Causal Associations Between Circulating Adipokines and Cardiovascular Disease: A Mendelian Randomization Study

Abstract

Context Observational studies have suggested associations between adipokines and cardiovascular disease (CVD), but the roles of certain adipokines remain controversial, and these associations have not yet been ascertained causally. Objective To investigate whether circulating adipokines causally affect the risk of CVD using two-sample Mendelian randomization (MR). Methods Independent genetic variants strongly associated with adiponectin, resistin, chemerin and retinol binding protein 4 (RBP4) were selected from public genome-wide association studies. Summary-level statistics for CVD, including coronary artery disease (CAD), myocardial infarction, atrial fibrillation (AF), heart failure (HF), stroke and its subtypes were collected. The inverse-variance weighted and Wald ratio methods were used for the MR estimates. The MR-PRESSO, weighted median, MR-Egger, leave-one-out analysis, MR Steiger and colocalization analysis were used in the sensitivity analysis. Results Genetically predicted resistin levels were positively associated with AF risk (OR 1.09; 95% CI, 1.04 to 1.13; P = 4.1×10 -5), which was attenuated to null after adjusting for blood pressure. We observed suggestive associations between higher genetically predicted chemerin levels and an increased risk of CAD (OR 1.27; 95% CI, 1.01 to 1.60; P = 0.040), higher genetically predicted RBP4 levels and an increased risk of HF (OR 1.14; 95% CI, 1.02 to 1.27; P = 0.024). There was no causal association between genetically predicted adiponectin levels and CVD risk. Conclusions Our findings reveal the causal association between resistin and AF, probably acting through blood pressure, and suggest potential causal associations between chemerin and CAD, RBP4 and HF.

Asthma and atopic dermatitis as risk factors for rheumatoid arthritis: a bidirectional mendelian randomization study

“…In addition, the IVW method and MR-Egger regression were used to investigate the presence of heterogeneity in the results, which was quantified using Cochran’s Q-test [ 24 ]. MR-Egger regression is also used to determine the likelihood of pleiotropy, with the intercept term indicating potential horizontal pleiotropy [ 25 ]. Meanwhile, we also used the “leave-one-out” method to remove single SNP which has a significant independent influence on the MR method [ 26 ].…”

Circulating adipokine levels and preeclampsia: A bidirectional Mendelian randomization study

“…As far as we know, there are no related MR analyses that have explored the bidirectional association of circulating adipokine levels with the risk of PET. A recent MR research revealed the causal role of resistin in the development of cardiovascular disease, which probably acted through blood pressure ( Chen et al, 2022 ). Another MR study provided evidence for a potential causal link between leptin level and blood pressure among smokers ( Shen et al, 2020 ).…”

“…As germline variants in parental genes tend to be randomly distributed to offspring in meiosis during gametogenesis and at conception, MR analysis can eliminate residual confounding from environmental factors and strengthen the causal inference ( Burgess et al, 2019 ). Based on the existing genome-wide association study (GWAS) databank, MR has been widely used to quantitatively assess the effect of circulating adipokine levels on the risk of various diseases, such as cancers, cardiovascular diseases, and auto-inflammatory disorders ( Dimou et al, 2021 ; Harroud et al, 2021 ; Chen et al, 2022 ).…”

No Evidence to Support a Causal Relationship between Circulating Adiponectin Levels and Ankylosing Spondylitis: A Bidirectional Two-Sample Mendelian Randomization Study

“…The IVW approach and MR–Egger regression were used to investigate the presence of heterogeneity in our results, which was quantified using Cochran’s Q test [ 31 ]. MR–Egger regression was also applied to determine the possibility of pleiotropy, whose intercept term represented the potential horizontal pleiotropy [ 32 ]. Furthermore, we used the leave-one-out analysis to investigate the effect of a specific single SNP on the causal relevance between CA levels and the risk of AS [ 33 ].…”