FGL1 as a modulator of plasma D-dimer levels: Exome-wide marker analysis of plasma tPA, PAI-1, and D-dimer
Por:
Thibord, F, Song, C, Pattee, J, Rodriguez, BAT, Chen, MH, O'Donnell, CJ, Kleber, ME, Delgado, GE, Guo, XQ, Yao, J, Taylor, KD, Ozel, AB, Brody, JA, McKnight, B, Gyorgy, B, Simonsick, E, Leonard, HL, Carrasquilla, GD, Guindo-Martinez, M, Silveira, A, Temprano-Sagrera, G, Yanek, LR, Becker, DM, Mathias, RA, Becker, LC, Raffield, LM, Kilpelainen, TO, Grarup, N, Pedersen, O, Hansen, T, Linneberg, A, Hamsten, A, Watkins, H, Sabater-Lleal, M, Nalls, MA, Tregouet, DA, Morange, PE, Psaty, BM, Tracy, RP, Smith, NL, Desch, KC, Cushman, M, Rotter, JI, de Vries, PS, Pankratz, ND, Folsom, AR, Morrison, AC, Marz, W, Tang, WH, Johnson, AD
Publicada:
1 ago 2021
Ahead of Print:
1 may 2021
Resumen:
Background Use of targeted exome-arrays with common, rare variants and functionally enriched variation has led to discovery of new genes contributing to population variation in risk factors. Plasminogen activator-inhibitor 1 (PAI-1), tissue plasminogen activator (tPA), and the plasma product D-dimer are important components of the fibrinolytic system. There have been few large-scale genome-wide or exome-wide studies of PAI-1, tPA, and D-dimer.
Objectives We sought to discover new genetic loci contributing to variation in these traits using an exome-array approach.
Methods Cohort-level analyses and fixed effects meta-analyses of PAI-1 (n = 15 603), tPA (n = 6876,) and D-dimer (n = 19 306) from 12 cohorts of European ancestry with diverse study design were conducted, including single-variant analyses and gene-based burden testing.
Results Five variants located in NME7, FGL1, and the fibrinogen locus, all associated with D-dimer levels, achieved genome-wide significance (P < 5 x 10(-8)). Replication was sought for these 5 variants, as well as 45 well-imputed variants with P < 1 x 10(-4) in the discovery using an independent cohort. Replication was observed for three out of the five significant associations, including a novel and uncommon (0.013 allele frequency) coding variant p.Trp256Leu in FGL1 (fibrinogen-like-1) with increased plasma D-dimer levels. Additionally, a candidate-gene approach revealed a suggestive association for a coding variant (rs143202684-C) in SERPINB2, and suggestive associations with consistent effect in the replication analysis include an intronic variant (rs11057830-A) in SCARB1 associated with increased D-dimer levels.
Conclusion This work provides new evidence for a role of FGL1 in hemostasis.
