiden, Netherlands
Leiden Univ, Med Ctr, Dept Thrombosis & Hemostasis, Leiden, Netherlands
Souto, JC:
Hosp Santa Creu & Sant Pau, Unitat Hemostasia & Trombosi, Barcelona, Spain
Dehghan, A:
Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands
Imperial Coll London, Dept Epidemiol & Biostat, London, England
Imperial Coll London, Sch Publ Hlth, Publ Hlth England Ctr Environm & Hlth, MRC, London, England
Imperial Coll London, UK Dementia Res Inst, London, England
Johnson, AD:
NHLBI, Populat Sci Branch, NIH, Framingham, MA USA
Framingham Heart Dis Epidemiol Study, Framingham, MA USA
Morrison, AC:
Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Dept Epidemiol Human Genet & Environm Sci, Human Genet Ctr, Houston, TX 77030 USA
O'Donnell, CJ:
NHLBI, Populat Sci Branch, NIH, Framingham, MA USA
VA Boston Healthcare Syst, Cardiol Sect, West Roxbury, MA USA
Smith, NL:
Univ Washington, Dept Epidemiol, 1730 Minor Ave,Suite 1360, Seattle, WA 98101 USA
Kaiser Permanente Washington, Kaiser Permanente Washington Res Inst, Seattle, WA USA
US Dept Vet Affairs, Seattle Epidemiol Res & Informat Ctr, Off Res & Dev, Seattle, WA USA
Green Published, Bronze
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