Polymorphisms in prothrombotic genes and their impact on ischemic stroke in a Sardinian population

Speranza Rubattu; Emanuele Di Angelantonio; Dorothea Nitsch; Bruna Gigante; Bastianina Zanda; Rosita Stanzione; Anna Evangelista; Angelo Pirisi; Giulio Rosati; Massimo Volpe

doi:10.1160/TH04-07-0457

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2005; 93(06): 1095-1100
DOI: 10.1160/TH04-07-0457

Blood Coagulation, Fibrinolysis and Cellular Haemostasis

Schattauer GmbH

Polymorphisms in prothrombotic genes and their impact on ischemic stroke in a Sardinian population

Speranza Rubattu

¹IRCCS Neuromed, Pozzilli (Is), University La Sapienza, Ospedale Sant’Andrea, Rome, Italy

²Department of Cardiology, II^nd School of Medicine, University La Sapienza, Ospedale Sant’Andrea, Rome, Italy

,

Emanuele Di Angelantonio

³Department of Internal Medicine, I^st School of Medicine, University La Sapienza, Rome, Italy

,

Dorothea Nitsch

⁴Dept of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, U. K.

,

Bruna Gigante

⁵Dept. of Clinical Medicine, Cardiovascular and Immunological Sciences, Federico II University, Naples, Italy

,

Bastianina Zanda

⁶Institute of Clinica Neurologica, University of Sassari, Italy

,

Rosita Stanzione

¹IRCCS Neuromed, Pozzilli (Is), University La Sapienza, Ospedale Sant’Andrea, Rome, Italy

,

Anna Evangelista

¹IRCCS Neuromed, Pozzilli (Is), University La Sapienza, Ospedale Sant’Andrea, Rome, Italy

,

Angelo Pirisi

⁶Institute of Clinica Neurologica, University of Sassari, Italy

,

Giulio Rosati

⁶Institute of Clinica Neurologica, University of Sassari, Italy

,

Massimo Volpe

¹IRCCS Neuromed, Pozzilli (Is), University La Sapienza, Ospedale Sant’Andrea, Rome, Italy

²Department of Cardiology, II^nd School of Medicine, University La Sapienza, Ospedale Sant’Andrea, Rome, Italy

› Author Affiliations

Abstract

Summary

Genetic factors are involved in the individual predisposition to develop ischemic stroke (IS). In the present study we tested the role of the Factor VII G10976A and –C122T polymorphisms on the susceptibility to develop IS in a genetically homogenous and clinically well ascertained case-control study including 294 cases (median age 75 years; 176 males/118 females) and 286 controls (median age 73 years; 163 males/123 females) in Sardinia, Italy. In addition, we carried out an exploratory analysis with respect to other frequently studied polymorphisms of haemostatic factor genes: Factor II G20210A, Factor V G1691A,, Fibrinogen α-chain Thr312Ala, Fibrinogen β-chain –C148T, Factor XIII G185T, GPIIb/IIIa T1565C. Among all the genes tested, FVII –C122T showed a significant, independent contribution to IS predisposition both in crude and adjusted analyses (crude OR 1.52, 95% CI 1.09–2.10, P=0.013; adjusted OR 1.48, 95% CI 1.04–2.09, P=0.028, respectively). Haplotype analyses revealed a conserved population structure with high linkage disequilibrium between both FVII mutations tested. Blood levels of FVII had an inverse relationship with the polymorphism involved. Apart from genetic influence, there was a significant role for hypertension (OR=1.7, 95% CI 1.19–2.43, P=0.003), hypercholesterolemia (OR=2.21, 95% CI 1.38–3.54, P=0.001) and atrial fibrillation (OR=1.66, 95% CI 1.06–2.58, P=0.026) on IS occurrence. In summary, we describe evidence for a possible direct association of FVII gene molecular variants with the occurrence of IS in a genetically homogenous human sample.

