Aim: To investigate the association of soluble Interleukin 6 receptor (sIL6R) levels with the risk of myocardial infarction (MI) in a large population base case-control study, the Stockholm Heart Epidemiology Program (SHEEP) and to explore whether circulating levels of the soluble gp130 (sgp130), a natural antagonist of the sIL6R, might modify this association.
Methods: 1213 non-fatal MI and 1561 age, sex and residential matched controls from the SHEEP study were investigated. sIL6R (ng/mL) were measured in the available serum samples from 682 cases and 1103 controls. Sgp130 (ng/mL) concentrations were measured in participants exposed to low sIL6R (value <25th, Q1) (n=424) and to high sIL6R (value >75th, Q4) (n=438) levels. MI risk was calculated by unconditional logistic regression models and expressed as odds ratio (OR) with 95% confidence intervals (CI). Risk estimates were adjusted for the matching variables (crude) and for hypertension, diabetes, hypercholesterolemia, body mass index, smoking and non-steroid anti-inflammatory drugs (adjusted model).
Results: sIL6R median and interquartile ranges (IQR) values were higher in cases 43 (32-65) than in controls 41(32-54), p=0.0016. High (>75th=54.5) sIL6R levels were associated with an increased risk of MI, with an OR of 1.6 (95% CI 1.3-2.0) (crude model) and an OR of 1.4 (95% CI, 1.1 -1.8) at adjusted analysis, as compared to sIL6R<75th. Median (IQR) sgp130 levels did not differ between individuals exposed to low (Q1) and high (Q4) sIL6R ( p=0.83). Compared to low sIL6R (Q1), exposure to Q4 sIL6R increased the MI risk [OR 1.4 (95% CI, 1.0–1.9)] at the crude and at the adjusted analysis [1.2 (95% CI, 0.9-1.7)]. Inclusion of sgp130 in the crude model did not modify this association OR to 1.4 (95% CI, 1.0-1.9). A secondary analysis was performed to investigate the effect of sgp130 on the MI risk associated with sIL6R levels within the highest (Q4) sIL6R quartile. In this stratum, when compared to the lowest quartile, participants in the highest quartile had a risk of MI of 2.3 (95% CI, 1.2-4.2). We then analyzed the MI risk in this group (Q4) according to serum sgp130 levels. In the presence of sgp130 higher than the median value, comparing Q4 with Q1, we observed a reduction in the OR associated with high sIL6R [OR 1.0 (95% CI, 0.3-2.8), an effect modification not observed in the presence of sgp130 levels below the median value [OR 2.9 (95% CI, 1.7-7.2)].
Conclusions: Elevated circulating levels of sIL6R are associated with an increased risk of MI. In the presence of high serum sIL6R levels, circulating sgp130 levels seem to modify this association.