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Significant genetic association of a functional TFPI variant with circulating fibrinogen levels and coronary artery disease

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Abstract

The tissue factor pathway inhibitor (TFPI) gene encodes a protease inhibitor with a critical role in regulation of blood coagulation. Some genomic variants in TFPI were previously associated with plasma TFPI levels, however, it remains to be further determined whether TFPI variants are associated with other coagulation factors. In this study, we carried out a large population-based study with 2313 study subjects for blood coagulation data, including fibrinogen levels, prothrombin time (PT), activated partial thromboplastin time (APTT), and thrombin time (TT). We identified significant association of TFPI variant rs10931292 (a functional promoter variant with reduced transactivation) with increased plasma fibrinogen levels (P = 0.017 under a recessive model), but not with PT, APTT or TT (P > 0.05). Using a large case–control association study population with 4479 CAD patients and 3628 controls, we identified significant association between rs10931292 and CAD under a recessive model (OR 1.23, P = 0.005). For the first time, we show that a TFPI variant is significantly associated with fibrinogen levels and risk of CAD. Our finding contributes significantly to the elucidation of the genetic basis and biological pathways responsible for fibrinogen levels and development of CAD.

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Abbreviations

TFPI:

Tissue factor pathway inhibitor

CAD:

Coronary artery disease

MI:

Myocardial infarction

FIG or Fg:

Fibrinogen levels

PT:

Prothrombin time

APTT:

Activated partial thromboplastin time

TT:

Thrombin time

IRF1:

Interferon regulatory factor 1

PCCB:

Propionyl coenzyme A carboxylase

NLRP3:

NLR family pyrin domain containing 3 isoform

OR:

Odds ratio

95% CI:

95% confidence interval

References

  • Amini NA, Iles D (2008) Analysis of a T-287C polymorphism in the tissue factor pathway inhibitor gene and identification of a repressor element in the promoter. Thromb Res 121:813–819

    Article  Google Scholar 

  • Bezemer ID, Rosendaal FR (2007) Predictive genetic variants for venous thrombosis: what’s new? Semin Hematol 44:85–92

    Article  CAS  PubMed  Google Scholar 

  • Chee YL (2014) Coagulation. J R Coll Physicians Edinb 44:42–45

    Article  CAS  PubMed  Google Scholar 

  • Chen S, Wang C, Wang X, Xu C, Wu M, Wang P, Tu X, Wang QK (2015) Significant association between CAV1 variant rs3807989 on 7p31 and atrial fibrillation in a Chinese Han population. J Am Heart Assoc 4:e001980

    Article  PubMed  PubMed Central  Google Scholar 

  • Chen S, Wang X, Wang J, Zhao Y, Wang D, Tan C, Fa J, Zhang R, Wang F, Xu C, Huang Y, Li S, Yin D, Xiong X, Li X, Chen Q, Tu X, Yang Y, Xia Y, Xu C, Wang QK (2016) Genomic variant in CAV1 increases susceptibility to coronary artery disease and myocardial infarction. Atherosclerosis 246:148–156

