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. 2024 Sep 13;14(1):21452.
doi: 10.1038/s41598-024-72195-4.

Exploring the therapeutic potential of interleukin-6 receptor blockade in cardiovascular disease treatment through Mendelian randomization

Guangyang Ou  1 , Huzhi Cai  2 , Kunpeng Yao  1 , Zerui Qiu  1 , Yang Yang  1 , Yaowu Chen  1 , Xinyu Chen  3
Affiliations

Exploring the therapeutic potential of interleukin-6 receptor blockade in cardiovascular disease treatment through Mendelian randomization

Guangyang Ou et al. Sci Rep. .

Abstract

Interleukin-6 (IL-6) plays a crucial role in the pathogenesis of cardiovascular disease (CVD), and IL-6 receptor (IL-6R) blockade has emerged as a promising therapeutic option. However, their specific therapeutic effects in different types of CVDs remain unclear. This study aimed to assess the efficacy of IL-6R blockade in the management of various CVDs, including hypertension (HTN), coronary heart disease (CHD), myocardial infarction (MI), atrial fibrillation (AF), and heart failure (HF). The Mendelian randomization (MR) approach was utilized to investigate the therapeutic impact of IL-6R blockade on HTN, CHD, MI, AF, and HF based on the genome-wide association study (GWAS) summary statistics. MR-Egger intercept test, Cochran's Q test, and leave-one-out analysis were used for sensitivity analysis to verify the reliability of the MR results. The Bonferroni method was used to correct for bias caused by multiple comparisons. Inverse variance weighted (IVW) results demonstrated that IL-6R blockade significantly influenced CHD (odds ratio (OR) = 0.757, 95% confidence interval (CI): 0.690 - 0.832, P = 5.804 × 10-9) and MI (OR = 0.840, 95% CI: 0.744 - 0.949, P = 0.005). However, IL-6R blockade had no significant effect on HTN (OR = 1.015, 95% CI: 0.950 - 1.084, P = 0.663), AF (OR = 0.905, 95% CI: 0.800 - 1.025, P = 0.116) and HF (OR = 1.012, 95% CI: 0.921 - 1.113, P = 0.805). Genetically predicted IL-6R blockade was associated with a protective effect on CHD and MI, but not HTN, AF and HF. This study's findings offer valuable insights for tailoring IL-6R blockade treatment for different types of CVD, and serve as a reference for future research.

Keywords: Cardiovascular disease; Coronary heart disease; Drug treatment; Interleukin-6 receptor blockade; Mendelian randomization study; Myocardial infarction.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig.1
Fig.1
Overview of the research workflow employed in this study. IL-6R, interleukin-6 receptor; CRP, C-reactive protein; CVD, cardiovascular disease; SNP, single nucleotide polymorphism; EAF, effect alleles frequency; IVW, inverse variance weighted; MR, mendelian randomization.
Fig.2
Fig.2
Results of MR analysis between IL-6R blockade and CVDs. Nsnp, number of single nucleotide polymorphism; OR, odds ratio; CI, confidence interval; WME, weighted median; IVW-FE, inverse variance weighted fixed effects; IVW-MRE, inverse variance weighted multiplicative random effects; SM, simple mode; WM, weighted mode. This figure shows the results of the MR analysis, namely that the IL-6R blockade has a protective effect on CHD and MI, but has no significant effect on HTN, AF and HF. RA is used as a positive control. The IVW is the primary analysis method. When heterogeneity is detected, the IVW-MRE method is used to reduce bias, otherwise, the IVW-FE method is applied. MR Egger, WM, SM, and WM serve as supplementary methods. Significance is determined by a Bonferroni-corrected IVW p-values < 0.01 and consistent OR directions across methods. In this picture, the dots represent the OR values and the line segments represent the 95% confidence intervals. An OR less than 1 represents a protective effect of IL-6R blockade, and an OR greater than 1 represents a risk effect of IL-6R blockade.
Fig.3
Fig.3
Results of MR analysis between IL-6R blockade and CVDs for repeated analysis. Nsnp, number of single nucleotide polymorphism; OR, odds ratio; CI, confidence interval; WME, weighted median; IVW-FE, inverse variance weighted fixed effects; IVW-MRE, inverse variance weighted multiplicative random effects; SM, simple mode; WM, weighted mode. This figure shows the results of the repeated MR analysis after changing the data source of CRP, namely that the IL-6R blockade has a protective effect on CHD and MI, but has no significant effect on HTN, AF and HF. RA is used as a positive control. The IVW method is the primary analysis method. When heterogeneity is detected, the IVW-MRE method is used to reduce bias, otherwise, the IVW-FE method is applied. The MR Egger, WME, SM, and WM serve as supplementary methods. Significance is determined by a Bonferroni-corrected IVW p-values < 0.01 and consistent OR directions across methods. The dots represent the OR values and the line segments represent the 95% confidence intervals, where an OR less than 1 suggests a protective effect of IL-6R blockade, and an OR greater than 1 indicates an increased risk.
Fig.4
Fig.4
The leave-one-out analysis of IL-6R on RA and CVDs. (A)RA, (B) HTN, (C) CHD, (D) MI, (E) AF, (F) HF. This figure presents the leave-one-out sensitivity analysis of IL-6R on RA and CVDs, namely that in the MR analyses between IL-6R blockade and RA, CHD, and MI, no individual SNP has a significant influence on the overall results. Each plot displays the results of excluding one SNP at a time to test the robustness of the findings. The x-axis represents the MR leave-one-out sensitivity analysis estimates, while the y-axis lists the SNPs. The black dots indicate the effect estimates for each leave-one-out analysis, with horizontal lines showing the 95% confidence intervals. The red line represents the overall estimate without excluding any SNPs.
Fig.5
Fig.5
The leave-one-out analysis of IL-6R on RA and CVDs for repeated analyses. (A) RA, (B) HTN, (C) CHD, (D) MI, (E) AF, (F) HF. This figure displays the results of a repeated leave-one-out sensitivity analysis with alternative datasets, that is, in the repeated MR analyses between IL-6R blockade and RA, CHD and MI, no individual SNP had a significant influence on the overall results. In each plot, individual SNPs are excluded one at a time to assess the robustness of the results. The x-axis represents the MR leave-one-out sensitivity analysis estimates, while the y-axis lists the SNPs. The black dots indicate the effect estimates for each leave-one-out analysis, with horizontal lines representing the 95% confidence intervals. The red line represents the overall estimate without excluding any SNPs.
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