Single nucleotide polymorphisms in the VKORC1 gene and the risk of stroke in the Southern German population

Marie-Luise Arnold; Christoph Lichy; Inge Werner; Alexander Radbruch; Simone Wagner; Caspar Grond-Ginsbach

doi:10.1160/TH07-10-0617

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2008; 100(04): 614-617
DOI: 10.1160/TH07-10-0617

Blood Coagulation, Fibrinolysis and Cellular Haemostasis

Schattauer GmbH

Single nucleotide polymorphisms in the VKORC1 gene and the risk of stroke in the Southern German population

Marie-Luise Arnold

¹Department of Neurology, University of Heidelberg, Heidelberg, Germany

,

Christoph Lichy

¹Department of Neurology, University of Heidelberg, Heidelberg, Germany

,

Inge Werner

¹Department of Neurology, University of Heidelberg, Heidelberg, Germany

,

Alexander Radbruch

¹Department of Neurology, University of Heidelberg, Heidelberg, Germany

,

Simone Wagner

¹Department of Neurology, University of Heidelberg, Heidelberg, Germany

,

Caspar Grond-Ginsbach

¹Department of Neurology, University of Heidelberg, Heidelberg, Germany

› Author Affiliations

Abstract

Summary

Variation in the gene that encodes the vitamin K epoxide reductase subunit 1 (VKORC1) was recently proposed as a genetic risk factor for stroke in a Chinese population. In this ethnic group, only two common haplotypes were observed, with the C-allele of the polymorphism rs2359612 (VKORC1: c.283+837C>T) associated with stroke and other cardiovascular diseases. Recently, the influence of VKORC1 haplotypes on venous thrombosis and coronary heart disease was analyzed in study populations from France and Northern Germany. We studied the frequencies of theVKORC1 haplotypes in a series of young (<50 years, n = 158) patients with ischemic stroke from Southern Germany. The data were compared with findings from age-matched healthy control subjects from the same population (n = 213). In a replica study we also analysed older stroke patients (>50 years, n = 135) and matched control subjects (n = 113). Neither in the young population, nor in the replica study, we observed significant differences in VKORC1 haplotype distributions between healthy control subjects and patients with ischemic stroke. Our data do not confirm the association between polymorphism in the VKORC1 gene and stroke in the German population.

Keywords

Stroke - vitamin K epoxide reductase - haplotype - SNP

Full Text

References

References
1 Dichgans M. Genetics of ischaemic stroke. Lancet Neurol 2007; 06: 149-161.
2 Casa JP, Hingorani AD, Bautista LE. et al. Meta-analysis of genetic studies in ischemic stroke. Arch Neurol 2004; 61: 1652-1661.
3 Rost S, Fregin A, Ivaskevicius V. et al. Mutations in VKORC1 cause warfarin resistance and multiple coagulation factor deficiency type 2. Nature 2004; 427: 537-541.
4 Li T, Chang CY, Jin DY. et al. Identification of the gene for vitamin K epoxide reductase. Nature 2004; 427: 541-544.
5 Berkner KL. The vitamin K-dependent carboxylase. Ann Rev Nutr 2005; 25: 127-149.
6 Berkner KL, Runge KW. The physiology of vitamin K nutriture and vitamin K-dependent protein function in atherosclerosis. J Throm Haemost 2004; 02: 2118-2132.
7 Wang Y, Zhang W, Zhang Y. et al. VKORC1 haplotypes are associated with arterial vascular diseases (stroke, coronary heart disease, and aortic dissection). Circulation 2006; 113: 1615-1621.
8 Lacut K, Larramendy-Gozalo C, Le Gal G. et al. Vitamin K epoxide reductase genetic polymorphism is associated with venous thromboembolism: results from the EDITH Study. J Thromb Haemost 2007; 05: 2020-2024.
9 Hindorff LA, Heckbert SR, Smith N. et al. Common VKORC1 variants are not associated with arterial or venous thrombosis. J Throm Haemost 2007; 05: 2025-2027.
10 Reitsma PH. VKORC1 gene variation and venous thrombosis: ‘another one bites the dust’?. J Throm Haemost 2007; 05: 2017-2019.
11 Watzka M, Nebel A, El Mokhtari NE. et al. Functional promoter polymorphism in theVKORC1 gene is no major genetic determinant for coronary heart disease in Northern Germans. Thromb Haemost 2007; 97: 998-1002.
12 Lichy C, Stoll F, Kropp S. et al. Cerebral ischemia in young adults and genetic polymorphisms of coagulation factors II, V and VII. Thromb Haemost 2004; 91: 825-827.
13 Lichy C, Meiser H, Grond-Ginsbach C. et al. Lipopolysaccharide receptor CD14 polymorphism and risk of stroke in a South-German population. J Neurol 2002; 249: 821-823.
14 Dörfer CE, Becher H, Ziegler CM. et al. Theassociation of gingivitis and periodontitis with ischemic stroke. J Clin Periodontol 2004; 31: 396-401.
15 Geisen C, Watzka M, Sittinger K. et al. VKORC1 haplotypes and their impact on the inter-individual and inter-ethnical variability of oral anticoagulation. Throm Haemost 2005; 94: 773-779.
16 Rieder MJ, Reiner AP, Gage BF. et al. Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose. N Engl J Med 2005; 352: 2285-2293.
17 Sconce EA, Khan TI, Wynne HA. et al. The impact of CYP2C9 and VKORC1 genetic polymorphism and patient characteristics upon warfarin dose requirements: proposal for a new dosing regimen. Blood 2005; 106: 2329-2333.
18 Yuan HY, Chen JJ, Lee MTM. et al. A novel functional VKORC1 promoter polymorphism is associated with inter-individual and inter-ethnic differences in warfarin sensitivity. Hum Mol Genet 2005; 14: 1745-1751.
19 Herman D, Peternel P, Stegnar M. et al. The influence of sequence variations in factor VII, γ-glutamyl carboxylase and vitamin K epoxide reductase complex genes on warfarin dose requirement. Thromb Haemost 2006; 95: 782-787.
20 OsmanA EnströmC, Arbring K. et al. Main haplotypes and mutational analysis of vitamin K epoxide reductase (VKORC1) in a Swedish population: a retrospective analysis of case records. J Throm Haemost 2006; 04: 1723-1729.
21 Oldenburg J, Bevans CG, Fregin A. et al. Current pharmacogenetic developments in oral anticoagulation therapy: the influence of variant VKORC1 and CYP2C9 alleles. Thromb Haemost 2007; 98: 570-578.
22 Loebstein R, Dvoskin I, Halkin H. et al. A coding VKORC1 Asp36Tyr polymorphism predisposes to warfarin resistance. Blood 2007; 109: 2477-2480.
23 Lee SC, Ng SS, Oldenburg J. et al. Interethnic variability of warfarin maintenance requirement is explained by VKORC1 genotype in an Asian population. Clin Pharmacol Ther 2006; 79: 197-205.
24 Obayashi K, Nakamura K, Kawana J. et al. VKORC1 gene variations are the major contributors of variation in warfarin dose in Japanese patients. Clin Pharmacol Ther 2006; 80: 169-178.
25 Cho HJ, Sohn KH, Park HM. et al. Factors affecting the interindividual variability of warfarin dose requirement in adult Korean patients. Pharmacogenomics 2007; 08: 329-337.