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Thromb Haemost 2015; 113(01): 66-76
DOI: 10.1160/TH14-02-0189
Coagulation and Fibrinolysis
Schattauer GmbH

Haemostaseome-associated SNPs: has the thrombotic phenotype a greater influence than ethnicity?

GMT study from Aquitaine including Basque individuals
Geneviève Freyburger
1   Laboratory for Hematology, Pellegrin University Hospital, Bordeaux, France
2   EA 4576, University of Bordeaux, Bordeaux, France
3   Genomic and Sequencing Facility of Bordeaux, Bordeaux, France
,
Sylvie Labrouche
1   Laboratory for Hematology, Pellegrin University Hospital, Bordeaux, France
2   EA 4576, University of Bordeaux, Bordeaux, France
,
Christophe Hubert
3   Genomic and Sequencing Facility of Bordeaux, Bordeaux, France
,
Frédéric Bauduer
2   EA 4576, University of Bordeaux, Bordeaux, France
4   Department of Hematology, CH Côte Basque, Bayonne, France
› Author Affiliations
Further Information

Publication History

Received: 28 February 2014

Accepted after major revision: 15 August 2014

Publication Date:
27 November 2017 (online)

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Summary

The Genetic Markers for Thrombosis (GMT) study compared the relative influence of ethnicity and thrombotic phenotype regarding the distribution of SNPs implicated in haemostasis pathophysiology (“haemostaseome”). We assessed 384 SNPs in three groups, each of 480 subjects: 1) general population of Aquitaine region (Southwestern France) used as control; 2) patients with venous thromboembolism from the same area; and 3) autochthonous Basques, a genetic isolate, who demonstrate unusual characteristics regarding the coagulation system. This study sought to evaluate i) the value of looking for a large number of genes in order to identify new genetic markers of thrombosis, ii) the value of investigating low risk factors and potential preferential associations, iii) the impact of ethnicity on the characterisation of markers for thrombosis. We did not detect any previously unrecognised SNP significantly associated with thrombosis risk or any preferential associations of low-risk factors in patients with thrombosis. The sum of ϰ2 values for our 110 significant SNPs demonstrated a smaller genetic distance between patients and controls (321 cumulated ϰ2 value) than between Basques and controls (1,570 cumulated ϰ2 value). Hence, our study confirms the genetic particularity of Basques especially regarding a significantly lower expression of the non-O blood group (p< 0.0004). This is mitigated by a higher prevalence of factor II Leiden (p< 0.02) while factor V Leiden prevalence does not differ. Numerous other differences covering a wide range of proteins of the haemostaseome may result in an overall different genetic risk for venous thromboembolism.

Keywords

SNP - venous thromboembolism - risk factors - Basques - population genetics - epidemiology

 