Keywords

Stroke - genetics - coagulation factors - polymorphisms

Full Text

References

References
1 Rubattu S, Giliberti R, Volpe M. Etiology and pathophysiology of stroke as a complex phenotypic trait. Am J Hypertens 2000; 13: 1239-48.
2 Rubattu S, Volpe M, Kreutz R. et al. Chromosomal mapping of quantitative trait loci contributing to stroke in a rat model of human disease. Nature Genetics 1996; 13: 429-33.
3 Jeffs B, Clark J, Anderson N. et al. Sensitivity to cerebral ischemic insult in a rat model of stroke is determined by a single genetic locus. Nature Genetics 1997; 16: 364-7.
4 Hassan A, Markus H. Genetics and ischemic stroke. Brain 2000; 123: 1784-812.
5 Rubattu S, Ridker P, Stampfer MJ. et al. The gene encoding atrial natriuretic peptide and the risk of human stroke. Circulation 1999; 100: 1722-6.
6 Rubattu S, Stanzione R, Di Angelantonio E. et al. Atrial natriuretic peptide gene polymorphisms and risk of ischemic stroke in humans. Stroke 2004; 35: 814-8.
7 Smith FB, Lee AJ, Fowkes FG. et al. Hemostatic factors as predictors of ischemic heart disease and stroke in the Edinburgh Artery Study. Arterioscl Thromb Vasc Biol 1997; 17: 3321-5.
8 Ridker PM, Hennekens CH, Lindpaintner K. et al. Mutation in the gene coding for coagulation factor V and the risk of myocardial infarction, stroke, and venous thrombosis in apparently healthy men. N Engl J Med 1995; 332: 912-7.
9 Poort SR, Rosendaal FR, Reitsman PH. et al. A common genetic variation in the 3'-untraslated region of the prothrombin gene is associated with elevated.
10 Voetsch B, Loscalzo J. Genetic determinants of arterial thrombosis. Arterioscl Thromb Vasc Biol 2004; 24: 1-14.
11 Endler G, Funk M, Haering D. et al. Is the factor XIII 34Val/Leu polymorphism a protective factor for cerebrovascular disease?. Br J Haematol 2003; 120: 310-4.
12 Corral J, Iniesta J, Gonzalez-Conejero R. et al. Polymorphisms of clotting factors modify the risk for primary intracranial hemorrhage. Blood 2001; 97: 2979-82.
13 Heywood D, Carter A, Catto A. et al. Polymorphisms of the Factor VII gene and circulating FVII:C levels in relation to acute cerebrovascular disease and poststroke mortality. Stroke 1997; 28: 816-21.
14 Nishiuma S, Kario K, Nakanishi K. et al. Factor VII R353Q polymorphism and lacunar stroke in Japanese hypertensive patients and normotensive controls. Blood coagulation and fibrinolysis 1997; 8: 525-30.
15 Kario K, Matsuo M, Miyata T. Are there any associations among coagulation factor VII gene polymorphisms, plasma activated factor VII levels, and cerebrovascular disease?. Circulation 2000; 101: E48
16 Cavalli-Sforza LL, Menozzi P, Piazza A. The history and geography of human genes. 1994. Princeton: Princeton University Press; pp 272-276.
17 Siniscalco M, Robledo R, Bender PK. et al. Population genomics in Sardinia: a novel approach to hunt for genomic combinations underlying complex traits and diseases. Cytogenet. Cell Genet 1999; 86: 148-52.
18 Lampis R, Morelli L, Congia M. et al. The inter-regional distribution of HLA class II haplotypes indicates the suitability of the Sardinian population for case-control association studies in complex diseases. Hum Mol Genet 2000; 9: 2959-65.
19 Rubattu S, Di Angelantonio E, Stanzione R. et al. Gene polymorphisms of the renin-angiotensin-aldosterone system and the risk of ischemic stroke: a role of the A1166C/AT1 gene variant. J Hypertens 2004; 22: 2129-34.
