Association after linkage analysis indicates that homozygosity for the 46C→T polymorphism in the F12 gene is a genetic risk factor for venous thrombosis

Summary

In a family-based study called GAIT (Genetic Analysis of Idiopathic Thrombophilia) that included a genome-wide scan we demonstrated that a polymorphism (46C→T) in the F12 locus jointly influences variability of plasma (Factor XII) FXII levels and susceptibility to thrombotic disease. It then became germane to determine the prevalence of the 46C→T polymorphism and its relative risk of thrombotic disease. We followed up evidence for genetic linkage with a case-control study, including 250 unrelated consecutive Spanish patients suffering from venous thrombotic disease and 250 Spanish subjects matched for sex and age as a controls. We measured FXII levels and genotyped the 46C→T polymorphism, as well as a number of classical risk factors for thrombotic disease. We confirmed that individuals with different genotypes for this polymorphism showed significant differences in their FXII levels. Most importantly, the mutated T allele in the homozygous state (genotype T/T) was associated with an increased risk of thrombosis (adjusted OR of 4.82; 95% CI 1.5-15.6), suggesting that the polymorphism itself is an independent risk factor for venous thromboembolism. This study confirms that the 46C→T polymorphism is a genetic risk factor for venous thrombosis in the Spanish population. In addition, our results confirm that a genome-wide scan coupled with a classical case-control association study is an extremely valuable approach to identify DNA variants that affect complex diseases.