  • References

  • 1 Souto JC. et al. Genetic susceptibility to thrombosis and its relationship to physiological risk factors: the GAIT study. Genetic Analysis of Idiopathic Thrombophilia. Am J Hum Genet 2000; 67: 1452-1459.
    CrossrefPubMedGoogle Scholar
  • 2 Larsen TB. et al. Major genetic susceptibility for venous thromboembolism in men: a study of Danish twins. Epidemiol Camb Mass 2003; 14: 328-332.
    PubMedGoogle Scholar
  • 3 Fechtel K. et al. Delineating the Haemostaseome as an aid to individualize the analysis of the hereditary basis of thrombotic and bleeding disorders. Hum Genet 2011; 130: 149-166.
    CrossrefPubMedGoogle Scholar
  • 4 Cavalli-Sforza L. The History and Geography of Human Genes. Princeton University Press.; 1994
    Google Scholar
  • 5 Bauduer F. et al. The Basques: review of population genetics and Mendelian disorders. Hum Biol 2005; 77: 619-637.
    CrossrefPubMedGoogle Scholar
  • 6 Bauduer F. et al. Factor XI deficiency in the French Basque Country. Haemophilia 1999; 05: 187-190.
    CrossrefPubMedGoogle Scholar
  • 7 Zivelin A. et al. Factor XI deficiency in French Basques is caused predominantly by an ancestral Cys38Arg mutation in the factor XI gene. Blood 2002; 99: 2448-2454.
    CrossrefPubMedGoogle Scholar
  • 8 Bauduer F. et al. Is there a ‘Basque’ profile regarding autosomal recessive deficiencies of coagulation factors?. Haemophilia 2004; 10: 276-279.
    CrossrefPubMedGoogle Scholar
  • 9 Bauduer F. et al. The prevalence of factor V G1691A but not of prothrombin G20210A and methylenetetrahydrofolate reductase C677T is remarkably low in French Basques. J Thromb Haemost 2004; 02: 361-362.
    CrossrefPubMedGoogle Scholar
  • 10 Seo J, Shneiderman B. Knowledge discovery in high-dimensional data: case studies and a user survey for the rank-by-feature framework. IEEE Trans Vis Comput Graph 2006; 12: 311-322.
    CrossrefPubMedGoogle Scholar
  • 11 Paré G. et al. Novel association of ABO histo-blood group antigen with soluble ICAM-1: results of a genome-wide association study of 6,578 women. PLoS Genet 2008; 04: e1000118.
    CrossrefPubMedGoogle Scholar
  • 12 Miletich JP. et al. Inherited predisposition to thrombosis. Cell 1993; 72: 477-480.
    CrossrefPubMedGoogle Scholar
  • 13 Dahlbäck B. et al. Familial thrombophilia due to a previously unrecognized mechanism characterized by poor anticoagulant response to activated protein C: prediction of a cofactor to activated protein C. Proc Natl Acad Sci USA 1993; 90: 1004-1008.
    CrossrefPubMedGoogle Scholar
  • 14 Poort SR. et al. A common genetic variation in the 3‘-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood 1996; 88: 3698-3703.
    PubMedGoogle Scholar
  • 15 McIntyre LM. et al. Circumventing multiple testing: a multilocus Monte Carlo approach to testing for association. Genet Epidemiol 2000; 19: 18-29.
    CrossrefPubMedGoogle Scholar
  • 16 Linghu B. et al. Genome-wide prioritisation of disease genes and identification of disease-disease associations from an integrated human functional linkage network. Genome Biol 2009; 10: R91.
    CrossrefPubMedGoogle Scholar
  • 17 Bezemer ID. et al. Gene variants associated with deep vein thrombosis. J Am Med Assoc 2008; 299: 1306-1314.
    CrossrefPubMedGoogle Scholar
  • 18 Trégouét D-A. et al. Common susceptibility alleles are unlikely to contribute as strongly as the FV and ABO loci to VTE risk: results from a GWAS approach. Blood 2009; 113: 5298-5303.
    CrossrefPubMedGoogle Scholar
  • 19 Germain M. et al. Genetics of venous thrombosis: insights from a new genome wide association study. PloS One 2011; 06: e25581.
    CrossrefPubMedGoogle Scholar
  • 20 Durbin RM. et al. A map of human genome variation from population-scale sequencing. Nature 2010; 467: 1061-1073.
    CrossrefPubMedGoogle Scholar
