Family history in relation to myocardial infarction, and analyses of gene-environment interactions involving factors of haemostasis

Family history of coronary heart disease (CHD) has frequently been shown to increase the risk of MI. However, the mechanisms are not well understood. Probably, both genetic- and environmental effects contribute. It is possible that family history in combination with other cardiovascular risk factors is of particular importance in the aetiology of myocardial infarction (MI). Haemostatic factors seem to contribute in the causation of MI, although this is not established. Plasma fibrinogen and plasminogen activator inhibitor-1 (PAI-1) are two potentially important risk factors, with their genetic variants possibly influencing effects. The potential involvements of these factors in interactions with other cardiovascular risk factors are poorly understood.

The aims of the present thesis were to assess the influence of family history of CHD on risk of first non-fatal MI in men and women, respectively, and to explore its potential role as a biologically interacting factor. The thesis also aimed to study the importance of fibrinogen and the G-455 A polymorphism, and PAI-1 and the 4G/5G polymorphism, in relation to risk of MI. Here a particular aim was also to explore potential synergistic effects for exposure combinations involving these factors regarding risk of MI. A final aim was to explore which cardiovascular risk factors may be most important for the long-term prognosis after a non-fatal MI.

Data are derived from the Stockholm Heart Epidemiology Program (SHEEP), a populationbased case-control study of MI performed between 1992 and 1994 at the ten emergency hospitals within the county of Stockholm. The present analyses were restricted to 1643 men and women who had suffered a first-time non-fatal MI, and 2339 controls. Data on exposures were available from questionnaires, anthropometric measurements, blood samples, and medical records.

A family history of CHD (defined as >=1 first-degree relative affected before the age of 65) was observed to be associated with risk of MI in both men and women. Synergistic effects were observed in women exposed to family history of CHD in combination with current smoking and with a high LDL/HDL quotient, respectively. In men, family history of CHD and diabetes mellitus seemed to act in synergy.

High level of plasma fibrinogen was associated with increased risk of MI in both men and women, although the OR decreased after adjusting for other cardiovascular risk factors. Presence of the A-455 allele was associated with increased fibrinogen level but not with increased risk of MI. No clear synergistic effects were observed. High plasma PAI-1 activity was associated with increased risk of MI, and in men it also interacted with smoking in increasing the risk synergistically. In women, presence of the 4G allele was associated although weakly with increased risk of MI.

Diabetes mellitus, job strain and abdominal adiposure had an impact on prognosis after MI in men. In women, prognostic importance was particularly noted for diabetes mellitus and for low level of Apolipoprotein AI. In both men and women the size of the initial infarction also had a prognostic value. In male survivors of MI, family history of CHD increased the risk of death from CHD during follow-up.

In conclusion, this thesis suggests the occurrence of several biological interactions between risk factors for MI. The involvement of family history in such interactions indicates that gene-environment interaction may be in operation. After MI, several primary and secondary exposures have an influence on the prognosis.

List of scientific papers

I. Leander K, Hallqvist J, Reuterwall C, Ahlbom A, de Faire U (2001). Family history of coronary heart disease, a strong risk factor for myocardial infarction interacting with other cardiovascular risk factors: results from the Stockholm Heart Epidemiology Program (SHEEP). Epidemiology. 12(2): 215-21.
https://pubmed.ncbi.nlm.nih.gov/11246583

II. Leander K, Wiman B, Hallqvist J, Falk G, De Faire U (2002). The G-455A polymorphism of the fibrinogen Bbeta-gene relates to plasma fibrinogen in male cases, but does not interact with environmental factors in causing myocardial infarction in either men or women. J Intern Med. 252(4): 332-41.
https://pubmed.ncbi.nlm.nih.gov/12366606

III. Leander K, Wiman B, Hallqvist J, Sten-Linder M, de Faire U; Stockholm Heart Epidemiology Program (2003). PAI-1 level and the PAI-1 4G/5G polymorphism in relation to risk of non-fatal myocardial infarction: results from the Stockholm Heart Epidemiology Program (SHEEP). Thromb Haemost. 89(6): 1064-71.
https://pubmed.ncbi.nlm.nih.gov/12783120

IV. Leander K, Andersson T, Hallqvist J, Wiman B, Ahlbom A, de Faire U (2005). Cardiovascular risk factors - importance for risk of recurrent myocardial infarction. [Manuscript]