No association between interleukin-18 levels and risk of cardiovascular disease: A Mendelian randomization study

Fan, Siyu; He, Pan; Guan, Jieqiong; Song, Wenjing; Huang, Zhi; Wang, Lina

doi:10.1186/s41065-020-00121-5

Cited by 9 publications

(4 citation statements)

References 34 publications

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“…There is high heterogeneity in both susceptibility to and severity of SARS-CoV-2 infection, with clinical severity [ 1 , 2 ] ranging from asymptomatic infection to life-threatening respiratory failure and death [ 3 ]. Epidemiological studies using both retrospective and prospective cohorts of different sizes and from multiple countries have reported evidence that underlying cardiometabolic conditions [ 4 – 29 ] may be associated with an increased risk of severe COVID-19 illness (i.e., hospitalization, intubation, mechanical ventilation, or death [ 30 ]).…”

Section: Introductionmentioning

confidence: 99%

Cardiometabolic risk factors for COVID-19 susceptibility and severity: A Mendelian randomization analysis

et al. 2021

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Background Epidemiological studies report associations of diverse cardiometabolic conditions including obesity with COVID-19 illness, but causality has not been established. We sought to evaluate the associations of 17 cardiometabolic traits with COVID-19 susceptibility and severity using 2-sample Mendelian randomization (MR) analyses. Methods and findings We selected genetic variants associated with each exposure, including body mass index (BMI), at p < 5 × 10−8 from genome-wide association studies (GWASs). We then calculated inverse-variance-weighted averages of variant-specific estimates using summary statistics for susceptibility and severity from the COVID-19 Host Genetics Initiative GWAS meta-analyses of population-based cohorts and hospital registries comprising individuals with self-reported or genetically inferred European ancestry. Susceptibility was defined as testing positive for COVID-19 and severity was defined as hospitalization with COVID-19 versus population controls (anyone not a case in contributing cohorts). We repeated the analysis for BMI with effect estimates from the UK Biobank and performed pairwise multivariable MR to estimate the direct effects and indirect effects of BMI through obesity-related cardiometabolic diseases. Using p < 0.05/34 tests = 0.0015 to declare statistical significance, we found a nonsignificant association of genetically higher BMI with testing positive for COVID-19 (14,134 COVID-19 cases/1,284,876 controls, p = 0.002; UK Biobank: odds ratio 1.06 [95% CI 1.02, 1.10] per kg/m2; p = 0.004]) and a statistically significant association with higher risk of COVID-19 hospitalization (6,406 hospitalized COVID-19 cases/902,088 controls, p = 4.3 × 10−5; UK Biobank: odds ratio 1.14 [95% CI 1.07, 1.21] per kg/m2, p = 2.1 × 10−5). The implied direct effect of BMI was abolished upon conditioning on the effect on type 2 diabetes, coronary artery disease, stroke, and chronic kidney disease. No other cardiometabolic exposures tested were associated with a higher risk of poorer COVID-19 outcomes. Small study samples and weak genetic instruments could have limited the detection of modest associations, and pleiotropy may have biased effect estimates away from the null. Conclusions In this study, we found genetic evidence to support higher BMI as a causal risk factor for COVID-19 susceptibility and severity. These results raise the possibility that obesity could amplify COVID-19 disease burden independently or through its cardiometabolic consequences and suggest that targeting obesity may be a strategy to reduce the risk of severe COVID-19 outcomes.

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Section: Introductionmentioning

confidence: 99%

Cardiometabolic risk factors for COVID-19 susceptibility and severity: A Mendelian randomization analysis

et al. 2021

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“…There is high heterogeneity in both susceptibility and severity of SARS-CoV2 infection with clinical severity 1,2 ranging from asymptomatic carriers to life-threatening respiratory failure and death 3 . Epidemiological studies using both retrospective and prospective cohorts of different sizes and from multiple countries have reported evidence that underlying cardiometabolic conditions 4-29 may be associated with an increased risk of severe COVID-19 illness (i.e., hospitalization, intubation, mechanical ventilation or death 30 ).…”

Section: Introductionmentioning

confidence: 99%

Cardiometabolic Risk Factors for COVID-19 Susceptibility and Severity: A Mendelian Randomization Analysis

