Antithrombin, Protein C, and Protein S: Genome and Transcriptome-Wide Association Studies Identify 7 Novel Loci Regulating Plasma Levels
Por:
Ji, YK, Temprano-Sagrera, G, Holle, LA, Bebo, A, Brody, JA, Le, NQ, Kangro, K, Brown, MR, Martinez-Perez, A, Sitlani, CM, Suchon, P, Kleber, ME, Emmert, DB, Ozel, AB, Dobson, DA, Tang, WH, Llobet, D, Tracy, RP, Deleuze, JF, Delgado, GE, Gogele, M, Wiggins, KL, Souto, JC, Pankow, JS, Taylor, KD, Tregouet, DA, Moissl, AP, Fuchsberger, C, Rosendaal, FR, Morrison, AC, Soria, JM, Cushman, M, Morange, PE, Marz, W, Hicks, AA, Desch, KC, Johnson, AD, de Vries, PS, Wolberg, AS, Smith, NL, Sabater-Lleal, M, INVENT Consortium
Publicada:
1 jul 2023
Ahead of Print:
27 abr 2023
Resumen:
Background:Antithrombin, PC (protein C), and PS (protein S) are circulating natural anticoagulant proteins that regulate hemostasis and of which partial deficiencies are causes of venous thromboembolism. Previous genetic association studies involving antithrombin, PC, and PS were limited by modest sample sizes or by being restricted to candidate genes. In the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, we meta-analyzed across ancestries the results from 10 genome-wide association studies of plasma levels of antithrombin, PC, PS free, and PS total. Methods:Study participants were of European and African ancestries, and genotype data were imputed to TOPMed, a dense multiancestry reference panel. Each of the 10 studies conducted a genome-wide association studies for each phenotype and summary results were meta-analyzed, stratified by ancestry. Analysis of antithrombin included 25 243 European ancestry and 2688 African ancestry participants, PC analysis included 16 597 European ancestry and 2688 African ancestry participants, PSF and PST analysis included 4113 and 6409 European ancestry participants. We also conducted transcriptome-wide association analyses and multiphenotype analysis to discover additional associations. Novel genome-wide association studies and transcriptome-wide association analyses findings were validated by in vitro functional experiments. Mendelian randomization was performed to assess the causal relationship between these proteins and cardiovascular outcomes. Results:Genome-wide association studies meta-analyses identified 4 newly associated loci: 3 with antithrombin levels (GCKR, BAZ1B, and HP-TXNL4B) and 1 with PS levels (ORM1-ORM2). transcriptome-wide association analyses identified 3 newly associated genes: 1 with antithrombin level (FCGRT), 1 with PC (GOLM2), and 1 with PS (MYL7). In addition, we replicated 7 independent loci reported in previous studies. Functional experiments provided evidence for the involvement of GCKR, SNX17, and HP genes in antithrombin regulation. Conclusions:The use of larger sample sizes, diverse populations, and a denser imputation reference panel allowed the detection of 7 novel genomic loci associated with plasma antithrombin, PC, and PS levels.
Filiaciones:
Ji, YK:
Univ Minnesota, Dept Med, Cardiovasc Div, Minneapolis, MN USA
Temprano-Sagrera, G:
Inst Invest Biomed St Pau IIB St PAU, Unit Genom Complex Dis, Barcelona, Spain
Holle, LA:
Univ North Carolina Chapel Hill, Dept Pathol & Lab Med, Chapel Hill, NC USA
Univ North Carolina Chapel Hill, UNC Blood Res Ctr, Chapel Hill, NC USA
Bebo, A:
Univ Texas Hlth Sci Ctr Houston, Human Genet Ctr, Sch Publ Hlth, Dept Epidemiol Human Genet & Environm Sci, Houston, TX USA
Brody, JA:
Univ Washington, Dept Med, Seattle, WA USA
Le, NQ:
Inst Invest Biomed St Pau IIB St PAU, Unit Genom Complex Dis, Barcelona, Spain
Kangro, K:
Univ North Carolina Chapel Hill, Dept Pathol & Lab Med, Chapel Hill, NC USA
Univ North Carolina Chapel Hill, UNC Blood Res Ctr, Chapel Hill, NC USA
Brown, MR:
