European Atherosclerosis Research Study: Genotype at the Fibrinogen Locus (G −455 -A β-Gene) Is Associated With Differences in Plasma Fibrinogen Levels in Young Men and Women From Different Regions in Europe

Abstract

The European Atherosclerosis Research Study (EARS) compares genetic and environmental factors in the offspring of fathers with myocardial infarction before the age of 55 years (designated cases) and control subjects from five different regions of Europe. Genotype was determined for a G-A polymorphism 455 bp upstream from the start of transcription of the β-fibrinogen gene. In 585 cases and 1106 control subjects, the relative frequency of the A allele was similar (0.223 and 0.217, respectively), with small and nonsignificant differences in frequency observed among the five regions. Because of evidence for an interaction between a number of factors and genotype in the determination of plasma 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 excluding women taking oral contraceptives (n=297). In agreement with previous reports, in all regions the A allele was associated with elevated plasma fibrinogen levels, with the strongest and most consistent effects being seen in men. In nonsmokers, after adjusting for the effects 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, than those with genotype G/G, whereas those with genotype G/A had intermediate levels ( P <.01). In female nonsmokers there was a similar but smaller and nonsignificant effect (A/A levels higher than G/G by 0.12 and 0.07 g/L, respectively). In both men and women, there was significant evidence for an interaction between genotype and smoking in the determination of fibrinogen levels, with genotype A/A being associated with the highest mean levels in nonsmoking individuals and the lowest mean levels in smoking individuals (interaction between smoking and genotype in men, P <.02). Part of the explanation for this difference may be that individuals with genotype A/A reported significantly lower consumption of tobacco per day than individuals with other genotypes (1.41 versus 2.87 g/d, P =.035), and this difference was observed consistently 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 and consistent predictor of plasma fibrinogen levels in all regions of Europe sampled but that the strength of the association is affected by factors such as gender, hormonal status, and smoking. In particular, the fibrinogen levels in individuals with genotype A/A (5% of the sample) who were smokers, who were female offspring of cases, or who used oral contraceptives show strong evidence of interaction, the mechanism of which is unknown. Although the G ₋₄₅₅ -A genotype itself is not a strong predictor of parental history of myocardial infarction, the data confirm the importance of a gene-environment interaction in determining plasma fibrinogen levels in individuals in Europe and thus risk of ischemic heart disease.