Abstract
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 × 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 × 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.
Highlights
The etiology of multiple sclerosis (MS) is varied and not fully understood (Dobson and Giovannoni, 2019)
We found that none of the 18 uric acid (UA)-associated single-nucleotide polymorphisms (SNPs) and the nine proxy SNPs were linkage disequilibrium (r2 ≤ 0.012) with any MS-associated SNPs that were reported in the two MS studies
We estimated that the total proportion of variance in serum UA concentrations explained by the 18 SNPs was ∼5.0%
Summary
The etiology of MS is varied and not fully understood (Dobson and Giovannoni, 2019). As a potent scavenger of peroxynitrite, previous studies suggested that UA may play an important role in the development of MS (Liu et al, 2012; Junqueira et al, 2017). Because of the inherent bias, it is not possible to determine the direction of causality between the serum UA level and risk of MS from the above-mentioned case–control studies. The method of MR can be used to clarify the causality of exposure factors in disease etiology (Smith and Ebrahim, 2003; Mokry et al, 2015a; Harroud and Richards, 2018; Howell et al, 2018). Because genetic variations are randomly allocated at meiosis, MR can mimic the design of randomized controlled trials and can solve the inherent bias of confounding and reverse causation in case–control studies (Smith and Ebrahim, 2003; Ong et al, 2018). The MR method has been used to determine the causal effects of many exposure factors on the risk of MS (Mokry et al, 2015b; Devorak et al, 2017; Harroud et al, 2019)
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