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Danesh J, Lewington S, Thompson SG, Lowe GD, Collins R, Kostis JB, Wilson AC, Folsom AR, Wu K, Benderly M, Goldbourt U, Willeit J, Kiechl S, Yarnell JW, Sweetnam PM, Elwood PC, Cushman M, Psaty BM, Tracy RP, Tybjaerg-Hansen A, Haverkate F, de Maat MP, Fowkes FG, Lee AJ, Smith FB, Salomaa V, Harald K, Rasi R, Vahtera E, Jousilahti P, Pekkanen J, D’Agostino R, Kannel WB, Wilson PW, Tofler G, Arocha-Pinango CL, Rodriguez-Larralde A, Nagy E, Mijares M, Espinosa R, Rodriquez-Roa E, Ryder E, Diez-Ewald MP, Campos G, Fernandez V, Torres E, Marchioli R, Valagussa F, Rosengren A, Wilhelmsen L, Lappas G, Eriksson H, Cremer P, Nagel D, Curb JD, Rodriguez B, Yano K, Salonen JT, Nyyssonen K, Tuomainen TP, Hedblad B, Lind P, Loewel H, Koenig W, Meade TW, Cooper JA, De SB, Knottenbelt C, Miller GJ, Cooper JA, Bauer KA, Rosenberg RD, Sato S, Kitamura A, Naito Y, Palosuo T, Ducimetiere P, Amouyel P, Arveiler D, Evans AE, Ferrieres J, Juhan-Vague I, Bingham A, Schulte H, Assmann G, Cantin B, Lamarche B, Despres JP, Dagenais GR, Tunstall-Pedoe H, Woodward M, Ben-Shlomo Y, Davey SG, Palmieri V, Yeh JL, Rudnicka A, Ridker P, Rodeghiero F, Tosetto A, Shepherd J, Ford I, Robertson M, Brunner E, Shipley M, Feskens EJ, Kromhout D, Dickinson A, Ireland B, Juzwishin K, Kaptoge S, Lewington S, Memon A, Sarwar N, Walker M, Wheeler J, White I, Wood A (2005) Plasma fibrinogen level and the risk of major cardiovascular diseases and nonvascular mortality: an individual participant meta-analysis. JAMA 294:1799–1809

    CAS  PubMed  Google Scholar 

  • de Lange M, Snieder H, Ariens RA, Spector TD, Grant PJ (2001) The genetics of haemostasis: a twin study. Lancet 357:101–105

    Article  PubMed  Google Scholar 

  • de Lange M, de Geus EJ, Kluft C, Meijer P, van Doornen LJ, Boomsma DI, Snieder H (2006) Genetic influences on fibrinogen, tissue plasminogen activator-antigen and von Willebrand factor in males and females. Thromb Haemost 95:414–419

    PubMed  Google Scholar 

  • de Vries PS, Chasman DI, Sabater-Lleal M, Chen MH, Huffman JE, Steri M, Tang W, Teumer A, Marioni RE, Grossmann V, Hottenga JJ, Trompet S, Muller-Nurasyid M, Zhao JH, Brody JA, Kleber ME, Guo X, Wang JJ, Auer PL, Attia JR, Yanek LR, Ahluwalia TS, Lahti J, Venturini C, Tanaka T, Bielak LF, Joshi PK, Rocanin-Arjo A, Kolcic I, Navarro P, Rose LM, Oldmeadow C, Riess H, Mazur J, Basu S, Goel A, Yang Q, Ghanbari M, Willemsen G, Rumley A, Fiorillo E, de Craen AJ, Grotevendt A, Scott R, Taylor KD, Delgado GE, Yao J, Kifley A, Kooperberg C, Qayyum R, Lopez LM, Berentzen TL, Raikkonen K, Mangino M, Bandinelli S, Peyser PA, Wild S, Tregouet DA, Wright AF, Marten J, Zemunik T, Morrison AC, Sennblad B, Tofler G, de Maat MP, de Geus EJ, Lowe GD, Zoledziewska M, Sattar N, Binder H, Volker U, Waldenberger M, Khaw KT, Mcknight B, Huang J, Jenny NS, Holliday EG, Qi L, Mcevoy MG, Becker DM, Starr JM, Sarin AP, Hysi PG, Hernandez DG, Jhun MA, Campbell H, Hamsten A, Rivadeneira F, Mcardle WL, Slagboom PE, Zeller T, Koenig W, Psaty BM, Haritunians T, Liu J, Palotie A, Uitterlinden AG, Stott DJ, Hofman A, Franco OH, Polasek O, Rudan I, Morange PE, Wilson JF, Kardia SL, Ferrucci L, Spector TD, Eriksson JG, Hansen T, Deary IJ, Becker LC, Scott RJ, Mitchell P, Marz W, Wareham NJ, Peters A, Greinacher A, Wild PS, Jukema JW, Boomsma DI, Hayward C, Cucca F, Tracy R, Watkins H, Reiner AP, Folsom AR, Ridker PM, O’Donnell CJ, Smith NL, Strachan DP, Dehghan A (2016) A meta-analysis of 120 246 individuals identifies 18 new loci for fibrinogen concentration. Hum Mol Genet 25:358–370

