Assessing the Causal Effects of Adipokines on Uric Acid and Gout: A Two-Sample Mendelian Randomization Study.

Ruyi Cong,Youxin Wang,Yizhi Liu,Xizhu Xu,Shanshan Chen,Xiaoyu Zhang,Guanhua Liu,Zihong Song,Fang Dong,Weijia Xing,Xiuyu Pang

doi:10.3390/nu14051091

Abstract

Previous observational studies have highlighted associations between adipokines and hyperuricemia, as well as gout, but the causality and direction of these associations are not clear. Therefore, we attempted to assess whether there are causal effects of specific adipokines (such as adiponectin (ADP) and soluble leptin receptors (sOB-R)) on uric acid (UA) or gout in a two-sample Mendelian randomization (MR) analysis, based on summary statistics from large genome-wide association studies. The inverse-variance weighted (IVW) method was performed as the primary analysis. Sensitivity analyses (including MR-Egger regression, weighted median, penalized weighted median, and MR pleiotropy residual sum and outlier methods) were also performed, to ensure reliable results. In the IVW models, no causal effect was found for sOB-R (odds ratios (OR), 1.002; 95% confidence intervals (CI), 0.999–1.004; p = 0.274) on UA, or ADP (OR, 1.198; 95% CI, 0.865–1.659; p = 0.277) or sOB-R (OR, 0.988; 95% CI, 0.940–1.037; p = 0.616) on gout. The results were confirmed in sensitivity analyses. There was no notable directional pleiotropy or heterogeneity. This study suggests that these specific adipokines may not play causal roles in UA or gout development.

Highlights

Uric acid (UA) is a waste product of purine catabolism
In order for causality to be valid in Mendelian randomization (MR) analysis, the following three hypotheses must be satisfied: (a) The instruments of genetic variations must be robustly related to the concentration of adipokines; (b) The genetic variations must not be associated with any confounder of the adipokines and UA, as well as gout associations; And (c) the selected genetic variations should not affect the UA or gout independently of its effect on adipokines [12]
The causal effect of ADP on UA was confirmed in the inverse-variance weighted (IVW) model (OR per 1 mg/dL decreased in ADP concentration: 0.978; 95% confidence intervals (CI), 0.961–0.996; p = 0.016), invalid results were found for the weighted median (OR, 0.987; 95% CI, 0.961–1.013; p = 0.324), penalized weighted median (OR, 0.987; 95% CI, 0.961–1.013; p = 0.311), and MR-Egger (OR, 0.977; 95% CI, 0.939–1.016; p = 0.256) analyses (Table 1)

Summary

Introduction

Uric acid (UA) is a waste product of purine catabolism. It can lead to gout when this molecule nucleates in a joint or other tissue to form crystals of monosodium urate [1]. A large amount of inconsistent evidence was found in observational studies, suggesting that confounders and reverse causality may be involved in the casual effects of adipokines on UA and gout. The limitations of previous studies can be effectively addressed by using MR [11]. MR method is a genetic epidemiological method, which can assess causal inference by exploiting the genetic variants influencing a modifiable risk factor. It is less susceptible to residual confounding and reverse causality, and it makes causal inferences about the effect of exposure on outcomes, using genetic variations closely related to the exposure of interest as instrumental variables (IVs); which addresses the shortcomings of previous observational epidemiology. We conducted this study based on a two-sample MR framework, to explore the causal effects of specific adipokines (i.e., ADP and sOB-R) on UA and gout

Materials and Methods

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Statistics Power and F-Statistics

Statistics Analysis

Results