Genetic Variants in Sulfonylurea Targets Affect Parkinson's Disease Risk: A Two-Sample Mendelian Randomization Study.

Abstract

Disease-modifying drugs are urgently required for the treatment of Parkinson's disease (PD). Recent evidence suggests that overactivation of ATP-sensitive potassium (KATP) channels may be critically involved in PD pathogenesis.1 Expression of the KATP-channel regulatory subunit that binds sulfonylurea (SUR1) is upregulated in the remaining dopaminergic neurons of PD patients.1 Sulfonylureas are commonly used for the treatment of type II diabetes, a well-established risk factor for PD.2, 3 However, results regarding the relation between sulfonylurea use and PD risk are inconclusive, which might reflect the poor blood–brain barrier penetrance of commonly prescribed sulfonylureas, as well as confounding by indication.4 Interestingly, mutations in ABCC8 or KCNJ11 genes that encode the SUR1 and Kir6.2 subunits of the KATP-channel, respectively, disrupt the potentiality of the channel and can cause neonatal diabetes. We, therefore, designed a two-sample Mendelian randomization (MR) study to assess whether variants in genes encoding sulfonylurea targets are causally related to PD risk.4 As instrumental variables for sulfonylurea targets we used five recently validated single nucleotide polymorphisms (SNPs) in the ABCC8 and KCNJ11 genes (Table 1).4 Subsequently, we obtained effect estimates and the corresponding standard errors of these SNPs on PD risk from the largest genome-wide association study to date by the International Parkinson's Disease Genomics Consortium, including 33 674 cases and 449 056 controls.5 The exposure and outcome SNP coefficients were then combined using MR regression based on the inverse variance weighting method. To assess specificity, we repeated the same analyses for other anti-glycemic drugs, including thiazolidinediones, as well as insulin and GLP-1 analogues (Table 1). The procedure for the curation of the specified SNPs as genetic instruments for different classes of antidiabetic drug targets has been extensively detailed before.4 Programming was performed in R (version 4.0.2) using the ‘TwoSampleMR’ package.6 Genetic variants in sulfonylurea targets were strongly associated with PD risk: every 1 mmol/L decrease in blood glucose lowered the risk of PD by more than 90% (odds ratio, 0.07 [95% confidence interval (CI), 0.01-0.39], P = 0.002) (Fig. 1). There was no evidence for heterogeneity (Cochran's Q, P = 0.59) or horizontal pleiotropy (MR Egger intercept 0.00 ± 0.04, P = 0.99). Leave-one-out analysis and other MR regression methods—including simple and weighted median, maximum likelihood and Egger regression—revealed both magnitudinal and directionally consistent estimates (Supplementary Tables S1 and S2). No variants in the targets of the other investigated anti-glycemic agents were associated with PD risk (all odds ratios, ≥2.10, all P ≥ 0.48) (Fig. 1). We show that genetic variants in the ABCC8 and KCNJ11 genes that increase the affinity of the subunits of the KATP-channel to the effects of sulfonylureas are also associated with a markedly lower risk of PD. Conversely, variants in genes coding for targets of other widely used anti-glycemic drugs did not affect PD risk, indicating that the observed protective effects of sulfonylureas are likely to be specific to their mechanism of action and not because of improved insulin sensitivity per se. Indeed, large-scale epidemiological studies have not identified a consistent link between use of anti-glycemic agents and PD risk,3 supporting the notion that the peripherally mediated anti-glycemic effects of sulfonylureas, which have a poor blood–brain barrier penetrance, are unlikely to be responsible for their protective effects. In contrast, the association between variants in genes coding for sulfonylurea targets, which are abundantly expressed on nigrostriatal dopaminergic neurons, and PD risk suggests that sulfonylureas could have neuroprotective effects in the central nervous system, possibly by blockage of KATP-channels and/or by inflammasome inhibition.1, 7 Our findings suggest that brain-penetrant sulfonylurea-derivatives could be promising targets for both prevention and disease modification in PD.7 (1) Research project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript: A. Writing of the First Draft, B. Review and Critique. N.A.A.: 1A, 1B, 1C, 2A, 2B, 3A, 3B. U.W.: 3A, 3B. Open Access funding enabled and organized by Projekt DEAL. The GWAS summary data are available through the website of the International Parkinson's Disease Genomics Consortium: https://pdgenetics.org/resources Table S1. Leave-one-out analysis. The leave-one-out sensitivity analysis demonstrated that the association between genetic variants in sulfonylurea targets and Parkinson's disease risk was not driven by a single genetic variant. Table S2. Sensitivity analysis with different Mendelian randomization methods. Effect estimates of genetic variants in sulfonylurea targets and Parkinson's disease risk using different Mendelian randomization methods showed consistent results with regard to both direction and magnitude of the effects. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.