THU0020 NO CAUSAL ASSOCIATION OF SERUM URATE OR GOUT WITH ALZHEIMER’S DISEASE: A MENDELIAN RANDOMIZATION ANALYSIS

Abstract

Background:Several epidmiologic studies have found a lower risk of Alzheimer’s disease (AD) among individuals with a history of gout1or high serum urate levels2, which are the precursor to gout. Serum urate may have neuroprotective benefits for AD, however it is possible that reverse causation and residual confounding could explain the observational evidence.Objectives:To study the causal associations of serum urate and gout with Alzheimer’s disease using Mendelian Randomization (MR) methods.Methods:Two-sample MR was performed to examine the causality of: 1) serum urate on Alzheimer’s disease and 2) gout on Alzheimer’s disease. Single nucleotide polymorphisms (SNP) identified from a genome-wide association study of 457,690 adults described 183 SNPs associated with serum urate and gout, which were used as instrumental variables3. Additional single-SNP analyses were conducted using SNPs from three genes identified as major determinants of urate levels (SLC2A9, SLC22A12, and ABCG2). SNPs for AD came from the International Genomics of Alzheimer’s Project, comprised of 35,274 AD cases and 59,163 cognitively normal elderly controls4. Inverse-variance weighted (IVW) models were the primary method used to examine the associations between each exposure and risk of AD. Additional analyses examined the potential impact of pleiotropy via MR-Egger models. Single-SNP analyses used the Wald ratio. All analyses were performed using R.Results:There was no evidence of a causal association between genetically-determined serum urate or gout and risk of AD from IVW analyses (both p>0.1) (Table 1). MR-Egger analyses yielded similar estimates (both p>0.1) and the intercepts of the MR-Egger regressions did not suggest the presence of directional pleiotropy (p=0.64 for serum urate exposure and p=0.98 for gout exposure) (Table 1). Additionally, none of the three individual SNPs were significantly associated with risk of AD (all p>0.05) (Table 2).Table 1.Association of combined SNPs for serum urate and gout with Alzheimer’s diseaseNumber of SNPsOR95% CIp valueMR-Egger intercept (p value)Serum urate exposure (per 1 mg/dL increase)IVW1581.040.98-1.110.187MR-Egger1581.060.96-1.170.228-0.001 (0.645)Gout exposure (gout vs. non-gout)IVW1581.030.99-1.060.161MR-Egger1581.030.98-1.070.2905.477 (0.976)Table 2.Association of individual SNPs for serum urate and gout with Alzheimer’s diseaseGeneSNPOR95% CIp-valueSerum urate exposure (per 1 mg/dL increase)SLC2A9rs37759471.121.00-1.260.059SLC22A12rs5317630.920.71-1.200.545ABDG2rs749049711.220.99-1.500.059Gout exposure (gout vs. non-gout)SLC2A9rs37759471.081.00-1.170.059SLC22A12rs5317630.940.77-1.150.545ABCG2rs749049711.061.00-1.130.059Conclusion:Using both serum urate and gout as instrumental variables in MR analysis, these findings suggest that serum urate and gout are not causal determinants for the development of AD. The inverse associations described in observational studies may in part be due to confounding or reverse causality.