    Article  PubMed  Google Scholar 

  • Dehghan A, Yang Q, Peters A, Basu S, Bis JC, Rudnicka AR, Kavousi M, Chen MH, Baumert J, Lowe GD, Mcknight B, Tang W, de Maat M, Larson MG, Eyhermendy S, Mcardle WL, Lumley T, Pankow JS, Hofman A, Massaro JM, Rivadeneira F, Kolz M, Taylor KD, van Duijn CM, Kathiresan S, Illig T, Aulchenko YS, Volcik KA, Johnson AD, Uitterlinden AG, Tofler GH, Gieger C, Psaty BM, Couper DJ, Boerwinkle E, Koenig W, O’Donnell CJ, Witteman JC, Strachan DP, Smith NL, Folsom AR (2009) Association of novel genetic Loci with circulating fibrinogen levels: a genome-wide association study in 6 population-based cohorts. Circ Cardiovasc Genet 2:125–133

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dennis J, Kassam I, Morange PE, Tregouet DA, Gagnon F (2015) Genetic determinants of tissue factor pathway inhibitor plasma levels. Thromb Haemost 114:245–257

    Article  CAS  PubMed  Google Scholar 

  • Guo CY, Gu Y, Li L, Jia EZ, Li CJ, Wang LS, Yang ZJ, Cao KJ, Ma WZ (2012) Association of SNP rs6903956 on chromosome 6p24.1 with angiographical characteristics of coronary atherosclerosis in a Chinese population. PLoS One 7:e43732

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hayward CP, Moffat KA, Liu Y (2012) Laboratory investigations for bleeding disorders. Semin Thromb Hemost 38:742–752

    Article  PubMed  Google Scholar 

  • Hessner MJ, Luhm RA (2000) The C536T transition in the tissue factor pathway inhibitor (TFPI) gene does not contribute to risk of venous thrombosis among carriers of factor V Leiden. Thromb Haemost 84:724–725

    CAS  PubMed  Google Scholar 

  • Hoffman M, Monroe DM (2007) Coagulation 2006: a modern view of hemostasis. Hematol Oncol Clin N Am 21:1–11

    Article  Google Scholar 

  • Huang EW, Peng LY, Zheng JX, Wang D, Xu QY, Huang L, Wu QP, Tang SB, Luo B, Liu SP, Liu XS, Li ZH, Quan L, Li Y, Shi H, Lv GL, Zhao J, Cheng JD, Liu C (2015a) Common variants in promoter of ADTRP associate with early-onset coronary artery disease in a Southern Han Chinese population. PLoS One 10:e0137547

    Article  PubMed  PubMed Central  Google Scholar 

  • Huang Y, Wang C, Yao Y, Zuo X, Chen S, Xu C, Zhang H, Lu Q, Chang L, Wang F, Wang P, Zhang R, Hu Z, Song Q, Yang X, Li C, Li S, Zhao Y, Yang Q, Yin D, Wang X, Si W, Li X, Xiong X, Wang D, Huang Y, Luo C, Li J, Wang J, Chen J, Wang L, Wang L, Han M, Ye J, Chen F, Liu J, Liu Y, Wu G, Yang B, Cheng X, Liao Y, Wu Y, Ke T, Chen Q, Tu X, Elston R, Rao S, Yang Y, Xia Y, Wang QK (2015b) Molecular basis of gene-gene interaction: cyclic cross-regulation of gene expression and post-GWAS gene–gene interaction involved in atrial fibrillation. PLoS Genet 11:e1005393

    Article  PubMed  PubMed Central  Google Scholar 

  • Kleesiek K, Schmidt M, Gotting C, Schwenz B, Lange S, Muller-Berghaus G, Brinkmann T, Prohaska W (1999) The 536C–>T transition in the human tissue factor pathway inhibitor (TFPI) gene is statistically associated with a higher risk for venous thrombosis. Thromb Haemost 82:1–5

