beta-Fibrinogen Promoter Gene Polymorphisms in Cerebral Small Vessel Disease

Park, Man Seok; Choi, Sung Min; Lee, Seung Han; Kim, Byeong Chae; Kim, Myeong Kyu; Cho, Ki Hyun

Abstract

Fibrinogens are major determinants of plasma hyperviscosity, platelet aggregation and endothelial cell injury, and play a central role in the formation of atherosclerotic thrombi. Polymorphisms at the beta- fibrinogen locus have been shown to be associated with elevated plasma concentration of fibrinogen and ischemic stroke. However, there are different pathomechanisms between cerebral small vessel disease and atherosclerotic cerebral infarction, so it is necessary to evaluate the association between polymorphisms at the beta-fibrinogen locus and plasma fibrinogen concentration in relation to the subtypes of ischemic stroke. In this study, we evaluated the physiological roles of 3 common nucleotide substitutions in the promoter region of the beta-fibrinogen gene at positions -148, -249, -455 from the transcriptional start site in patients with cerebral small vessel disease. One hundred and fifteen consecutive patients with cerebral small vessel disease and 100 patients with atherosclerotic large artery stroke were enrolled in this study. We compared plasma fibrinogen levels, risk factors of stroke and clinical features between the two groups. The genotypes of -148 C/T, -249 C/T, -455 G/A were determined by restriction fragment length polymorphism (RFLP) and automatic DNA sequencing in patients with cerebral small vessel disease. The frequencies of -148T, -249T, -455A allele in patients were 0.16, 0.38 and 0.16, respectively. One of these three polymorphisms, -455 G/A was significantly associated with increase of fibrinogen levels. These results suggest that 455G/A polymorphism in beta-fibrinogen promoter gene is a genetic predisposing factor of hyperfibrinogenemia, but the association between the polymorphism and cerebral small vessel disease remains to be clarified.