Filiaciones:
Thibord, F:
Natl Heart Lung & Blood Inst, Framingham Heart Study, Framingham, MA USA
Song, C:
Natl Heart Lung & Blood Inst, Framingham Heart Study, Framingham, MA USA
Pattee, J:
Univ Minnesota, Sch Publ Hlth, Div Biostat, Minneapolis, MN USA
Rodriguez, BAT:
Natl Heart Lung & Blood Inst, Framingham Heart Study, Framingham, MA USA
Chen, MH:
Natl Heart Lung & Blood Inst, Framingham Heart Study, Framingham, MA USA
O'Donnell, CJ:
Natl Heart Lung & Blood Inst, Framingham Heart Study, Framingham, MA USA
US Dept Vet Affairs, Boston, MA USA
Kleber, ME:
Heidelberg Univ, Med Fac Mannheim, Vth Dept Med, Mannheim, Germany
SYNLAB MVZ Humangenet Mannheim GmbH, Mannheim, Germany
Delgado, GE:
Heidelberg Univ, Med Fac Mannheim, Vth Dept Med, Mannheim, Germany
Guo, XQ:
UCLA Med Ctr, Lundquist Inst BioMed Innovat Harbor, Inst Translat Gen & Populat Sci, Dept Pediat, Torrance, CA USA
Yao, J:
UCLA Med Ctr, Lundquist Inst BioMed Innovat Harbor, Inst Translat Gen & Populat Sci, Dept Pediat, Torrance, CA USA
Taylor, KD:
UCLA Med Ctr, Lundquist Inst BioMed Innovat Harbor, Inst Translat Gen & Populat Sci, Dept Pediat, Torrance, CA USA
Ozel, AB:
Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA
Brody, JA:
Univ Washington, Cardiovasc Hlth Res Unit, Dept Med, Seattle, WA 98195 USA
Univ Washington, Cardiovasc Hlth Res Unit, Dept Epidemiol, Seattle, WA 98195 USA
Univ Washington, Cardiovasc Hlth Res Unit, Dept Hlth Serv, Seattle, WA 98195 USA
McKnight, B:
Univ Washington, Dept Biostat, Seattle, WA 98195 USA
Gyorgy, B:
Sorbonne Univ, Inst Cardiometab & Nutr, INSERM UMRS1166, ICAN, Paris, France
Simonsick, E:
NIA, NIH, Bethesda, MD 20892 USA
Leonard, HL:
NIA, NIH, Bethesda, MD 20892 USA
Carrasquilla, GD:
Univ Copenhagen, Novo Nord Fdn Ctr Basic Metab Res, Fac Hlth & Med Sci, Copenhagen, Denmark
Guindo-Martinez, M:
Univ Copenhagen, Novo Nord Fdn Ctr Basic Metab Res, Fac Hlth & Med Sci, Copenhagen, Denmark
Silveira, A:
Karolinska Inst, Dept Med Solna, Cardiovasc Med Unit, Ctr Mol Med, Stockholm, Sweden
Karolinska Univ Hosp Solna, Stockholm, Sweden
Temprano-Sagrera, G:
IIB St Pau, Res Inst Hosp Santa Creu & St Pau, Genom Complex Dis, Barcelona, Spain
Yanek, LR:
Johns Hopkins, GeneSTAR Res Program, Div Gen Internal Med, Sch Med, Baltimore, MD USA
Becker, DM:
Johns Hopkins, GeneSTAR Res Program, Div Gen Internal Med, Sch Med, Baltimore, MD USA
Mathias, RA:
Johns Hopkins, GeneSTAR Res Program, Div Gen Internal Med, Sch Med, Baltimore, MD USA
Johns Hopkins Sch Med, Div Allergy & Clin Immunol, Baltimore, MD USA
Becker, LC:
Johns Hopkins, GeneSTAR Res Program, Div Gen Internal Med, Sch Med, Baltimore, MD USA
Johns Hopkins Sch Med, Div Cardiol, Baltimore, MD USA
Raffield, LM:
Univ N Carolina, Dept Genet, Chapel Hill, NC 27515 USA
Kilpelainen, TO:
Univ Copenhagen, Novo Nord Fdn Ctr Basic Metab Res, Fac Hlth & Med Sci, Copenhagen, Denmark
Grarup, N:
Univ Copenhagen, Novo Nord Fdn Ctr Basic Metab Res, Fac Hlth & Med Sci, Copenhagen, Denmark
Pedersen, O:
