Does elevated plasma fibrinogen increase the risk of coronary heart disease? Evidence from a meta-analysis of genetic association studies

Objective - The purpose of this study was to assess whether a genetic variant associated with higher fibrinogen levels is associated with increased coronary heart disease (CHD) risk, as a test of the causal influence of fibrinogen on CHD. Methods and Results - We performed a meta-analysis of case-control and prospective studies of the G-455 --> A and C-1483T --> T beta-fibrinogen promoter region variants, in relation to CHD risk. The 19 studies found included 12,393 cases and 21,649 controls. Fibrinogen levels were robustly related to the genetic variants ( mean increase per allele, 0.117 g/L; 95% CI, 0.091 - 0.142 g/L). However, the genetic variants were unrelated to CHD risk ( odds ratio per allele, 0.976; 95% CI, 0.916 - 1.040). The predicted causal odds ratio for a 1 g/L higher plasma fibrinogen level, given the genetic variant - fibrinogen and genetic variant - CHD associations, was 0.81 ( 95% CI, 0.46 - 1.40). Conclusions - Although imprecise, the predicted causal effect of fibrinogen on CHD is clearly different from the odds ratio of 1.8 ( 95% CI, 1.6 - 2.0) for an increase of 1 g/L derived from a meta-analysis of observational studies. This evidence suggests that lowering the fibrinogen level may not, in itself, reduce CHD risk.