Fgb Gene And Coronary Heart Disease In Chinese Han Population Association Studies

Background:Myocardial infarction(MI),one of the leading causes of death worldwide,is a complex disorder influenced by multiple genetic and environmental factors.Approximately 90%of MI results from an acute thrombus that obstructs an atherosclerotic coronary artery.As the last target of coagulation,fibrinogen plays a pivotal role in the hemostatic balance by representing the substrate for fibrin clot formation,and the support for platelet aggregation.Fibrinogen is an acute phase protein,synthesized in the liver,the plasma levels of which acutely rise during inflammatory conditions.In some large prospective studies in Europe and the United States,elevated plasma fibrinogen levels has been shown to be strongly associated with the genetic variants in fibrinogen genes and an independent predictor of MI.In recent years,several polymorphisms in the genes for fibrinogen have been associated with increased plasma fibrinogen.The FGB gene(fibrinogenβ-chain gene) has been more extensively studied because theβ-chain synthesis is the limiting step in the production of mature fibrinogen.The association between MI and some polymorphisms in FGB gene,such as-455G/A and-148C/T,had been found in some studies,but others had not.The inconsistent results might be due to linkage relationships with other unidentified functional genetic variants in the FGB gene.The aim of the present study was to scan the whole FGB gene,and to identify all putative functional polymorphisms and further investigate whether these polymorphisms are associated with MI in Nothem Chinese Hart population.Methods:A case-control design was applied in this study.In brief,509 unrelated CHD patients who surrived an acute MI were enrolled from hospitalized patients of Fu Wai Hospital between October 1997 and September 2000.507 age-and sex-matched subjects were randomly recruited from individuals participating in a community-based survey of cardiovascular risk factors in Beijing.A detail of questionnaires about the risk factors of cardiovascular disease was available and physical examination was carried out in all subjects.We randomly selected 48 patients to detect all polymorphisms of the FGB gene by directly sequencing.We selected three polymorphisms in the FGB gene for genotyping by polymerase chain reaction-restriction fragment length polymorphism(PCR-RFLP) in all subjects. Univariate analysis was applied to measure the association of each polymorphism with MI.Multivariate analysis was performed to investigate the independent or interactive effect of polymorphisms/haplotypes on MI.Statistical analysis was conducted using the SPSS 13.0 version for Windows,2LD program and EH program, in conjunction with the haplo.score and haplo.glm programs.Results:(1) In a total length of 5.7 kb explored,we identified 18 SNPs,of which 6 were first reported,they were 5092G/A(intron 4),6401G/A and 6493T/C(intron 6), CyslllTyr(exon 3),Asn309Tyr(exon 6) and 8588G/A(3' flanking region) respectively.However,the latter three polymorphisms appeared only once in the 48 samples,their frequencies were less than 5%.(2) Allele frequencies of the most studied polymorphisms such as-455G/A and R448K are similar between our population and Caucasian populations.(3) Complete or nearly complete LD between polymorphisms was frequently observed.(4) Univariate analyses indicated that the 3 FGB polymorphisms were associated with MI in all of three genetic models(i.e. dominant,recessive and additive models).After adjusting other risk factors,however, only individuals carrying the 448K allele had an approx.30%reduction in risk of developing MI(OR 0.71,95%CI 0.52-0.96),and homozyosity for 8558G was associated with a 70%decreased risk of MI(GG:GC+CC,OR=0.28,P=0.046). Haplotype analyses showed that the A-K-G haplotype(-455A,448K,8558G) was associated with a protective effect against MI,whereas the most common haplotype (G-R-C) was related to an increased risk of MI,even after adjusting for environmental risk factors.Conclusions:Our study demonstrated the first evidence of a significant association between the FGB R448K polymorphism and MI in a Chinese Han population,which possession of the 448K allele may be protective against developing MI.However,the results should be interpreted with caution,given the small sample size.A larger cohort will ultimately be required to confirm whether or not this association is real.