Association of IL-6 and a functional polymorphism in the IL-6 gene with cardiovascular events in patients with CKD

Background and objectives High serumIL-6 is amajor risk factor for cardiovascular disease (CVD) in the general population. This cytokine is substantially increased in patientswith CKD, but it is still unknownwhether the link between IL-6 and CVD in CKD is causal in nature. Design, setting, participants, & measurements In a cohort of 755 patientswith stages 2-5 CKD, consecutively recruited from 22 nephrology units in southern Italy, this study assessed the relationship of serum IL-6 with history of CVD, as well as with incident cardiovascular (CV) events (mean follow up6SD, 31610 months) and used the functional polymorphism (2174 G/C) in the promoter of the IL-6 gene to investigate whether the link between IL-6 and CV events is causal. Results In adjusted analyses, serum IL-6 above the median value was associated with history of CVD (P,0.001) and predicted the incidence rate of CV events (hazard ratio, 1.66; 95% confidence interval [95% CI], 1.11 to 2.49; P=0.01). Patients homozygous for the risk allele (C) of the2174G/C polymorphismhad higher levels of IL-6 than did those with other genotypes (P=0.04). Homozygous CC patients more frequently had a history of CVD (odds ratio, 2.15; 95%CI, 1.15 to 4.00; P=0.02) as well as a 87%higher rate of incident CV events (hazard ratio, 1.87; 95% CI, 1.02 to 3.44; P=0.04) compared with other genotypes. Conclusions In patients with stages 2-5 CKD, high serum IL-6 is associated with history of CVD and predicts incident CV events. The parallel relationship with history of CVD and incident CV events of the 2174 G/C polymorphismin the IL-6 gene suggests that IL-6may be causally involved in the high CV risk in this population.