  • 21 Germain M. et al. Caution in interpreting results from imputation analysis when linkage disequilibrium extends over a large distance: a case study on venous thrombosis. PloS One 2012; 07: e38538.
    CrossrefPubMedGoogle Scholar
  • 22 De Haan HG. et al. Multiple SNP testing improves risk prediction of first venous thrombosis. Blood 2012; 120: 656-663.
    CrossrefPubMedGoogle Scholar
  • 23 Morange P-E. et al. A follow-up study of a genome-wide association scan identifies a susceptibility locus for venous thrombosis on chromosome 6p24.1. Am J Hum Genet 2010; 86: 592-595.
    CrossrefPubMedGoogle Scholar
  • 24 Ehret GB. et al. Follow-up of a major linkage peak on chromosome 1 reveals suggestive QTLs associated with essential hypertension: GenNet study. Eur J Hum Genet EJHG 2009; 17: 1650-1657.
    CrossrefPubMedGoogle Scholar
  • 25 Li Y. et al. Genetic variants associated with deep vein thrombosis: the F11 locus. J Thromb Haemost 2009; 07: 1802-1808.
    CrossrefPubMedGoogle Scholar
  • 26 Rosendaal FR, Reitsma PH. Genetics of venous thrombosis. J Thromb Haemost 2009; 07 (Suppl. 01) 301-304.
    CrossrefPubMedGoogle Scholar
  • 27 Gemmati D. et al. Factor XIIIA-V34L and factor XIIIB-H95R gene variants: effects on survival in myocardial infarction patients. Mol Med Camb Mass 2007; 13: 112-120.
    PubMedGoogle Scholar
  • 28 Lane DA, Grant PJ. Role of haemostatic gene polymorphisms in venous and arterial thrombotic disease. Blood 2000; 95: 1517-1532.
    PubMedGoogle Scholar
  • 29 Maitland-van der, Zee A-H. et al. The effect of nine common polymorphisms in coagulation factor genes (F2, F5, F7, F12 and F13) on the effectiveness of statins: the GenHAT study. Pharmacogenet Genomics 2009; 19: 338-344.
    CrossrefPubMedGoogle Scholar
  • 30 Mannila MN. et al. Epistatic and pleiotropic effects of polymorphisms in the fi-brinogen and coagulation factor XIII genes on plasma fibrinogen concentration, fibrin gel structure and risk of myocardial infarction. Thromb Haemost 2006; 95: 420-427.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 31 Tognazzo S. et al. Prognostic role of factor XIII gene variants in nonhealing venous leg ulcers. J Vasc Surg 2006; 44: 815-819.
    CrossrefPubMedGoogle Scholar
  • 32 Van Hylckama Vlieg A. et al. Proof of principle of potential clinical utility of multiple SNP analysis for prediction of recurrent venous thrombosis. J Thromb Haemost 2008; 06: 751-754.
    CrossrefPubMedGoogle Scholar
  • 33 Vossen CY, Rosendaal FR. The protective effect of the factor XIII Val34Leu mutation on the risk of deep venous thrombosis is dependent on the fibrinogen level. J Thromb Haemost 2005; 03: 1102-1103.
    CrossrefPubMedGoogle Scholar
  • 34 Keightley AM. et al. Variation at the von Willebrand factor (vWF) gene locus is associated with plasma vWF:Ag levels: identification of three novel single nu-cleotide polymorphisms in the vWF gene promoter. Blood 1999; 93: 4277-4283.
    PubMedGoogle Scholar
  • 35 Zhang H. et al. ABO Blood Groups and Cardiovascular Diseases. Int J Vasc Med 2012; 2012: 641917.
    PubMedGoogle Scholar
  • 36 Koster T. et al. Role of clotting factor VIII in effect of von Willebrand factor on occurrence of deep-vein thrombosis. Lancet 1995; 345: 152-155.
    CrossrefPubMedGoogle Scholar
  • 37 Jenkins PV. et al. Elevated factor VIII levels and risk of venous thrombosis. Br J Haematol 2012; 157: 653-663.
    CrossrefPubMedGoogle Scholar
  • 38 Nossent AY. et al. Haplotypes encoding the factor VIII 1241Glu variation and the risk of myocardial infarction. J Thromb Haemost 2007; 05: 619-621.
    CrossrefPubMedGoogle Scholar
  • 39 Smith NL. et al. Association of genetic variations with nonfatal venous thrombosis in postmenopausal women. J Am Med Assoc 2007; 297: 489-498.