    CAS  PubMed  Google Scholar 

  • Koenig W (1999) Fibrinogen and coronary risk. Curr Cardiol Rep 1:112–118

    Article  CAS  PubMed  Google Scholar 

  • Li X, Huang Y, Yin D, Wang D, Xu C, Wang F, Yang Q, Wang X, Li S, Chen S, Xiong X, Huang Y, Zhao Y, Wang L, Zhu X, Su Z, Zhou B, Zhang Y, Wang L, Chang L, Xu C, Li H, Ke T, Ren X, Cheng X, Yang Y, Liao Y, Tu X, Wang QK (2013) Meta-analysis identifies robust association between SNP rs17465637 in MIA3 on chromosome 1q41 and coronary artery disease. Atherosclerosis 231:136–140

    Article  CAS  PubMed  Google Scholar 

  • Lowe G, Rumley A (2014) The relevance of coagulation in cardiovascular disease: what do the biomarkers tell us? Thromb Haemost 112:860–867

    Article  PubMed  Google Scholar 

  • Luo C, Wang F, Qin S, Chen Q, Wang Q (2016) Coronary artery disease susceptibility gene ADTRP regulates cell cycle progression, proliferation and apoptosis by global gene expression regulation. Physiol Genomics 48:554–564

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lupu C, Zhu H, Popescu NI, Wren JD, Lupu F (2011) Novel protein ADTRP regulates TFPI expression and function in human endothelial cells in normal conditions and in response to androgen. Blood 118:4463–4471

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Maroney SA, Mast AE (2015) New insights into the biology of tissue factor pathway inhibitor. J Thromb Haemost 13(Suppl 1):S200–S207

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Maroney SA, Ellery PE, Wood JP, Ferrel JP, Martinez ND, Mast AE (2013) Comparison of the inhibitory activities of human tissue factor pathway inhibitor (TFPI)alpha and TFPIbeta. J Thromb Haemost 11:911–918

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mast AE (2016) Tissue factor pathway inhibitor: multiple anticoagulant activities for a single protein. Arterioscler Thromb Vasc Biol 36:9–14

    Article  CAS  PubMed  Google Scholar 

  • Opstad TB, Pettersen AA, Weiss T, Arnesen H, Seljeflot I (2010) Gender differences of polymorphisms in the TF and TFPI genes, as related to phenotypes in patients with coronary heart disease and type-2 diabetes. Thromb J 8:7

    Article  PubMed  PubMed Central  Google Scholar 

  • Sabater-Lleal M, Huang J, Chasman D, Naitza S, Dehghan A, Johnson AD, Teumer A, Reiner AP, Folkersen L, Basu S, Rudnicka AR, Trompet S, Malarstig A, Baumert J, Bis JC, Guo X, Hottenga JJ, Shin SY, Lopez LM, Lahti J, Tanaka T, Yanek LR, Oudot-Mellakh T, Wilson JF, Navarro P, Huffman JE, Zemunik T, Redline S, Mehra R, Pulanic D, Rudan I, Wright AF, Kolcic I, Polasek O, Wild SH, Campbell H, Curb JD, Wallace R, Liu S, Eaton CB, Becker DM, Becker LC, Bandinelli S, Raikkonen K, Widen E, Palotie A, Fornage M, Green D, Gross M, Davies G, Harris SE, Liewald DC, Starr JM, Williams FM, Grant PJ, Spector TD, Strawbridge RJ, Silveira A, Sennblad B, Rivadeneira F, Uitterlinden AG, Franco OH, Hofman A, van Dongen J, Willemsen G, Boomsma DI, Yao J, Swords JN, Haritunians T, Mcknight B, Lumley T, Taylor KD, Rotter JI, Psaty BM, Peters A, Gieger C, Illig T, Grotevendt A, Homuth G, Volzke H, Kocher T, Goel A, Franzosi MG, Seedorf U, Clarke R, Steri M, Tarasov KV, Sanna S, Schlessinger D, Stott DJ, Sattar N, Buckley BM, Rumley A, Lowe GD, Mcardle WL, Chen MH, Tofler GH, Song J, Boerwinkle E, Folsom AR, Rose LM, Franco-Cereceda A, Teichert M, Ikram MA, Mosley TH, Bevan S, Dichgans M, Rothwell PM, Sudlow CL, Hopewell JC, Chambers JC, Saleheen D, Kooner JS, Danesh J, Nelson CP, Erdmann J, Reilly MP, Kathiresan S, Schunkert H, Morange PE, Ferrucci L, Eriksson JG, Jacobs D, Deary IJ, Soranzo N, Witteman JC, de Geus EJ, Tracy RP, Hayward C, Koenig W, Cucca F, Jukema JW, Eriksson P, Seshadri S, Markus HS, Watkins H, Samani NJ, Wallaschofski H, Smith NL, Tregouet D, Ridker PM, Tang W, Strachan DP, Hamsten A, O’Donnell CJ (2013) Multiethnic meta-analysis of genome-wide association studies in >100 000 subjects identifies 23 fibrinogen-associated Loci but no strong evidence of a causal association between circulating fibrinogen and cardiovascular disease. Circulation 128:1310–1324

