Insulin resistance, genetic variation and cytokines : Associations to myocardial infarction risk

Abstract: Insulin resistance, inflammation and associated genes are considered as factors of potential importance for the pathogenesis of cardiovascular diseases, but their relationship to myocardial infarction (MI) and associated risk factors remains unclear. In the present thesis, insulin resistance and serum levels as well as genetic variants of interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-alpha), were investigated in the population-based study the Stockholm heart epidemiological program (SHEEP) (n=5452). The present analyses were restricted to 1643 men and women, who had suffered a first-time, non-fatal MI event, and 2339 healthy controls. Serum, DNA, anthropometric measurements and questionnaire-based information was available for the present analyses. In paper I, several genes of potential interest for insulin resistance and MI were identified by searching the public genome-databases. The selected genes were also scanned for the presence of previously described, and novel, genetic variants. Two genes, IL-6 and TNF-alpha, which were thought to be of particular interest, were then selected for further analysis in SHEEP. In paper II, the association between insulin resistance, measured as fasting-insulin and HOMA, and MI risk was investigated. Insulin resistance, which is closely related to other metabolic risk factors, infers an increased risk for MI. Insulin resistant individuals, particularly women, also appear to be particularly sensitive to the hazards of smoking. In papers III and IV, polymorphisms in the IL-6 and TNF-alpha genes were analysed in relation to their intermediate phenotype (i.e. IL-6 or TNF-alpha protein levels in serum) and to MI risk. Increased serum levels of both IL-6 and TNF-alpha are associated with an increased risk for MI. The contribution of these inflammatory markers as risk factors for MI seem to be dependent on gender, as the risk estimates were persistently higher for men. Men with elevated levels of IL-6 or TNF-alpha, who also display symptoms of the metabolic syndrome are at particularly high risk. Increased levels of these cytokines are most probably mainly regulated by non-genetic influences since the genetic variants of IL-6 and TNF-alpha, with one exception, do not significantly contribute to the determination of cytokine levels. It is possible that genetic variants in the TNF-alpha gene may be of some relevance for MI development. Also, IL-6 genotypes should be further investigated in relation to insulin resistance. The work presented in this thesis has led to the following conclusions: (i) insulin resistance is a risk factor for MI particularly through synergistic interaction with smoking and elevated serum levels of IL-6, (ii) there is a clear gender related discordance in gene-phenotype associations as elevated IL-6 and TNF-alpha serum levels are stronger markers for MI risk among men compared to women, (iii) healthy, male IL-6 -174C carriers have increased insulin levels, and (iv) female TNF-alpha -238A carriers have a reduced risk for MI.