    CrossrefPubMedGoogle Scholar
  • 40 Varela ML. et al. Major and potential prothrombotic genotypes in a cohort of patients with venous thromboembolism. Thromb Res 2001; 104: 317-324.
    CrossrefPubMedGoogle Scholar
  • 41 Viel KR. et al. A sequence variation scan of the coagulation factor VIII (FVIII) structural gene and associations with plasma FVIII activity levels. Blood 2007; 109: 3713-3724.
    CrossrefPubMedGoogle Scholar
  • 42 Bertina RM. Genetic approach to thrombophilia. Thromb Haemost 2001; 86: 92-103.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 43 Morris DL. et al. Variation in the upstream region of P-Selectin (SELP) is a risk factor for SLE. Genes Immun 2009; 10: 404-413.
    CrossrefPubMedGoogle Scholar
  • 44 Reiner AP. et al. Common haemostasis and inflammation gene variants and venous thrombosis in older adults from the Cardiovascular Health Study. J Thromb Haemost 2009; 07: 1499-1505.
    CrossrefPubMedGoogle Scholar
  • 45 Heit JA. et al. A genome-wide association study of venous thromboembolism identifies risk variants in chromosomes 1q24.2 and 9q. J Thromb Haemost 2012; 10: 1521-1531.
    CrossrefPubMedGoogle Scholar
  • 46 Wiggins KL. et al. ABO genotype and risk of thrombotic events and haemor-rhagic stroke. J Thromb Haemost 2009; 07: 263-269.
    CrossrefPubMedGoogle Scholar
  • 47 Bezemer ID. et al. Updated analysis of gene variants associated with deep vein thrombosis. J Am Med Assoc 2010; 303: 421-422.
    CrossrefPubMedGoogle Scholar
  • 48 Tanaka T. et al. Genome-wide association study of vitamin B6, vitamin B12, fo-late, and homocysteine blood concentrations. Am J Hum Genet 2009; 84: 477-482.
    CrossrefPubMedGoogle Scholar
  • 49 Kantola AK. et al. Independent regulation of short and long forms of latent TGF-beta binding protein (LTBP)-4 in cultured fibroblasts and human tissues. J Cell Physiol 2010; 223: 727-736.
    PubMedGoogle Scholar
  • 50 Thompson AR. et al. Assessment of the association between genetic polymorphisms in transforming growth factor beta, and its binding protein (LTBP), and the presence, and expansion, of Abdominal Aortic Aneurysm. Atherosclerosis 2010; 209: 367-373.
    CrossrefPubMedGoogle Scholar
  • 51 Chappell S. et al. Cryptic haplotypes of SERPINA1 confer susceptibility to chronic obstructive pulmonary disease. Hum Mutat 2006; 27: 103-109.
    CrossrefPubMedGoogle Scholar
  • 52 Vasse M. Protein Z a protein seeking a pathology. Thromb Haemost 2008; 100: 548-556.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 53 Wadelius M. et al. Association of warfarin dose with genes involved in its action and metabolism. Hum Genet 2007; 121: 23-34.
    CrossrefPubMedGoogle Scholar
  • 54 Russo F. et al. Hypolactasia and metabolic changes in post-menopausal women. Maturitas 1997; 26: 193-202.
    CrossrefPubMedGoogle Scholar
  • 55 Silander K. et al. Gender differences in genetic risk profiles for cardiovascular disease. PloS One 2008; 03: e3615.
    CrossrefPubMedGoogle Scholar
  • 56 Takeuchi F. et al. A genome-wide association study confirms VKORC1, CYP2C9, and CYP4F2 as principal genetic determinants of warfarin dose. PLoS Genet 2009; 05: e1000433.
    CrossrefPubMedGoogle Scholar
  • 57 Pérez-Andreu V. et al. Pharmacogenetic relevance of CYP4F2 V433M polymorphism on acenocoumarol therapy. Blood 2009; 113: 4977-4979.
    CrossrefPubMedGoogle Scholar
  • 58 Rieder MJ. et al. Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose. N Engl J Med 2005; 352: 2285-2293.
    CrossrefPubMedGoogle Scholar
  • 59 Rost S. et al. Mutations in VKORC1 cause warfarin resistance and multiple coagulation factor deficiency type 2. Nature 2004; 427: 537-541.
    CrossrefPubMedGoogle Scholar