Keywords

Thrombosis - genetics - risk factors - complex disease

• References

• 1 Coon WW, Park WW, Keller JB. Venous thromboemolism and other venous disease in the Tecumseh Community Health Study. Circulation 1973; 48: 839-46.
• 2 Nordstrom M, Lindblad B, Bergqvist D. et al. A prospective study of the incidence of deepvein thrombosis within a defined urban population. J Intern Med 1992; 232: 155-60.
• 3 Anderson FA, Wheeler HB, Goldberg RJ. et al. A population-based perspective of the hospital incidence and case-fatality rates of deep vein thrombosis and pulmonary embolism. The Worcester DVT Study. Arch Intern Med 1991; 151: 933-8.
• 4 Murray CJ, Lopez AD. Mortality by cause for eight regions of the world: global burden of disease study. Lancet 1997; 349: 1269-76.
• 5 Soria JM, Almasy L, Souto JC. et al. Linkage analysis demonstrated that the prothrombin G20210A mutation jointly influences plasma prothrombin levels and risk of thrombosis. Blood 2000; 95: 2780-5.
• 6 Soria JM, Almasy L, Souto JC. et al. A quantitative-trait locus in the human factor XII gene influences both plasma factor XII levels and susceptibility to thrombotic disease. Am J Hum Genet 2002; 70: 567-74.
• 7 Dahlback B. Successful hunt for quantitative trait locus in thrombophilia. Arterioscler Thromb Vasc Biol 2003; 23: 376-7.
• 8 Souto JC, Almasy L, Borrell M. et al. Genetic determinants of hemostasis phenotypes in Spanish families. Circulation 2000; 101: 1546-51.
• 9 Dahlbäck B, Carlsson M, Svensson PJ. Familial thrombophilia due to a previously unrecognized mechanism characterized by a poor anticoagulant reponse to activated protein C: prediction of a cofactor to activated protein C. Proc Natl Acad Sci USA 1993; 90: 1004-8.
• 10 Hyland K, Bottiglieri T. Measurement of total plasma and cerebrospinal homocysteine by fluorescence following high-performance liquid chromatography and precolumn with opthaldialdehyde. J Chromatography 1992; 79: 55-62.
• 11 Exner T, Rickard KA, Kronenberg H. A sensitive test demonstrating lupus anticoagulant and its behavioral patterns. Br J Haematol 1987; 40: 143-51.
• 12 Gharavi AE, Harris EN, Asherson RA. et al. Anticardiolipin antibodies: isotype distribution and phospholipid specificity. Ann Rheum Dis 1987; 46: 1-6.
• 13 Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acid Res 1988; 16: 1215.
• 14 Kanaji T, Okamura T, Osaki K. et al. A common genetic polymorphism (46 C to T substitution) in the 5’-untranslated region of the coagulation factor XII gene is associated with low translation efficiency and decrease in plasma factor XII level. Blood 1998; 91: 2010-4.
• 15 Bertina RM, Koeleman BPC, Koster T. et al. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994; 369: 64-7.
• 16 Poort SR, Rosendaal FR, Reitsma PH. 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: 3698-703.
• 17 Souto JC, Coll I, Llobet D. et al. The Prothrombin 20210A allele is the most prevalent genetic risk factor for venous thromboembolism in the Spanish population. Thromb Haemost 1998; 80: 366-9.
• 18 Rowen L, Mahairas G, Hood L. Sequencing the human genome. Science 1997; 278: 605-7.
• 19 Gelbert LM, Gregg RE. Will genetics really revolutionize the drug discovery process?. Curr Opin Biotechnol 1997; 08: 669-74.
• 20 Endler G, Exner M, Mannhalter C. et al. A common C→T polymorphism at nt 46 in the promoter region of coagulation factor XII is associated with decreased factor XII activity. Thromb Res 2001; 101: 255-60.
• 21 Zito F, Drummond F, Bujac SR. et al. Epidemiological and genetics associations of activated factor XII concentration with factor VII activity, fibrinopeptide A concentration, and risk of coronary heart disease in men. Circulation 2000; 102: 2058-62.
• 22 Rees DC, Cox M, Clegg JB. World distribution of factor V Leiden. Lancet 1995; 346: 1133-4.
• 23 Rosendaal FR, Doggen CJM, Zivelin A. et al. Geographic distribution of the 20210 G to A prothrombin variant. Thromb Haemost 1998; 79: 706.
• 24 van der Meer FJM, Koster T, Vanderçnbroucke JP. et al. The Leiden Thrombophilia Study (LETS). Thromb Haemost 1997; 78: 631-5.
• 25 Lane DA, Grant PJ. Role of hemostatic gene polymorphisms in venous and arterial thrombotic disease. Blood 2000; 95: 1517-32.
• 26 Rosendaal FR. Venous thrombosis: a multicausal disease. Lancet 1999; 353: 1167-73.
• 27 Souto JC, Almasy L, Borrell M. et al. Genetic susceptibility to thrombosis and its relationship to physiological risk factors: The GAIT study. Am J Hum Genet 2000; 67: 1452-9.
• 28 Ishii K, Oguchi S, Murata M. et al. Activated factor XII levels are dependent on factor XII 46 C/T genotypes and factor XII zymogen levels, and are associated with vascular risk factors in patients and healthy subjects. Blood Coagul Fibrinolysis 2000; 11: 277-84.
• 29 Kholer HP, Carter AM, Stickland MH. et al. Levels of activated FXII in survivors of myocardial infarction-association with circulating risk factors and extent of coronary artery disease. Thromb Haemost 1998; 79: 14-8.
• 30 Oguchi S, Ito D, Murata M. et al. Genotype distribution of the 46 C/T polymorphism of coagulation factor XII in the japanese population: absence of its association with ischemic cerebrovascular disease. Throm Haemost 2000; 83: 178-9.
• 31 Kohler HP, Fusters TS, Granbt PJ. FXII (46C→T) polymorphism and in vivo generation of FXII activity- gene frequencies and relationship in patients with coronary artery disease. Thromb Haemost 1999; 81: 745-7.
• 32 Gambaro G, Anglani F, D’Angelo A. Association studies of genetic polymophisms and complex disease. Lancet 2000; 355: 308-11.
• 33 Almasy L, MacCluer JW. Association studies of vascular phenotypes: how and why?. Arterioscler Thromb Vasc Biol 2002; 22: 1055-7.
• 34 Editorial. Freely associating. Nature Genetics 1999; 22: 1-2.
• 35 Cooper DN, Nussabaum RL, Krawczak M. Proposed guidelines for papers describing DNA polymorphism-disease associations. Hum Genet 2002; 110: 207-8.
• 36 Sterne JA, Smith D. Sifting the evidencewhat’s wrong with significance tests?. BMJ 2001; 322: 226-31.
• 37 Foncea N, Gomez MBeldarrain, Ruiz JOjeda. et al. Ischemic stroke in a patient with factor XII (Hageman) deficiency. Neurologia 2001; 16: 227-8.
• 38 Braat EA, Dooijewaard G, Rijken DC. Fibrinolytic of activated FXII. Eur J Bichem 1999; 263: 904-11.
• 39 Miller GJ, Esnouf MP, Burgess AI. et al. Risk of coronary heart disease and activation of factor XII in middle-aged men. Aterioscler Thromb Vasc Biol 1997; 17: 2103-6.