Using multiple Mendelian randomization approaches and genetic correlations to understand obesity, urate, and gout

Abstract

Observational studies suggest relationships between obesity, urate, and gout but are possibly confounded. We assessed whether genetically determined obesity, higher urate (and related traits), and gout were causal using multiple Mendelian randomization (MR) approaches and linkage disequilibrium score regression for genetic correlations (rg). For data, we used genome-wide association study summary statistics available through MR-Base. We observed that obesity increased urate (beta = 0.127; 95% CI = 0.098, 0.157; P-value = 1.2E−17; rg = 0.25 [P-value = 0.001]) and triglycerides (beta = 0.082; 95% CI = 0.065, 0.099; P-value = 1.2E−21; rg = 0.23 [P-value = 8.8E−12]) and decreased high-density lipoprotein cholesterol (HDL) (beta = − 0.083; 95% CI = − 0.101, − 0.065; P-value = 2.5E−19; rg = − 0.28; [P-value = 5.2E−24]). Higher triglycerides increased urate (beta = 0.198; 95% CI = 0.146, 0.251; P-value = 8.9E−14; rg = 0.29 [P-value = 0.001]) and higher HDL decreased urate (beta = − 0.109; 95% CI = − 0.148, − 0.071; P-value = 2.7E− 08; rg = − 0.21 [P-value = 9.8E−05]). Higher urate (OR = 1.030; 95% CI = 1.028, 1.032; P-value = 1.1E−130; rg = 0.89 [P-value = 1.7E−55]) and obesity caused gout (OR = 1.003; 95% CI = 1.001, 1.004; P-value = 1.3E−04; rg = 0.23 [P-value = 2.7E−05]). Obesity on gout with urate as a mediator revealed all the effect of obesity on gout occurred through urate. Obesity on low-density lipoprotein cholesterol (LDL) was null (beta = −0.011; 95% CI = −0.030, 0.008; P-value = 2.6E−01; rg = 0.03 [P-value = 0.369]). A multivariable MR of obesity, HDL, and triglycerides on urate showed obesity influenced urate when accounting for HDL and triglycerides. Obesity’s impact on urate was exacerbated by it decreasing HDL.

Associations of Circulating Biomarkers with Disease Risks: a Two-Sample Mendelian Randomization Study

“…We provide validation for our analysis by demonstrating agreement using 4 or more analysis methods that have been previously demonstrated in MR studies such as urate with gout 17 and LDL, 18 triglycerides, 10 lipoprotein A, 19 and apolipoprotein B 20 with coronary heart disease. We also found previously demonstrated relationships shown in MR studies between lipoprotein A 21 and LDL 22 with myocardial infarction.…”

Body Mass Index and the Risk of Rheumatic Disease: Linear and Nonlinear Mendelian Randomization Analyses

“…A causal effect of BMI on rheumatoid arthritis (12), osteoarthritis (13), and gout (14,15) have been identified in previous MR studies. However, a possible causal effect of BMI on psoriatic arthropathy and inflammatory spondylitis has not yet been investigated.…”

Association between uric acid and risk of venous thromboembolism in East Asian populations: a cohort and Mendelian randomization study

“…After removing SNPs with pairwise r 2 > 0.2 within 500 kb windows, 596 SNPs were included in the analysis. Two common methods for multivariable MR, the residual regression method proposed by Burgess 24 and the multivariable IVW with weighting for the inverse variance of the outcome, 25 were used. In the analysis, a P-value < 0.05 was considered evidence of a causal effect of SUA on VTE.…”