  • 60 Sconce EA. et al. Vitamin K epoxide reductase complex subunit 1 (VKORC1) polymorphism influences the anticoagulation response subsequent to vitamin K intake: a pilot study. J Thromb Haemost 2008; 06: 1226-1228.
    CrossrefPubMedGoogle Scholar
  • 61 Wilms EB. et al. A new VKORC1 allelic variant (p.Trp59Arg) in a patient with partial resistance to acenocoumarol and phenprocoumon. J Thromb Haemost 2008; 06: 1224-1226.
    CrossrefPubMedGoogle Scholar
  • 62 Yin T, Miyata T. Warfarin dose and the pharmacogenomics of CYP2C9 and VKORC1 - rationale and perspectives. Thromb Res 2007; 120: 1-10.
    CrossrefPubMedGoogle Scholar
  • 63 Wang Y. et al. VKORC1 haplotypes are associated with arterial vascular diseases (stroke, coronary heart disease, and aortic dissection). Circulation 2006; 113: 1615-1621.
    CrossrefPubMedGoogle Scholar
  • 64 Lacut K. et al. Vitamin K epoxide reductase genetic polymorphism is associated with venous thromboembolism: results from the EDITH Study. J Thromb Hae-most 2007; 05: 2020-2024.
    CrossrefPubMedGoogle Scholar
  • 65 Pomp ER. et al. Polymorphisms in the protein C gene as risk factor for venous thrombosis. Thromb Haemost 2009; 101: 62-67.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 66 Greliche N. et al. A genome-wide search for common SNP x SNP interactions on the risk of venous thrombosis. BMC Med Genet 2013; 14: 36.
    PubMedGoogle Scholar
  • 67 Behar DM. et al. The Basque paradigm: genetic evidence of a maternal continuity in the Franco-Cantabrian region since pre-Neolithic times. Am J Hum Genet 2012; 90: 486-493.
    CrossrefPubMedGoogle Scholar
  • 68 Rees DC. The population genetics of factor V Leiden (Arg506Gln). Br J Haema-tol 1996; 95: 579-586.
    CrossrefPubMedGoogle Scholar
  • 69 Osier MV. et al. ALFRED: An allele frequency database for anthropology. Am J Phys Anthropol 2002; 119: 77-83.
    CrossrefPubMedGoogle Scholar
  • 70 Itan Y. et al. A worldwide correlation of lactase persistence phenotype and genotypes. BMC Evol Biol 2010; 10: 36.
    CrossrefPubMedGoogle Scholar
  • 71 Bersaglieri T. et al. Genetic signatures of strong recent positive selection at the lactase gene. Am J Hum Genet 2004; 74: 1111-1120.
    CrossrefPubMedGoogle Scholar
  • 72 Plantinga TS. et al. Low prevalence of lactase persistence in Neolithic SouthWest Europe. Eur J Hum Genet 2012; 20: 778-782.
    CrossrefPubMedGoogle Scholar
  • 73 Crouau-Roy B. et al. Strong association between microsatellites and anHLA-B, DR haplotype (B18-DR3): implication for microsatellite evolution. Immuno-genetics 1996; 43: 255-260.
    CrossrefPubMedGoogle Scholar
  • 74 Qidwai T, Khan F. Tumour necrosis factor gene polymorphism and disease prevalence. Scand J Immunol 2011; 74: 522-547.
    CrossrefPubMedGoogle Scholar
  • 75 Zee RYL. et al. Genetic risk factors in recurrent venous thromboembolism: A multilocus, population-based, prospective approach. Clin Chim Acta Int J Clin Chem 2009; 402: 189-192.
    CrossrefPubMedGoogle Scholar
  • 76 Lee LH, Liu TC, Kuperan P. et al. Hereditary thrombophilia in an unselected cohort of venous thrombosis patients in Singapore. J Clin Pathol 2011; 64: 814-817.
    CrossrefPubMedGoogle Scholar
  • 77 Nguyen TT. et al. Making medical decisions in dependence of genetic background: estimation of the utility of DNA testing in clinical, pharmaco-epidemi-ological or genetic studies. Genet Epidemiol 2013; 37: 311-322.
    CrossrefPubMedGoogle Scholar
  • 78 Lotta LA. et al. Next-generation sequencing study finds an excess of rare, coding single-nucleotide variants of ADAMTS13 in patients with deep vein thrombosis. J Thromb Haemost 2013; 11: 1228-1239.
    CrossrefPubMedGoogle Scholar
  • 79 Montagnana M. et al. The role of ethnicity, age and gender in venous throm-boembolism. J Thromb Thrombolysis 2010; 29: 489-496.
    CrossrefPubMedGoogle Scholar
