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A common mutation (G-455--> A) in the promoter region of the beta-fibrinogen gene has been associated with elevated plasma fibrinogen levels. Whether fibrinogen genotype affects plasma fibrinogen levels and risk of ischemic heart disease in the general population has not been studied. We investigated the association between fibrinogen genotype, plasma fibrinogen levels, and ischemic heart disease in a general population sample (n = 9,127). The A-allele (relative frequency, 0.20) was associated with elevated plasma fibrinogen levels in both genders (P < 0.001). While the effect of the A-allele on fibrinogen level was additive in men, the effect was dominant in postmenopausal women. The A-allele raising effect appeared to be two- to threefold greater in individuals with ischemic heart disease than in those without. An increase of 1 SD in plasma fibrinogen increased the odds ratio for ischemic heart disease by approximately 20% (P < 0.01 for women and < 0.005 for men). However, the frequency of the A-allele was similar in those with and without ischemic heart disease, and genotype was not a predictor of disease. These results demonstrate that the (G-455--> A) mutation in the promoter region of the beta-fibrinogen gene is associated with an increase in plasma fibrinogen in both genders in the general population. This increase does not appear to cause ischemic heart disease.