Genetic variants lowering lipoprotein(a) and downregulating interleukin-6 signalling are additively associated with a decreased risk of cardiovascular disease

AIMS: Observational studies have yielded conflicting evidence regarding the interdependence between lipoprotein(a) [Lp(a)]-related cardiovascular risk and systemic inflammation. It remains unclear whether combined targeting of Lp(a) and inflammation provides additive cardiovascular benefits. This study aimed to investigate the associations between genetically predicted lower Lp(a) and cardiovascular disease (CVD) across interleukin-6 (IL-6) signalling levels and the combined effects of lower Lp(a) and IL-6 signalling activity on CVD risk. METHODS AND RESULTS: This study included UK Biobank participants of European ancestry. Genetic scores for LPA and IL-6 receptor (IL6R)-mediated signalling were calculated to mimic the effects of therapies targeting Lp(a) and IL-6 signalling, respectively. We investigated the associations of separate and combined exposure to lower Lp(a) and IL-6 signalling with coronary heart disease (CHD), ischaemic stroke (IS), heart failure (HF), atrial fibrillation (AF), peripheral artery disease (PAD), and aortic aneurysm (AA), using Mendelian randomization analyses and validating the findings in observational analyses. This study included 408 687 UK Biobank individuals (mean age, 57 years; 54% women). Genetically predicted lower Lp(a) was associated with reduced risks of CHD [odds ratio (OR) per 50 mg/dL reduction in Lp(a) levels, 0.68; 95% confidence interval (CI), 0.65-0.71], IS (0.89, 0.80-0.98), PAD (0.68, 0.62-0.76), HF (0.82, 0.77-0.88), and AA (0.71, 0.61-0.82). Genetically lower IL-6 signalling was associated with lower risks of CHD (OR per 0.5 log[mg/L] reduction in log-transformed C-reactive protein levels, 0.67; 95% CI, 0.55-0.82), AF (0.72, 0.55-0.94), and AA (0.43, 0.23-0.83). The genetic association between Lp(a) and CVD was consistent among individuals with different IL-6 signalling activity (P for difference > 0.05). Combined exposure to genetically predicted lower Lp(a) and IL-6 signalling was associated with an additive decrease in CHD risk (lower Lp(a): 0.67, 0.63-0.71; lower IL-6 signalling: 0.61, 0.46-0.80; combined: 0.25, 0.21-0.30; P for interaction = 0.144). In observational analyses, IL-6 levels below the median and Lp(a) concentrations below 50 mg/dL were also independently and additively associated with lower CHD risk (Lp(a) < 50 mg/dL: hazard ratio, 0.82; 95% CI, 0.72-0.93; IL-6 < median: 0.79, 0.65-0.96; combined: 0.65, 0.56-0.74; P for interaction = 0.102). CONCLUSION: Lower Lp(a) levels were associated with a reduced risk of CVD, independent of IL-6 signalling activity. Combined exposure to genetic variants lowering Lp(a) and downregulating IL-6 signalling was associated with an additive reduction in cardiovascular risk. These findings indicate that concurrent Lp(a)-lowering and anti-inflammatory therapies may reduce residual cardiovascular risk through additive effects.