    Article  CAS  PubMed  Google Scholar 

  • Shen GQ, Li L, Girelli D, Seidelmann SB, Rao S, Fan C, Park JE, Xi Q, Li J, Hu Y, Olivieri O, Marchant K, Barnard J, Corrocher R, Elston R, Cassano J, Henderson S, Hazen SL, Plow EF, Topol EJ, Wang QK (2007) An LRP8 variant is associated with familial and premature coronary artery disease and myocardial infarction. Am J Hum Genet 81:780–791

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shen GQ, Li L, Rao S, Abdullah KG, Ban JM, Lee BS, Park JE, Wang QK (2008a) Four SNPs on chromosome 9p21 in a South Korean population implicate a genetic locus that confers high cross-race risk for development of coronary artery disease. Arterioscler Thromb Vasc Biol 28:360–365

    Article  CAS  PubMed  Google Scholar 

  • Shen GQ, Rao S, Martinelli N, Li L, Olivieri O, Corrocher R, Abdullah KG, Hazen SL, Smith J, Barnard J, Plow EF, Topol EJ, Wang QK (2008b) Association between four SNPs on chromosome 9p21 and myocardial infarction is replicated in an Italian population. J Hum Genet 53:144–150

    Article  PubMed  Google Scholar 

  • Shen GQ, Abdullah KG, Wang QK (2009) The TaqMan method for SNP genotyping. Methods Mol Biol 578:293–306

    Article  CAS  PubMed  Google Scholar 

  • Shen GQ, Li L, Wang QK (2012) Genetic variant R952Q in LRP8 is associated with increased plasma triglyceride levels in patients with early-onset CAD and MI. Ann Hum Genet 76:193–199

    Article  CAS  PubMed  Google Scholar 

  • Shen GQ, Girelli D, Li L, Olivieri O, Martinelli N, Chen Q, Topol EJ, Wang QK (2013) Multi-allelic haplotype association identifies novel information different from single-SNP analysis: a new protective haplotype in the LRP8 gene is against familial and early-onset CAD and MI. Gene 521:78–81

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shen GQ, Girelli D, Li L, Rao S, Archacki S, Olivieri O, Martinelli N, Park JE, Chen Q, Topol EJ, Wang QK (2014) A novel molecular diagnostic marker for familial and early-onset coronary artery disease and myocardial infarction in the LRP8 gene. Circ Cardiovasc Genet 7:514–520

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Souto JC, Almasy L, Borrell M, Gari M, Martinez E, Mateo J, Stone WH, Blangero J, Fontcuberta J (2000) Genetic determinants of hemostasis phenotypes in Spanish families. Circulation 101:1546–1551

    Article  CAS  PubMed  Google Scholar 

  • Tayebi N, Ke T, Foo JN, Friedlander Y, Liu J, Heng CK (2013) Association of single nucleotide polymorphism rs6903956 on chromosome 6p24.1 with coronary artery disease and lipid levels in different ethnic groups of the Singaporean population. Clin Biochem 46:755–759