Univ Texas Hlth Sci Ctr Houston, Human Genet Ctr, Sch Publ Hlth, Dept Epidemiol Human Genet & Environm Sci, Houston, TX USA
Martinez-Perez, A:
Inst Invest Biomed St Pau IIB St PAU, Unit Genom Complex Dis, Barcelona, Spain
Sitlani, CM:
Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA
Suchon, P:
Aix Marseille Univ, INSERM, INRAE, C2VN, Marseille, France
La Timone Hosp, Lab Haematol, Marseille, France
Kleber, ME:
Synlab MVZ Humangenet Mannheim, Mannheim, Germany
Heidelberg Univ, Med Fac Mannheim, Dept Med 5, Heidelberg, Germany
Emmert, DB:
Univ Lubeck, Eurac Res, Inst Biomed, Bolzano, Italy
Ozel, AB:
Univ Michigan, CS Mott Childrens Hosp, Dept Human Genet, Ann Arbor, MI USA
Dobson, DA:
Univ North Carolina Chapel Hill, Dept Pathol & Lab Med, Chapel Hill, NC USA
Univ North Carolina Chapel Hill, UNC Blood Res Ctr, Chapel Hill, NC USA
Tang, WH:
Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA
Llobet, D:
Hosp Santa Creu & Sant Pau, Unit Thrombosis & Hemostasis, Barcelona, Spain
Tracy, RP:
Univ Vermont, Coll Med, Dept Pathol & Lab Med, Burlington, VT USA
Deleuze, JF:
CEA, Ctr Natl Rech Genom Humaine, Fontenay Aux Roses, France
Fdn Jean Dausset, Ctr Etud Polymorphisme Humain, Paris, France
Lab Excellence Med Genom GenMed, Paris, France
Delgado, GE:
Heidelberg Univ, Med Fac Mannheim, Dept Med 5, Heidelberg, Germany
Gogele, M:
Univ Lubeck, Eurac Res, Inst Biomed, Bolzano, Italy
Wiggins, KL:
Univ Washington, Dept Med, Seattle, WA USA
Souto, JC:
Inst Invest Biomed St Pau IIB St PAU, Unit Genom Complex Dis, Barcelona, Spain
Hosp Santa Creu & Sant Pau, Unit Thrombosis & Hemostasis, Barcelona, Spain
Pankow, JS:
Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA
Taylor, KD:
Harbor UCLA Med Ctr, Lundquist Inst Biomed Innovat, Inst Translat Genom & Populat Sci, Dept Pediat, Torrance, CA USA
Tregouet, DA:
Lab Excellence Med Genom GenMed, Paris, France
Bordeaux Populat Hlth Res Ctr, INSERM, UMR 1219, Bordeaux, France
Moissl, AP:
Heidelberg Univ, Med Fac Mannheim, Dept Med 5, Heidelberg, Germany
Friedrich Schiller Univ Jena, Inst Nutr Sci, Jena, Germany
Competence Cluster Nutr & Cardiovasc Hlth nutriCA, Jena, Germany
Fuchsberger, C:
Univ Lubeck, Eurac Res, Inst Biomed, Bolzano, Italy
Rosendaal, FR:
Leiden Univ, Med Ctr, Dept Clin Epidemiol, Leiden, Netherlands
Morrison, AC:
Univ Texas Hlth Sci Ctr Houston, Human Genet Ctr, Sch Publ Hlth, Dept Epidemiol Human Genet & Environm Sci, Houston, TX USA
Soria, JM:
Inst Invest Biomed St Pau IIB St PAU, Unit Genom Complex Dis, Barcelona, Spain
Cushman, M:
Univ Vermont, Larner Coll Med, Burlington, VT USA
Morange, PE:
Aix Marseille Univ, INSERM, INRAE, C2VN, Marseille, France
La Timone Hosp, Lab Haematol, Marseille, France
Marz, W:
Heidelberg Univ, Med Fac Mannheim, Dept Med 5, Heidelberg, Germany
Synlab Holding Deutschland GmbH, Synlab Acad, Augsburg, Germany
Hicks, AA:
Univ Lubeck, Eurac Res, Inst Biomed, Bolzano, Italy
Desch, KC:
Univ Michigan, CS Mott Childrens Hosp, Dept Pediat, Ann Arbor, MI USA
Johnson, AD:
NHLBI, Div Intramural Res, Populat Sci Branch, Framingham Heart Study, Boston, MA USA
de Vries, PS:
Univ Texas Hlth Sci Ctr Houston, Human Genet Ctr, Sch Publ Hlth, Dept Epidemiol Human Genet & Environm Sci, Houston, TX USA
Wolberg, AS:
Univ North Carolina Chapel Hill, Dept Pathol & Lab Med, Chapel Hill, NC USA
Univ North Carolina Chapel Hill, UNC Blood Res Ctr, Chapel Hill, NC USA
Smith, NL:
Univ Washington, Dept Epidemiol, Seattle, WA USA
Kaiser Permanente Washington Hlth Res Inst, Seattle, WA USA
Dept Vet Affairs Off Res & Dev, Seattle Epidemiol Res & Informat Ctr, Seattle, WA USA
Sabater-Lleal, M:
Inst Invest Biomed St Pau IIB St PAU, Unit Genom Complex Dis, Barcelona, Spain
Karolinska Inst, Ctr Mol Med, Dept Med, Cardiovasc Med Unit, Stockholm, Sweden
Bronze, Green Submitted, All Open Access
|