  • 80 Smith NL. et al. Variation in 24 haemostatic genes and associations with nonfatal myocardial infarction and ischemic stroke. J Thromb Haemost 2008; 06: 45-53.
    PubMedGoogle Scholar
  • 81 Calafell F. et al. Sequence variation and genetic evolution at the human F12 locus: mapping quantitative trait nucleotides that influence FXII plasma levels. Hum Mol Genet 2010; 19: 517-525.
    CrossrefPubMedGoogle Scholar
  • 82 Cochery-Nouvellon E. et al. Homozygosity for the C46T polymorphism of the F12 gene is a risk factor for venous thrombosis during the first pregnancy. J Thromb Haemost 2007; 05: 700-707.
    CrossrefPubMedGoogle Scholar
  • 83 Tirado I. et al. Association after linkage analysis indicates that homozygosity for the 46C-->T polymorphism in the F12 gene is a genetic risk factor for venous thrombosis. Thromb Haemost 2004; 91: 899-904.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 84 Houlihan LM. et al. Common variants of large effect in F12, KNG1, and HRG are associated with activated partial thromboplastin time. Am J Hum Genet 2010; 86: 626-631.
    CrossrefPubMedGoogle Scholar
  • 85 Smith SMG. et al. PAR-1 genotype influences platelet aggregation and proco-agulant responses in patients with coronary artery disease prior to and during clopidogrel therapy. Platelets 2005; 16: 340-345.
    CrossrefPubMedGoogle Scholar
  • 86 Undas A. et al. Tissue factor +5466A>G polymorphism determines thrombin formation following vascular injury and thrombin-lowering effects of simvasta-tin in patients with ischemic heart disease. Atherosclerosis 2009; 204: 567-572.
    CrossrefPubMedGoogle Scholar
  • 87 Damani SB, Topol EJ. Future use of genomics in coronary artery disease. J Am Coll Cardiol 2007; 50: 1933-1940.
    CrossrefPubMedGoogle Scholar
  • 88 Bhatnagar P. et al. Genetic variants in platelet factor 4 modulate inflammatory and platelet activation biomarkers. Circ Cardiovasc Genet 2012; 05: 412-421.
    CrossrefPubMedGoogle Scholar
  • 89 Scott BT. et al. Genetic screening of candidate genes for a prothrombotic interaction with type I protein C deficiency in a large kindred. Thromb Haemost 2001; 85: 82-87.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 90 Willige SU de. et al. Proteolytic and genetic variation of the alpha-2-antiplasmin C-terminus in myocardial infarction. Blood 2011; 117: 6694-6701.
    CrossrefPubMedGoogle Scholar
  • 91 Gandrille S. Endothelial cell protein C receptor and the risk of venous thrombosis. Haematologica 2008; 93: 812-816.
    CrossrefPubMedGoogle Scholar
  • 92 Dentali F. et al. Polymorphisms of the Z protein protease inhibitor and risk of venous thromboembolism: a meta-analysis. Br J Haematol 2008; 143: 284-287.
    CrossrefPubMedGoogle Scholar
  • 93 Asselbergs FW, Williams SM, Hebert PR. et al. The effects of polymorphisms in genes from the renin-angiotensin, bradykinin, and fibrinolytic systems on plasma t-PA and PAI-1 levels are dependent on environmental context. Hum Genet 2007; 122: 275-281.
    CrossrefPubMedGoogle Scholar
  • 94 Podgoreanu MV. et al. Inflammatory gene polymorphisms and risk of postoperative myocardial infarction after cardiac surgery. Circulation 2006; 114: I275-281.
    PubMedGoogle Scholar
  • 95 De Angelis V. et al. Pro-inflammatory genotype as a risk factor for aPL-associ-ated thrombosis: Report of a family with multiple anti-phospholipid positive members. J Autoimmun 2009; 32: 60-63.
    CrossrefPubMedGoogle Scholar
  • 96 Mello TBT. et al. Low density lipoprotein receptor-related protein polymorphisms are not risk factors for venous thromboembolism. Thromb Res 2008; 121: 625-629.
    CrossrefPubMedGoogle Scholar
  • 97 Cresci S. PPAR Genomics and Pharmacogenomics: Implications for Cardiovascular Disease. PPAR Res 2008; 2008: 374549.
    PubMedGoogle Scholar