    Article  CAS  PubMed  Google Scholar 

  • Tu X, Nie S, Liao Y, Zhang H, Fan Q, Xu C, Bai Y, Wang F, Ren X, Tang T, Xia N, Li S, Huang Y, Liu J, Yang Q, Zhao Y, Lv Q, Li Q, Li Y, Xia Y, Qian J, Li B, Wu G, Wu Y, Yang Y, Wang QK, Cheng X (2013) The IL-33-ST2L pathway is associated with coronary artery disease in a Chinese Han population. Am J Hum Genet 93:652–660

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang Q, Rao S, Shen GQ, Li L, Moliterno DJ, Newby LK, Rogers WJ, Cannata R, Zirzow E, Elston RC, Topol EJ (2004) Premature myocardial infarction novel susceptibility locus on chromosome 1P34-36 identified by genomewide linkage analysis. Am J Hum Genet 74:262–271

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang F, Xu CQ, He Q, Cai JP, Li XC, Wang D, Xiong X, Liao YH, Zeng QT, Yang YZ, Cheng X, Li C, Yang R, Wang CC, Wu G, Lu QL, Bai Y, Huang YF, Yin D, Yang Q, Wang XJ, Dai DP, Zhang RF, Wan J, Ren JH, Li SS, Zhao YY, Fu FF, Huang Y, Li QX, Shi SW, Lin N, Pan ZW, Li Y, Yu B, Wu YX, Ke YH, Lei J, Wang N, Luo CY, Ji LY, Gao LJ, Li L, Liu H, Huang EW, Cui J, Jia N, Ren X, Li H, Ke T, Zhang XQ, Liu JY, Liu MG, Xia H, Yang B, Shi LS, Xia YL, Tu X, Wang QK (2011) Genome-wide association identifies a susceptibility locus for coronary artery disease in the Chinese Han population. Nat Genet 43:345–349

    Article  CAS  PubMed  Google Scholar 

  • Wassel CL, Lange LA, Keating BJ, Taylor KC, Johnson AD, Palmer C, Ho LA, Smith NL, Lange EM, Li Y, Yang Q, Delaney JA, Tang W, Tofler G, Redline S, Taylor HA Jr, Wilson JG, Tracy RP, Jacobs DR Jr, Folsom AR, Green D, O’Donnell CJ, Reiner AP (2011) Association of genomic loci from a cardiovascular gene SNP array with fibrinogen levels in European Americans and African-Americans from six cohort studies: the Candidate Gene Association Resource (CARe). Blood 117:268–275

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wood JP, Bunce MW, Maroney SA, Tracy PB, Camire RM, Mast AE (2013) Tissue factor pathway inhibitor-alpha inhibits prothrombinase during the initiation of blood coagulation. Proc Natl Acad Sci USA 110:17838–17843

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xiong X, Xu C, Li X, Wang B, Wang F, Yang Q, Wang D, Wang X, Li S, Chen S, Zhao Y, Yin D, Huang Y, Zhu X, Wang L, Wang L, Chang L, Xu C, Li H, Ke T, Ren X, Wu Y, Zhang R, Wu T, Xia Y, Yang Y, Ma X, Tu X, Wang QK (2013) BRG1 variant rs1122608 on chromosome 19p13.2 confers protection against stroke and regulates expression of pre-mRNA-splicing factor SFRS3. Hum Genet 133:499–508

    Article  PubMed  PubMed Central  Google Scholar 

  • Xu C, Yang Q, Xiong H, Wang L, Cai J, Wang F, Li S, Chen J, Wang C, Wang D, Xiong X, Wang P, Zhao Y, Wang X, Huang Y, Chen S, Yin D, Li X, Liu Y, Liu J, Wang J, Li H, Ke T, Ren X, Wu Y, Wu G, Wan J, Zhang R, Wu T, Wang J, Xia Y, Yang Y, Cheng X, Liao Y, Chen Q, Zhou Y, He Q, Tu X, Wang QK (2014) Candidate pathway-based genome-wide association studies identify novel associations of genomic variants in the complement system associated with coronary artery disease. Circ Cardiovasc Genet 7:887–894

