Fibrinogen and susceptibility to myocardial infarction : role of gene-gene and gene-environment interactions

Fibrinogen, the precursor of fibrin, is a glycoprotein synthesized in the liver and maintained in plasma at concentrations normally ranging between 2-4 g/L. The fibrinogen molecule consists of two sets of three non-identical polypeptide chains, which are encoded by the fibrinogen gamma (FGG), fibrinogen alpha (FGA) and fibrinogen beta (FGB) genes clustered on chromosome 4. Elevated plasma fibrinogen concentration is considered an independent predictor of myocardial infarction (MI), while the role of the less abundant fibrinogen gamma chain variant has not as yet been explored in this context.

The aim of the present thesis was to study the impact of genetic and environmental factors on total plasma fibrinogen and fibrinogen gamma concentrations, fibrin gel structure and the risk of MI, using well defined clinical cohorts and biochemical, molecular biological and molecular genetic techniques.

The results presented in this thesis are based on findings from three case-control studies comprising survivors of a first MI and population-based controls. The Hypercoagulability and Impaired Fibrinolytic function MECHanisms (HIFMECH) study was designed to identify genetic and environmental factors underlying differences in risk of MI between high-risk (Stockholm and London) and low-risk (Marseille and San Giovanni Rotondo) centres in the North and in the South of Europe. The Stockholm Coronary Atherosclerosis Risk Factor (SCARF) and the Stockholm Heart Epidemiology Program (SHEEP) studies are two independent case-control studies undertaken to investigate genetic, biochemical and environmental factors predisposing to precocious MI.

Both elevated total plasma fibrinogen and fibrinogen gamma concentrations related to MI. However, the former entity appeared to contribute differently to MI in the European centres participating in the HIFMECH study, and was an independent discriminator between cases and controls only in London. In general, IL6, smoking and BMI seem to contribute to the variation in total plasma fibrinogen concentration, while fibrinogen and the FGG 9340T>C and FGA 2224G>A haplotype tag single nucleotide polymorphisms (htSNPs) contribute to the plasma fibrinogen gamma concentration.

Several SNPs were detected in candidate regions in the fibrinogen genes, presumed to play a role in the regulation of the plasma fibrinogen concentration and the fibrin clot structure and therefore to influence the risk of MI. Neither individual fibrinogen SNPs nor FGB haplotypes appeared to influence the risk of MI. On the other hand, fibrinogen haplotypes inferred using genotype data from the FGG 9340T>C and FGA 2224G>A htSNPs seemed to contribute to the risk of MI, independently of the plasma fibrinogen concentration.

Effects on fibrin clot porosity appeared to partly explain the lowered risk of MI conferred by the haplotype consisting of the minor FGG 9340C and FGA 2224A alleles. Furthermore, the fibrinogen haplotypes seem to exert pleiotropic effects on the serum IL6 concentration that are consistent with their impact on the risk of MI, i.e. the haplotype that conferred an increased risk (containing the major FGG 9340T and F GA 2224G alleles) was associated with significantly higher IL6 concentrations than the seemingly protective haplotype (containing the minor FGG 9340C and FGA 2224A alleles).

In addition, gene-gene and gene-enviromnent interaction analyses were performed. Risk factors such as dyslipidemia and high waist-to-hip ratio were stronger predictors of MI than the SNPs included in these analyses. However, a high-order interaction between the total plasma fibrinogen and fibrinogen gamma concentrations and the FGG 9340T>C and FGA 2224G>A htSNPs was noted, yielding a ~3 fold increase in the risk of MI.

In conclusion, total plasma fibrinogen and fibrinogen gamma concentrations are related to MI. Also, genetic variation in the fibrinogen genes contribute to the risk of MI, and this relationship seems to be mediated via effects on plasma V' fibrinogen concentration and fibrin clot structure, and pleiotropic effects on serum IL6 concentration.

List of scientific papers

I. Mannila MN, Silveira A, Hawe E, Eriksson P, Aillaud MF, Juhan-Vague I, Yudkin J, Margaglione M, di Minno G, Mussoni L, Tremoli E, Humphries S, Hamsten A; The HIFMECH Study Group (2004). Plasma fibrinogen concentration predicts the risk of myocardial infarction differently in various parts of Europe: effects of beta-fibrinogen genotype and environmental factors. The HIFMECH Study. Thromb Haemost. 92(6): 1240-9.
https://pubmed.ncbi.nlm.nih.gov/15583729

II. Mannila MN, Eriksson P, Lundman P, Samnegard A, Boquist S, Ericsson CG, Tornvall P, Hamsten A, Silveira A (2005). Contribution of haplotypes across the fibrinogen gene cluster to variation in risk of myocardial infarction. Thromb Haemost. 93(3): 570-7.
https://pubmed.ncbi.nlm.nih.gov/15735812

III. Mannila MN, Eriksson P, Ericsson CG, Hamsten A, Silveira A (2006). Epistatic and pleiotropic effects of polymorphisms in the fibrinogen and coagulation factor XIII genes on plasma fibrinogen concentration, fibrin gel structure and risk of myocardial infarction. Thromb Haemost. 95(3): 420-7.
https://pubmed.ncbi.nlm.nih.gov/16525568

IV. Mannila MN, Lovely R, Kazmiercxak SC, Eriksson P, sammegard A, Farrel DH, Hamsten A, Silveira A (2006). Elevated plasma fibrinogen gamma concentration increases the risk of myocardial infarction: effects of genetic variation in fibrinogen genes and environmental factors. [Manuscript]

V. Mannila MN, Eriksson P, Leander K, Wiman B, de Faire U, Hamsten A, Silveira A (2006). The association between fibrinogen haplotypes and myocardial infarction in men is partly mediated through pleiotropic effects on the serum IL6 concentration. [Manuscript]