Leong

Cole

Brenner

et al. 2020

Preprint

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Importance: Early epidemiological studies report associations of diverse cardiometabolic conditions especially body mass index (BMI), with COVID-19 susceptibility and severity, but causality has not been established. Identifying causal risk factors is critical to inform preventive strategies aimed at modifying disease risk. Objective: We sought to evaluate the causal associations of cardiometabolic conditions with COVID-19 susceptibility and severity. Design: Two-sample Mendelian Randomization (MR) Study. Setting: Population-based cohorts that contributed to the genome-wide association study (GWAS) meta-analysis by the COVID-19 Host Genetics Initiative. Participants: Patients hospitalized with COVID-19 diagnosed by RNA PCR, serologic testing, or clinician diagnosis. Population controls defined as anyone who was not a case in the cohorts. Exposures: Selected genetic variants associated with 17 cardiometabolic diseases, including diabetes, coronary artery disease, stroke, chronic kidney disease, and BMI, at p<5 x 10-8 from published largescale GWAS. Main outcomes: We performed an inverse-variance weighted averages of variant-specific causal estimates for susceptibility, defined as people who tested positive for COVID-19 vs. population controls, and severity, defined as patients hospitalized with COVID-19 vs. population controls, and repeated the analysis for BMI using effect estimates from UKBB. To estimate direct and indirect causal effects of BMI through obesity-related cardiometabolic diseases, we performed pairwise multivariable MR. We used p<0.05/17 exposure/2 outcomes=0.0015 to declare statistical significance. Results: Genetically increased BMI was causally associated with testing positive for COVID-19 [6,696 cases / 1,073,072 controls; p=6.7 x 10-4, odds ratio and 95% confidence interval 1.08 (1.03, 1.13) per kg/m2] and a higher risk of COVID-19 hospitalization [3,199 cases/897,488 controls; p=8.7 x 10-4, 1.12 (1.04, 1.21) per kg/m2]. In the multivariable MR, the direct effect of BMI was abolished upon conditioning on the effect on type 2 diabetes but persisted when conditioning on the effects on coronary artery disease, stroke, chronic kidney disease, and c-reactive protein. No other cardiometabolic exposures tested were associated with a higher risk of poorer COVID-19 outcomes. Conclusions and Relevance: Genetic evidence supports BMI as a causal risk factor for COVID-19 susceptibility and severity. This relationship may be mediated via type 2 diabetes. Obesity may have amplified the disease burden of the COVID-19 pandemic either single-handedly or through its metabolic consequences.

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“…As the adaptive immune system is involved in the development of atherosclerosis, the importance of IL-18 is considered crucial, especially when we focus on CKD-related atherosclerosis and its clinically relevant consequences [ 28 ]. Although data on the role of IL-18 in predicting coronary events are contradictory [ 29 , 30 ], many studies have shown its utility as a strong independent predictor of death from CV causes in patients with coronary artery disease regardless of the clinical status at admission [ 26 , 31 , 32 ]. This strongly supports the evidence of an IL-18-mediated inflammatory process, leading to the acceleration and vulnerability of the atherosclerotic plaque.…”

Section: Discussionmentioning

confidence: 99%

The Mutual Contribution of 3-NT, IL-18, Albumin, and Phosphate Foreshadows Death of Hemodialyzed Patients in a 2-Year Follow-Up

Kasprzak¹,

Twardawa

Formanowicz

et al. 2022

Antioxidants

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Patients with chronic kidney disease (CKD), especially those who are hemodialyzed (HD), are at significantly high risk of contracting cardiovascular disease and having increased mortality. This study aimed to find potential death predictors, the measurement of which may reflect increased mortality in HD patients, and then combine the most promising ones in frames of a simple death risk assessment model. For this purpose, HD patients (n=71) with acute myocardial infarction in the last year (HD group) and healthy people (control group) as a comparative group (n=32) were included in the study. Various laboratory determinations and non-invasive cardiovascular tests were performed. Next, patients were followed for two years, and data on cardiovascular (CV) deaths were collected. On this basis, two HD groups were formed: patients who survived (HD-A, n=51) and patients who died (HD-D, n=20). To model HD mortality, 21 out of 90 potential variables collected or calculated from the raw data were selected. The best explanatory power (95.5%) was reached by a general linear model with four variables: interleukin 18, 3-nitrotyrosine, albumin, and phosphate. The interplay between immuno-inflammatory processes, nitrosative and oxidative stress, malnutrition, and calcium-phosphate disorders has been indicated to be essential in predicting CV-related mortality in studied HD patients. ClinicalTrials.gov Identifier: NCT05214872.

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No association between interleukin-18 levels and risk of cardiovascular disease: A Mendelian randomization study

Cited by 9 publications

References 34 publications

Cardiometabolic risk factors for COVID-19 susceptibility and severity: A Mendelian randomization analysis

Cardiometabolic risk factors for COVID-19 susceptibility and severity: A Mendelian randomization analysis

Cardiometabolic Risk Factors for COVID-19 Susceptibility and Severity: A Mendelian Randomization Analysis

The Mutual Contribution of 3-NT, IL-18, Albumin, and Phosphate Foreshadows Death of Hemodialyzed Patients in a 2-Year Follow-Up

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