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yang Q, Tofler GH, Cupples LA, Larson MG, Feng D, Lindpaintner K, Levy D, D’Agostino RB, O’Donnell CJ (2003) A genome-wide search for genes affecting circulating fibrinogen levels in the Framingham Heart Study. Thromb Res 110:57–64

    Article  CAS  PubMed  Google Scholar 

  • Yin D, Naji DH, Xia Y, Li S, Bai Y, Jiang G, Zhao Y, Wang X, Huang Y, Chen S, Fa J, Tan C, Zhou M, Zhou Y, Wang L, Liu Y, Chen F, Liu J, Chen Q, Tu X, Xu C, Wang QK (2017) Genomic variant in IL-37 confers a significant risk of coronary artery disease. Sci Rep 7:42175

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank the study subjects for their participation and support of this study and all members of the GeneID team for help and assistance.

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Author notes

  1. Duraid Hamid Naji, Chengcheng Tan, Fabin Han and Yuanyuan Zhao contributed equally to this work.

Authors and Affiliations

  1. Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, Hubei, People’s Republic of China

    Duraid Hamid Naji, Chengcheng Tan, Yuanyuan Zhao, Dan Wang, Jingjing Fa, Sisi Li, Shanshan Chen, Chengqi Xu & Qing K. Wang

  2. The Institute for Translational Medicine, The Second Affiliated Hospital, Shandong University, Jinan, Shandong, People’s Republic of China

    Fabin Han

  3. University Hospital, Huazhong University of Science and Technology, Wuhan, Hubei, People’s Republic of China

    Junhan Wang

  4. Department of Molecular Cardiology, Center for Cardiovascular Genetics, Cleveland Clinic, Cleveland, OH, 44195, USA

    Qiuyun Chen & Qing K. Wang

  5. Department of Molecular Medicine/CCLCM, Case Western Reserve University, Cleveland, OH, 44195, USA

    Qiuyun Chen & Qing K. Wang

  6. Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, 44195, USA

    Qing K. Wang

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  1. Duraid Hamid Naji
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  2. Chengcheng Tan
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  10. Qiuyun Chen
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  11. Chengqi Xu
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  12. Qing K. Wang
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Contributions

DHN, CCT, FH and YZ contributed equally to this study. Study concept and design: QKW, CX and DHN. Acquisition of data: DHN, CCT, FH, YZ, DW, JF, SL and SC. Analysis and interpretation of data: DHN, CCT, QC, CX and QKW. Drafting of the manuscript: DHN, CCT and QKW. Critical revision of the manuscript for important intellectual content: CCT, CX and QC. Statistical analysis: DHN and CCT. Obtained funding: QKW and CX. Study supervision: QKW, QC and CX.

Corresponding authors

Correspondence to Qiuyun Chen, Chengqi Xu or Qing K. Wang.

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Funding

This study was supported by the China National Natural Science Foundation Grants (31430047, 81630002 and 31671302), Chinese National Basic Research Programs (973 Programs 2013CB531101 and 2012CB517801), Hubei Province’s Outstanding Medical Academic Leader Program, Hubei Province Natural Science Program (2014CFA074 and 2016CFB224), the China National Natural Science Foundation Grant (91439129, NSFC-J1103514), NIH/NHLBI Grants R01 HL121358 and R01 HL126729, Specialized Research Fund for the Doctoral Program of Higher Education from the Ministry of Education, and the “Innovative Development of New Drugs” Key Scientific Project (2011ZX09307-001-09). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Conflict of interest

All authors have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of College of Life Science and Technology, Huazhong University of Science and Technology and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Additional information

Communicated by S. Hohmann.

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Naji, D.H., Tan, C., Han, F. et al. Significant genetic association of a functional TFPI variant with circulating fibrinogen levels and coronary artery disease. Mol Genet Genomics 293, 119–128 (2018). https://doi.org/10.1007/s00438-017-1365-6

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