Univ Copenhagen, Novo Nord Fdn Ctr Basic Metab Res, Fac Hlth & Med Sci, Copenhagen, Denmark
Hansen, T:
Univ Copenhagen, Novo Nord Fdn Ctr Basic Metab Res, Fac Hlth & Med Sci, Copenhagen, Denmark
Linneberg, A:
Bispebjerg & Frederiksberg Hosp, Ctr Clin Res & Prevent, Frederiksberg, Denmark
Hamsten, A:
Karolinska Inst, Dept Med Solna, Cardiovasc Med Unit, Ctr Mol Med, Stockholm, Sweden
Karolinska Univ Hosp Solna, Stockholm, Sweden
Watkins, H:
Univ Oxford, Radcliffe Dept Med, Oxford, England
Sabater-Lleal, M:
Karolinska Inst, Dept Med Solna, Cardiovasc Med Unit, Ctr Mol Med, Stockholm, Sweden
Karolinska Univ Hosp Solna, Stockholm, Sweden
IIB St Pau, Res Inst Hosp Santa Creu & St Pau, Genom Complex Dis, Barcelona, Spain
Nalls, MA:
NIA, NIH, Bethesda, MD 20892 USA
Tregouet, DA:
Sorbonne Univ, Inst Cardiometab & Nutr, INSERM UMRS1166, ICAN, Paris, France
Univ Bordeaux, INSERM, BPH, Bordeaux, France
Morange, PE:
Aix Marseille Univ, INSERM, INRAE, Marseille, France
Psaty, BM:
Univ Washington, Cardiovasc Hlth Res Unit, Dept Med, Seattle, WA 98195 USA
Univ Washington, Cardiovasc Hlth Res Unit, Dept Epidemiol, Seattle, WA 98195 USA
Univ Washington, Cardiovasc Hlth Res Unit, Dept Hlth Serv, Seattle, WA 98195 USA
Tracy, RP:
Univ Vermont, Larner Coll Med, Vermont Ctr Cardiovasc & Brain Hlth, Dept Pathol & Lab Med, Burlington, VT USA
Univ Vermont, Larner Coll Med, Vermont Ctr Cardiovasc & Brain Hlth, Dept Med, Burlington, VT USA
Smith, NL:
Univ Washington, Cardiovasc Hlth Res Unit, Dept Med, Seattle, WA 98195 USA
Univ Washington, Cardiovasc Hlth Res Unit, Dept Epidemiol, Seattle, WA 98195 USA
Univ Washington, Cardiovasc Hlth Res Unit, Dept Hlth Serv, Seattle, WA 98195 USA
Kaiser Permanente Washington, Kaiser Permanente Washington Hlth Res Inst, Seattle, WA USA
Univ Washington, Dept Epidmiol, Seattle, WA USA
Seattle Epidmiol Res & Informat Ctr, Dept Vet Affairs Off Res & Dev, Seattle, WA USA
Desch, KC:
Univ Michigan, Cell & Mol Biol Program, Dept Pediat, Ann Arbor, MI 48109 USA
Cushman, M:
Univ Vermont, Larner Coll Med, Vermont Ctr Cardiovasc & Brain Hlth, Dept Pathol & Lab Med, Burlington, VT USA
Univ Vermont, Larner Coll Med, Vermont Ctr Cardiovasc & Brain Hlth, Dept Med, Burlington, VT USA
Rotter, JI:
UCLA Med Ctr, Lundquist Inst BioMed Innovat Harbor, Inst Translat Gen & Populat Sci, Dept Pediat, Torrance, CA USA
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
Pankratz, ND:
Univ Minnesota, Sch Med, Dept Lab Med & Pathol, Minneapolis, MN USA
Folsom, AR:
Univ Minnesota, Sch Publ Hlth, Div Epidmiol & Community Hlth, Minneapolis, MN 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
Marz, W:
Heidelberg Univ, Med Fac Mannheim, Vth Dept Med, Mannheim, Germany
Synlab Holding Deutschland GmbH, Synlab Acad, Mannheim, Germany
Tang, WH:
Univ Minnesota, Sch Publ Hlth, Div Epidmiol & Community Hlth, Minneapolis, MN USA
Johnson, AD:
Natl Heart Lung & Blood Inst, Framingham Heart Study, Framingham, MA USA
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