Serum Uric Acid Level and Multiple Sclerosis: A Mendelian Randomization Study

Previous observational studies have shown that the serum uric acid (UA) level is decreased in persons with multiple sclerosis (MS). We used the two-sample Mendelian randomization (MR) method to determine whether the serum UA level is causally associated with the risk of MS. We screened 26 single-nucleotide polymorphisms (SNPs) in association with serum UA level (p < 5 x 10(-8)) from a large genome-wide meta-analysis involving 110,347 individuals. The SNP outcome effects were obtained from two large international genetic studies of MS involving 38,589 individuals and 27,148 individuals. A total of 18 SNPs, including nine proxy SNPs, were included in the MR analysis. The estimate based on SNP rs12498742 that explained the largest proportion of variance showed that the odds ratio (OR) of UA (per mg/dl increase) for MS was 1.00 [95% confidence interval (CI) 0.90-1.11; p = 0.96]. The main MR analysis based on the random effects inverse variance weighted method showed that the pooled OR was 1.05 (95% CI 0.92-1.19; p = 0.50). Although there was no evidence of net horizontal pleiotropy in MR-Egger regression (p = 0.48), excessive heterogeneity was found via Cochran's Q statistic (p = 9.6 x 10(-4)). The heterogeneity showed a substantial decrease after exclusion of two outlier SNPs (p = 0.17). The pooled ORs for the other MR methods ranged from 0.89 (95% CI 0.65-1.20; p = 0.45) to 1.05 (95% CI 0.96-1.14; p = 0.29). The results of sensitivity analyses and additional analyses all showed similar pooled estimates. MR analyses by using 81 MS -associated SNPs as instrumental variables showed that genetically predicted risk of MS was not significantly associated with serum UA level. The pooled OR was 1.00 (95% CI 0.99-1.02; p = 0.74) for the main MR analysis. This MR study does not support a causal effect of genetically determined serum UA level on the risk of MS, nor does it support a causal effect of genetically determined risk of MS on serum UA level.