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. 2024 May 6:52:101422.
doi: 10.1016/j.ijcha.2024.101422. eCollection 2024 Jun.

Genetically predicted systemic inflammation and the risk of atrial fibrillation: A bidirectional two-sample Mendelian randomization study

Sijin Wu  1 , Chenxi Yuan  2 , Zhongli Chen  1 , Yuan Gao  1 , Xiaogang Guo  1 , Ruohan Chen  1 , Yan Dai  1 , Keping Chen  1
Affiliations

Genetically predicted systemic inflammation and the risk of atrial fibrillation: A bidirectional two-sample Mendelian randomization study

Sijin Wu et al. Int J Cardiol Heart Vasc. .

Abstract

Background: Systemic inflammation has been proposed to be associated with the incidence of atrial fibrillation (AF), but whether it is a cause or a consequence of AF remains uncertain. We sought to explore the causal associations between systemic inflammation and AF using bidirectional Mendelian randomization (MR) analysis.

Methods: Independent genetic variants strongly associated with AF were selected as instrumental variables from the largest genome-wide association study (GWAS) with up to 1,030,836 individuals. Regarding inflammation traits, genetic associations with 41 inflammatory cytokines and 5 inflammatory biomarkers were obtained from their corresponding GWASs databases. Effect estimates were primarily evaluated using the inverse-variance weighted (IVW) method, supplemented by sensitivity analyses using MR-Egger, weighted median, and MR-PRESSO methods.

Results: In our initial MR analyses, we observed suggestive associations of genetically predicted interleukin-17 (IL-17), interleukin-2 receptor subunit alpha (IL-2rα), and procalcitonin (PCT) with AF. One standard deviation (SD) increase in IL-17, IL-2rα, and PCT caused an increase in AF risk by 6.3 % (OR 1.063, 95 %CI 1.011---1.118, p = 0.018), 4.9 % (OR 1.049, 95 %CI 1.007---1.094, p = 0.023) and 3.4 % (OR 1.034, 95 %CI 1.005---1.064, p = 0.022), respectively. Furthermore, our reverse MR analyses indicated that genetically predicted AF contributed to a suggestive increase in the levels of macrophage inflammatory protein-1β (MIP1β) (β 0.055, 95 %CI 0.006 to 0.103, p = 0.028), while a decrease in the levels of fibrinogen (Fbg) (β -0.091, 95 %CI -0.140 to -0.041, p < 0.001), which remained significant after multiple test correction.

Conclusions: Our MR study identified several inflammatory biomarkers with suggestive causal associations regarding the upstream and downstream regulation of AF occurrence, offering new insights for therapeutic exploitation of AF. Further research is required to validate the underlying link between systemic inflammation and AF in larger cohorts.

Keywords: Atrial fibrillation; Bidirectional; Cytokines; Inflammation; Mendelian randomization.

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Conflict of interest statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Fig. 1
Fig. 1
The overall design of this bidirectional Mendelian randomization study. SNPs that strongly linked to exposures were selected as IVs, based on the fact that alleles are randomly allocated during meiosis. The IVs selection adhered to the three fundamental assumptions: (A) relevance: the instrumental variables, represented by SNPs, exhibit robust correlations with the exposure; (B) independence: the genetic variants are independent of other confounders; (C) exclusion restriction: the genetic variants exclusively influence the outcome through the investigated exposure. Significant IVs were identified for 46 inflammatory cytokines/biomarkers and atrial fibrillation, and the bidirectional MR analysis were then performed. Abbreviations: IVs, instrumental variables; MR, Mendelian randomization; SNPs, single nucleotide polymorphisms.
Fig. 2
Fig. 2
Associations of inflammatory cytokines/biomarkers with atrial fibrillation using Mendelian randomization (with SNPs reaching p < 5 × 10-8). The change in the odds ratio (OR) of atrial fibrillation per one-SD increase in the level of cytokines/biomarkers is shown by OR and 95 % confidence interval (95 %CI). All results were obtained using the inverse variance weighted method. Abbreviations: CRP, C-Reactive Protein; Fer, Ferritin; IL, Interleukin; MCP1, Monocyte chemotactic protein-1; MIP1β, Macrophage inflammatory protein-1β; PDGFbb, Platelet derived growth factor BB; SCGFβ, Stem cell growth factor beta; SNPs, single-nucleotide polymorphisms; TRAIL, TNF-related apoptosis inducing ligand.
Fig. 3
Fig. 3
Associations of inflammatory cytokines/biomarkers with atrial fibrillation using Mendelian randomization (with SNPs reaching p < 5 × 10-6). The change in the odds ratio (OR) of atrial fibrillation per one-SD increase in the level of cytokines/biomarkers is represented by the OR and its corresponding 95 % confidence interval (95 % CI). All results were obtained using the inverse variance weighted method. Abbreviations: βNGF, beta nerve growth factor; bFGF, basic fibroblast growth factor; CRP, C-Reactive Protein; CTACK, cutaneous T-cell attracting chemokine; Fbg, Fibrinogen; Fer, Ferritin; GCSF, granulocyte colony-stimulating factor; GROa, Growth regulated oncogene-α; HGF, hepatocyte growth factor; IFN-γ, interferon gamma; IL, interleukin; IP10, interferon-gamma-induced protein 10; MCP1, monocyte chemotactic protein-1; MCP3, monocyte-specific chemokine 3; MCSF, macrophage colony-stimulating factor; MIF, macrophage-migration inhibitory factor; MIG, monokine induced by interferon gamma; MIP1α, macrophage inflammatory protein-1α; MIP1β, macrophage inflammatory protein-1β; PCT, Procalcitonin; PDGFbb, platelet-derived growth factor BB; RANTES, regulated on Activation, Normal T Cell Expressed and Secreted; SAA1, Serum amyloid A-1 protein; SCF, stem cell factor; SCGFβ, stem cell growth factor beta; SDF1α, stromal cell-derived factor-1 alpha; SNPs, single-nucleotide polymorphisms; TNFα, tumour necrosis factor alpha; TNFβ, tumour necrosis factor beta; TRAIL, TNF-related apoptosis-inducing ligand; VEGF, vascular endothelial growth factor.
Fig. 4
Fig. 4
Associations of atrial fibrillation with inflammatory cytokines/biomarkers using Mendelian randomization. Beta and 95% confidence interval (CI) represent the change in the SD of inflammatory cytokines/biomarkers per log odds increase in atrial fibrillation. All results were obtained using the inverse variance weighted method. The abbreviations were the same as Fig. 3.
Fig. 5
Fig. 5
Scatter plots for the causal associations of inflammatory regulators/biomarkers with atrial fibrillation in MR analyses. The slope of the lines represents the estimated causal effect of the MR methods. (A) the causal associations of IL-17 with AF; (B) the causal associations of PCT with AF; (C) the causal associations of AF with MIP1β; (D) the causal associations of AF with Fbg. Abbreviations: AF, atrial fibrillation; Fbg, fibrinogen; IL-17, interleukin-17; MIP1β, macrophage inflammatory protein-1β; MR, Mendelian randomization; PCT, procalcitonin.
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