GENETIC-REGULATION OF FIBRINOGEN

Prospective epidemiological studies have shown that elevated levels of fibrinogen are associated with thrombosis and ischaemic heart disease. Several sequence changes in the promoter region of the beta-fibrinogen gene have been detected that are associated with slightly raised plasma fibrinogen levels in healthy, non-smoking carriers, but which have much larger genotype-associated effects in smokers. In in vitro assays, these sequence changes affect the binding of liver nuclear proteins and may alter the rate of transcription of the gene and thus the rate of fibrinogen production. One sequence change is close to the consensus sequence for the binding of a nuclear factor responsive to interleukin-6, one of the cytokines responsible for the acute-phase changes seen upon infection or injury. This provides a molecular explanation for the different effects on fibrinogen levels seen in smokers, who are experiencing a 'chronic' and low-grade response to injury. Thus, for elevated plasma fibrinogen, which is associated with a risk of thrombosis, a genetic variation has been detected that determines, in part, its plasma level; but the variability in an individual's response to environmental changes may also be determined in part by their genotype at this locus. In the future, such individual-specific genetic information may be of prognostic and therapeutic use.