  • 98 Meisinger C. et al. A genome-wide association study identifies three loci associated with mean platelet volume. Am J Hum Genet 2009; 84: 66-71.
    CrossrefPubMedGoogle Scholar
  • 99 Tsai MY. et al. Genetic causes of mild hyperhomocysteinemia in patients with premature occlusive coronary artery diseases. Atherosclerosis 1999; 143: 163-170.
    CrossrefPubMedGoogle Scholar
  • 100 Voetsch B. et al. Promoter polymorphisms in the plasma glutathione perox-idase (GPx-3) gene: a novel risk factor for arterial ischemic stroke among young adults and children. Stroke J Cereb Circ 2007; 38: 41-49.
    CrossrefPubMedGoogle Scholar
  • 101 Souto JC. et al. A genomewide exploration suggests a new candidate gene at chromosome 11q23 as the major determinant of plasma homocysteine levels: results from the GAIT project. Am J Hum Genet 2005; 76: 925-933.
    CrossrefPubMedGoogle Scholar
  • 102 Berger M. et al. Association of ADAMDEC1 haplotype with high factor VIII levels in venous thromboembolism. Thromb Haemost 2008; 99: 905-908.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 103 Schettert IT. et al. Association between ADAMTS13 polymorphisms and risk of cardiovascular events in chronic coronary disease. Thromb Res 2010; 125: 61-66.
    CrossrefPubMedGoogle Scholar
  • 104 Hasstedt SJ. et al. Cell adhesion molecule 1: a novel risk factor for venous thrombosis. Blood 2009; 114: 3084-3091.
    CrossrefPubMedGoogle Scholar
  • 105 MacClellan LR. et al. Relation of candidate genes that encode for endothelial function to migraine and stroke: the Stroke Prevention in Young Women study. Stroke J Cereb Circ 2009; 40: e550-557.
    CrossrefPubMedGoogle Scholar
  • 106 Van Loon JE. et al. Relationship between thrombospondin gene variations, von Willebrand factor levels and the risk of coronary heart disease in an older population: Letters to the Editor. J Thromb Haemost 2011; 09: 1415-1417.
    CrossrefPubMedGoogle Scholar
  • 107 Yang Q. et al. Genome-wide association and linkage analyses of haemostatic factors and hematological phenotypes in the Framingham Heart Study. BMC Med Genet 2007; 08 (Suppl. 01) S12.
    CrossrefPubMedGoogle Scholar
  • 108 Mustafa S. et al. Genetic variation in heme oxygenase 1 (HMOX1) and the risk of recurrent venous thromboembolism. J Vasc Surg 2008; 47: 566-570.
    CrossrefPubMedGoogle Scholar
  • 109 Soranzo N. et al. A novel variant on chromosome 7q22.3 associated with mean platelet volume, counts, and function. Blood 2009; 113: 3831-3837.
    CrossrefPubMedGoogle Scholar
  • 110 Zee RYL. et al. Purinergic receptor P2Y, G-protein coupled, 12 gene variants and risk of incident ischemic stroke, myocardial infarction, and venous throm-boembolism. Atherosclerosis 2008; 197: 694-699.
    CrossrefPubMedGoogle Scholar
  • 111 Morange P-E. et al. KNG1 Ile581Thr and susceptibility to venous thrombosis. Blood 2011; 117: 3692-3694.
    CrossrefPubMedGoogle Scholar
  • 112 Kaur-Knudsen D. et al. Nicotinic acetylcholine receptor polymorphism, smoking behavior, and tobacco-related cancer and lung and cardiovascular diseases: a cohort study. J Clin Oncol Off J Am Soc Clin Oncol 2011; 29: 2875-2882.
    CrossrefPubMedGoogle Scholar
  • 113 Heit JA. et al. Genetic variation within the anticoagulant, procoagulant, fibri-nolytic and innate immunity pathways as risk factors for venous thromboem-bolism. J Thromb Haemost 2011; 09: 1133-1142.
    CrossrefPubMedGoogle Scholar
  • 114 Samani NJ. et al. WTCCC and the Cardiogenics Consortium. Genomewide association analysis of coronary artery disease. N Engl J Med 2007; 357: 443-453.
    CrossrefPubMedGoogle Scholar
  • 115 Samani NJ, Erdmann J, Hall AS. et al. WTCCC and the Cardiogenics Consortium. Genomewide association analysis of coronary artery disease. N Engl J Med 2007; 357: 443-453.
    CrossrefPubMedGoogle Scholar