A causal relationship between high density lipoprotein cholesterol (HDL-C) and gout was established in a Mendelian randomization study published in the Journal of Human Genetics.
Genetic data and HDL-C, low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), and triglyceride (TG) concentrations from 110,347 individuals of European ancestry included in the Global Lipids Genetics Consortium were examined in relation to a gout diagnosis (n=69,374) using additive regression adjusted for covariates.
A significant relationship between HDL-C and gout was observed: for every 12.26 mg/dL increase in HDL-C, the odds of having gout were decreased (odds ratio [OR], 0.75; 95% CI, 0.62-0.91; P =3.31×10-3).
To further examine the relationship between HDL-C and gout, the investigators employed a leave-one-out approach to test the contribution of 92 instrumental HDL-C variables. The 2 largest effects were observed for the gene Aldehyde Dehydrogenase 1 Family Member A2 (ALDH1A2) and microRNA AC012181.1. The effect sizes of these 2 variables were low and did not affect the association between HDL-C and gout (OR, 0.74; 95% CI, 0.60-0.91; P =4.18×10-3).
Concentrations of other lipids did not significantly alter odds of having gout. For every 30.25 mg/dL increase in LDL-C, the OR for gout was 0.81 (95% CI, 0.61-1.07; P =.079). A 36.32 mg/dL increase in TC was associated with an OR for gout of 0.98 (95% CI, 0.90-1.06; P =.604) and a 112.33 mg/dL increase in TG was associated with an OR of 1.16 for gout (95% CI, 0.93-1.45; P =.186).
Serum urate was negatively associated with HDL-C (estimated causal effect, -0.09; 95% CI, -0.12 to -0.05; P =7.00×10-4) and positively associated with TG (estimated causal effect, 0.10; 95% CI, 0.06-0.14; P =9.87×10-5).
Using a mediation analysis, the total effect of HDL-C on gout was -0.154 (95% CI, -0.256 to -0.051; P =3.31×10-3), the direct effect was -0.106 (95% CI, -0.189 to -0.022; P =1.35×10-2), and the mediation effect was -0.020 (95% CI, -0.033 to -0.008; P =1.67×10-3). The mediation effect accounted for 13.0% of the total variance, indicating that urate may be an important mediator of gout and HDL-C.
In the mediation analysis, TG had a similar but inverse relationship, in which the total effect on gout was 0.082 (95% CI, -0.039 to 0.202; P =1.86×10-1), the direct effect was 0.048 (95% CI, -0.057 to 0.152; P =3.71×10−1), and the mediation effect was 0.023 (95% CI, 0.010–0.037; P =8.39×10−4). This mediation effect of urate on gout accounted for 28.0% of the total variance.
This study was limited by its sample size. Although the study included tens of thousands of adults with gout, the cases only represented 3.1% of the total dataset, possibly limiting the study power.
These data confirmed the causal association between HDL-C and TG with gout and found that serum urate levels likely mediate these relationships.
Yu X, Wang T, Huang S, et al. Evaluation of the causal effects of blood lipid levels on gout with summary level GWAS data: two-sample Mendelian randomization and mediation analysis. [published online October 25, 2020] J Hum Genet. doi:10.1038/s10038-020-00863-0