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Candidate Gene Testing in Clinical Cohort Studies with Multiplexed Genotyping and Mass Spectrometry
Published on: June 21, 2018
Genetically predicted systemic inflammation and the risk of atrial fibrillation: A bidirectional two-sample Mendelian
Sijin Wu1, Chenxi Yuan2, Zhongli Chen1
1Arrhythmia Center, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
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.
Insights
This study used Mendelian randomization to investigate the causal link between systemic inflammation and atrial fibrillation (AF). Results suggest certain inflammatory markers like IL-17 may increase AF risk, while AF may influence other markers.
Area of Science:
- Cardiovascular Genetics
- Immunology
- Epidemiology
Background:
- Systemic inflammation is linked to atrial fibrillation (AF), but causality is unclear.
- Bidirectional Mendelian randomization (MR) is employed to explore causal relationships.
- Investigating inflammation's role in AF pathogenesis is crucial for therapeutic strategies.
Purpose of the Study:
- To determine the causal associations between systemic inflammation and atrial fibrillation (AF).
- To investigate whether inflammation causes AF or if AF influences inflammation.
- To identify potential inflammatory biomarkers for AF risk and treatment.
Main Methods:
- Utilized large-scale genome-wide association study (GWAS) data for AF and 41 inflammatory cytokines/5 biomarkers.
- Employed inverse-variance weighted (IVW) method as primary analysis.
- Conducted sensitivity analyses using MR-Egger, weighted median, and MR-PRESSO for robustness.
Main Results:
- Genetically predicted interleukin-17 (IL-17), IL-2rα, and procalcitonin (PCT) showed suggestive associations with increased AF risk.
- A one SD increase in IL-17, IL-2rα, and PCT correlated with 6.3%, 4.9%, and 3.4% AF risk increases, respectively.
- Reverse MR indicated AF may increase macrophage inflammatory protein-1β (MIP1β) and decrease fibrinogen (Fbg) levels.
Conclusions:
- Identified suggestive causal links between specific inflammatory biomarkers and AF occurrence.
- Findings offer novel insights into the upstream and downstream regulation of AF.
- Further validation in larger cohorts is recommended to confirm the systemic inflammation-AF link.
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