Genetically Determined Inflammatory Biomarkers and the Risk of Heart Failure: A Mendelian Randomization Study.
Background: Positive associations between inflammatory biomarkers and the risk of heart failure (HF) have been reported in conventional observational studies. However, the causal effects of inflammatory biomarkers on HF have not been fully elucidated. We conducted a Mendelian randomization (MR) study to examine the possible etiological roles of inflammatory biomarkers in HF. Methods: Summary statistical data for the associations between single nucleotide polymorphisms (SNPs) and C-reactive protein (CRP), fibrinogen, and components of the interleukin-1 (IL-1)-interleukin-6 (IL-6) inflammatory signaling pathway, namely, interleukin-1β (IL-1β), IL-1 receptor antagonist (IL-1ra), IL-6, and soluble IL-6 receptor (sIL-6r), were obtained from genome-wide association studies (GWASs) for individuals of European descent. The GWAS dataset of 977,323 participants of European ancestry, which included 47,309 HF cases and 930,014 controls, was collected to identify genetic variants underlying HF. A two-sample Mendelian randomization framework was implemented to examine the causality of the association between these inflammatory biomarkers and HF. Results: Our MR analyses found that genetically determined CRP and fibrinogen were not causally associated with HF risk (odds ratio [OR] = 0.93, 95% confidence interval [CI] = 0.84-1.02, p = 0.15; OR = 0.94, 95% CI = 0.55-1.58, p = 0.80, respectively). These findings remained consistent using different Mendelian randomization methods and in sensitivity analyses. For the IL-1-IL-6 pathway, causal estimates for IL-6 (OR = 0.86, 95% CI 0.81-0.91, p < 0.001), but not for IL-1β, IL-1ra, or sIL-6r, were significant. However, the association between genetically determined IL-6 and HF risk became non-significant after excluding SNPs with potential pleiotropy (OR = 0.89, 95% CI = 0.77-1.03, p = 0.12). Conclusion: Our study did not identify convincing evidence to support that CRP and fibrinogen, together with their upstream IL-1-IL-6 signaling pathway, were causally associated with HF risk.
Li X
，Peng S
，Guan B
，Chen S
，Zhou G
，Wei Y
，Gong C
，Xu J
，Lu X
，Zhang X
，Liu S
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Inflammation and heart failure: a two-sample Mendelian randomization study.
It is hypothesized that inflammation leads to heart failure. Results from observational studies thus far have been inconsistent and it is unclear whether inflammation is causally associated with new-onset heart failure. Mendelian randomization analyses are less prone to biases common in observational studies such as reverse causation and unmeasured confounding. The aim of this study was to investigate the causal relation between various inflammatory biomarkers with risk of new-onset heart failure by using a two-sample Mendelian randomization approach.
Ten inflammatory biomarkers with available genome-wide association studies (GWAS) among individuals of European ancestry were identified and included C-reactive protein (CRP), immunoglobulin E, tumour necrosis factor (TNF), toll-like receptor 4, interleukin 1 receptor antagonist, interleukin 2 receptor subunit α, interleukin 6 receptor subunit α, interleukin 16, 17 and 18. For the associations between the identified SNPs and heart failure, we used the largest GWAS meta-analysis performed by the Heart Failure Molecular Epidemiology for Therapeutic Targets Consortium with 47 309 participants with heart failure and 930 014 controls. For our main analyses, we used the inverse-variance weighted method.
We included 63 SNPs. CRP, TNF, interleukin 2, 16 and 18 were not associated with heart failure with odds ratios (ORs) of 1.01 [95% confidence interval (95% CI: 0.94-1.09), 1.11 (95% CI: 0.80-1.48), 0.97 (95% CI: 0.93-1.02), 0.99 (95% CI: 0.96-1.03) and 1.01 (95% CI: 0.97-1.06), respectively. The other biomarkers were also not associated with the risk of heart failure and suffered from weak instrument bias.
This Mendelian randomization study could not determine a causal relationship between inflammation and risk of heart failure. However, some biomarkers suffered from weak instrument bias.
Remmelzwaal S
，van Oort S
，Handoko ML
，van Empel V
，Heymans SRB
，Beulens JWJ
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