20 Marchetti G, Patracchini P, Gemmati D. et al. Detection of two missense mutations and characterization of a repeat polymorphism in the factor VII gene (F7). Hum Genetic 1992; 89: 497-502.
21 Dell'Acqua G, Iacoviello L, D'Orazio A. et al. A polymorphic cluster in the 5' region of the human coagulation coagulation Factor VII gene: detection, frequency, and linkage disequilibrium. Thromb Res 1997; 88: 445-8.
22 Bertina RM, Koeleman BPC, Loster T. et al. Mutation in blood coagulation Factor V is associated with resistance to activated protein C. Nature 1994; 369: 64-79.
23 Carter AM, Catto AJ, Grant PJ. Association of the α -fibrinogen Thr312Ala polymorphism with poststroke mortality in subjects with atrial fibrillation. Circulation 1999; 99: 2323-426.
24 Blake GJ, Schmitz C, Lindpaintner K. et al. Mutation in the promoter of the b-fibrinogen gene and the risk of future myocardial infarction, stroke, and venous thrombosis. Eur Heart J 2001; 22: 2262-6.
25 Mikkola H, Syrjala M, Rasi V. et al. Deficiency in the A-subunit of coagulation factor XIII: two novel point mutations demonstrate different effects on transcript levels. Blood 1994; 84: 517-25.
26 Ridker PM, Hennekens CH, Schmitz C. et al. P1A1/A2 polymorphism of platelet glycoprotein IIIa and risks of myocardial infarction, stroke and venous thrombosis. Lancet 1997; 349: 385-8.
27 Falconer D. Introduction to quantitative genetics. 1994. UK: Longman Scientific and Technical; 385-8.
28 Mickey R, Greenland S. The impact of confounder selection criteria on effect estimation. Am J Epidemiol 1989; 129: 125-37.
29 SNPHAP: A Program for Estimating Frequencies of Large Haplotypes of SNPs. http://www-gene.cimr. cam.ac.uk/clayton/software/snphap.txt
30 Di Castelnuov A, D'Orazio A, Amore C. et al. Genetic modulation of coagulation Factor VII plasma levels: contribution of different polymorphisms and gender-related effects. Thromb Hemost 1998; 80: 592-7.
31 Bernardi F, Marchetti G, Pinotti M. et al. Factor VII gene polymorphisms contribute about one third of the Factor VII level variation in plasma. Arterioscler Thromb Vasc Biol 1996; 16: 72-6.
32 Endler G, Mannhalter C. Polymorphisms in coagulation factor genes and their impact on arterial and venous thrombosis. Clinica Chimica Acta 2003; 330: 31-55.
33 Wu A, Tsongalis G. Correlation of polymorphisms to coagulation and biochemical risk factors for cardiovascular diseases. Am J Cardiol 2001; 87: 1361-6.
34 Shifman S, Darvasi A. The value of isolated populations. Nature Genetics 2001; 28: 309-10.
35 Elbaz A, Poirier O, Canaple S. et al. The association between the Val34Leu polymorphism in the factor XIII gene and brain infarction. Blood 2000; 95: 586-91.
36 Reiner A, Frank MB, Schwartz SM. et al. Coagulation factor XIII polymorphisms and the risk of myocardial infarction and ischaemic stroke in young women. Br J Haematol 2002; 116: 376-82.
37 Ariens RS, Lai T-S, Weisel JW. et al. Role of factor XIII in fibrin clot formation and effects of genetic polymorphisms. Blood 2002; 100: 743-54.
38 Ridker CM, Hennekens CH, Schmitz C. et al. PIA1/A2 polymorphism of platelet glycoprotein IIIa and risks of myocardial infarction, stroke, and venous thrombosis. Lancet 1997; 349: 385-8.
39 Blake GJ, Schmitz C, Lindpaintner K. et al. Mutation in the promoter region of the beta-fibrinogen gene and the risk of future myocardial infarction, stroke and venous thrombosis. Eur Heart J 2001; 22: 2262-6.