On the genetic variation of interleukin-6 in health and coronary heart disease

There is increasing evidence that inflammation plays an important role in the development of atherosclerosis and coronary heart disease (CHD). Prospective studies on healthy individuals and on patients with unstable angina pectoris or non-Q-wave myocardial infarction have shown that individuals with high interleukin-6 (IL-6) concentrations have an increased risk of myocardial infarction and death due to cardiovascular disease.

The mechanisms responsible for triggering and sustaining elevation of IL-6 in healthy subjects and patients with CHD are largely unknown and remain to be defined. Thrombosis underlies most of the acute manifestations of CHD including myocardial infarction. The causes of thrombosis are not fully clear, but an important mechanism might be the connection between inflammation and coagulation. The present research program was set up to investigate the genetic variation of IL-6 in vivo in health and CHD and connection between inflammation and coagulation.

In study I 222 patients with ST-elevation myocardial infarction were included. They were genotyped for -174 G>C single nucleotide polymorphism (SNP) of the IL-6 gene. Plasma IL-6 concentration was measured at admission and after 48 hrs. This study showed that patients with IL-6 above the median at admission had an increased risk for CHD death or a new myocardial infarction, whereas the genotype did not influence CHD risk or plasma IL-6 levels.

In study II and III, the effect of an inflammatory stimulus on circulating IL-6 and factor VIIa (FVlla) concentrations depending on genotype was investigated in forty healthy subjects by challenged vaccination with Salmonella typhii vaccine. The study subjects were genotyped for the -174 G>C SNP of the IL-6 gene and for the Arg353GIn SNP of the FVII gene. The result demonstrates that the response differed according to genotype, indicating that IL-6 and FVIIa are influenced by genetic variation.

In study IV the influence of environmental factors and IL-6 genotype on IL-6 concentration was investigated. Three hundred eighty-seven patients with their first myocardial infarction before the age of 60 and matched healthy controls were enrolled. Antibodies against different pathogens were examined. Patients and controls were genotyped for the - 174 G>C SNP of the IL-6 gene. Plasma IL6 concentrations were significantly higher in patients compared to healthy controls when measured 3 months after the acute event. Furthermore, patients who were homozygous for the G-allele had higher IL-6 levels compared to those being hetereo- or homozygotes for the C-allele. In healthy controls no such genotype-phenotype association was found. We were not able to show any association between -174 G>C genotype and risk of CHD. Neither a single, nor a number of antibodies against multiple pathogens differed between patients and healthy controls and no associations between these and circulating IL-6 concentration were indicated.

Conclusion: This thesis demonstrates that circulating IL-6 concentration is influenced by genetic variation of the IL-6 gene in vivo both in health and CHD. However, we found no association between the -174 G>C genotype of the IL-6 gene and CHD. Nonetheless, our results showed that patients with myocardial infarction and a plasma IL-6 concentration above the median at admission had an increased cardiovascular risk, which supports the importance of IL-6 as a risk marker in CHD.

List of scientific papers

I. Bennermo M, Held C, Green F, Strandberg LE, Ericsson CG, Hansson LO, Watkins H, Hamsten A, Tornvall P (2004). Prognostic value of plasma interleukin-6 concentrations and the -174 G > C and -572 G > C promoter polymorphisms of the interleukin-6 gene in patients with acute myocardial infarction treated with thrombolysis. Atherosclerosis. 174(1): 157-63.
https://doi.org/10.1016/j.atherosclerosis.2004.01.019

II. Bennermo M, Held C, Stemme S, Ericsson CG, Silveira A, Green F, Tornvall P (2004). Genetic predisposition of the interleukin-6 response to inflammation: implications for a variety of major diseases? Clin Chem. 50(11): 2136-40.
https://doi.org/10.1373/clinchem.2004.037531

III. Bennermo M, Held C, Ericsson CG, Silveira A, Hamsten A, Tornvall P (2005). Genotype-specific increase in plasma concentrations of activated coagulation factor VII in response to experimental inflammation. A link between infection and acute myocardial infarction? [Submitted]

IV. Bennermo M, Nordin M, Lundman P, Boqvist S, Held C, Samnegard A, Ericsson CG, Silveira A, Hamsten A, Tornvall P (2005). Genetic and environmental influences on circulating interleukin-6 concentrations in patients with a recent myocardial infarction. A case-control study. [Manuscript]