EUROPEAN ATHEROSCLEROSIS RESEARCH STUDY - GENOTYPE AT THE FIBRINOGEN LOCUS (G(-455)-A BETA-GENE) IS ASSOCIATED WITH DIFFERENCES IN PLASMA-FIBRINOGEN LEVELS IN YOUNG MEN AND WOMEN FROM DIFFERENT REGIONS IN EUROPE - EVIDENCE FOR GENDER GENOTYPE ENVIRONMENT INTERACTION

The European Atherosclerosis Research Study (EARS) compares genetic an d environmental factors in the offspring of fathers with myocardial in farction before the age of 55 years (designated cases) and control sub jects from five different regions of Europe. Genotype was determined f or a G-A polymorphism 455 bp upstream from the start of transcription of the beta-fibrinogen gene. In 585 cases and 1106 control subjects, t he relative frequency of the A allele was similar (0.223 and 0.217, re spectively), with small and nonsignificant differences in frequency ob served among the five regions. Because of evidence for an interaction between a number of factors and genotype in the determination of plasm a fibrinogen levels (in particular among female cases who reported use of oral contraceptives), the data were analyzed without adjusting for covariates except for age and region, and analyses were carried out e xcluding women taking oral contraceptives (n=297). In agreement with p revious reports, in all regions the A allele was associated with eleva ted plasma fibrinogen levels, with the strongest and most consistent e ffects being seen in men. In nonsmokers, after adjusting for the effec ts of age and region, male cases and control subjects with genotype A/ A had mean fibrinogen levels 0.49 and 0.33 g/L higher, respectively, t han those with genotype G/G, whereas those with genotype G/A had inter mediate levels (P<.01). In female nonsmokers there was a similar but s maller and nonsignificant effect (A/A levels higher than G/G by 0.12 a nd 0.07 g/L, respectively). In both men and women, there was significa nt evidence for an interaction between genotype and smoking in the det ermination of fibrinogen levels, with genotype A/A being associated wi th the highest mean levels in nonsmoking individuals and the lowest me an levels in smoking individuals (interaction between smoking and geno type in men, P<.02). Part of the explanation for this difference may b e that individuals with genotype A/A reported significantly lower cons umption of tobacco per day than individuals with other genotypes (1.41 versus 2.87 g/d, P=.035), and this difference was observed consistent ly in both genders, in all regions, and in cases and control subjects. Overall, the data show that the G(-455)-A substitution is a strong an d consistent predictor of plasma fibrinogen levels in all regions of E urope sampled but that the strength of the association is affected by factors such as gender, hormonal status, and smoking. In particular, t he fibrinogen levels in individuals with genotype A/A (5% of the sampl e) who were smokers, who were female offspring of cases, or who used o ral contraceptives show strong evidence of interaction, the mechanism of which is unknown. Although the G(-455)-A genotype itself is not a s trong predictor of parental history of myocardial infarction, the data confirm the importance of a gene-environment interaction in determini ng plasma fibrinogen levels in individuals in Europe and thus risk of ischemic heart disease.