SNPs rs11240569, rs708727, and rs823156 in SLC41A1 Do Not Discriminate Between Slovak Patients with Idiopathic Parkinson's Disease and Healthy Controls: Statistics and Machine-Learning Evidence

Abstract

Gene SLC41A1 (A1) is localized within Parkinson's disease-(PD)-susceptibility locus PARK16 and encodes for the Na⁺/Mg²⁺-exchanger. The association of several A1 SNPs with PD has been studied. Two, rs11240569 and rs823156, have been associated with reduced PD-susceptibility primarily in Asian populations. Here, we examined the association of rs11240569, rs708727, and rs823156 with PD in the Slovak population and their power to discriminate between PD patients and healthy controls. The study included 150 PD patients and 120 controls. Genotyping was performed with the TaqMan^® approach. Data were analyzed by conventional statistics and Random Forest machine-learning (ML) algorithm. Individually, none of the three SNPs is associated with an altered risk for PD-onset in Slovaks. However, a combination of genotypes of SNP-triplet GG_(rs11240569)/AG_(rs708727)/AA_(rs823156) is significantly (p < 0.05) more frequent in the PD (13.3%) than in the control (5%) cohort. ML identified the power of the tested SNPs in isolation or of their singlets (joined), duplets and triplets to discriminate between PD-patients and healthy controls as zero. Our data further substantiate differences between diverse populations regarding the association of A1 polymorphisms with PD-susceptibility. Lack of power of the tested SNPs to discriminate between PD and healthy cases render their clinical/diagnostic relevance in the Slovak population negligible.

Keywords: Na+/Mg2+ exchanger; Parkinson’s disease; SLC41A1; locus PARK16; machine-learning; polymorphism.

Figure A1

ROC (receiver operating characteristic) curves with the area under the ROC curve (AUC) for the machine-learning Random Forest algorithm with the three individual A1 SNPs (summarized in Table 1) as isolated predictors: (A) rs11240569, (B) rs708727, (C) rs823156. Abbreviations: (TPR) true positive rate, (FPR) false positive rate.

Figure A2

ROC (receiver operating characteristic) curves with the area under the ROC curve (AUC) for the machine-learning Random Forest algorithm with the nine genotypic duplets (summarized in Table A2) of the paired A1 SNPs as predictors: (A) rs11240569 + rs708727, (B) rs11240569 + rs823156, (C) rs708727 + rs823156. Abbreviations: (TPR) true positive rate, (FPR) false positive rate.

Figure 1

Factors regulating activity of Na⁺/Mg²⁺ exchange via SLC41A1 (A1). Among the most prominent intracellular A1 activity-regulating factors belong: cAMP-dependent PKA (activator), Akt/PKB (inhibitory effect via activation of cAMP degradation by phosphodiesterase 3b (PDE3b)) [14], transcription activity of A1, and intracellular concentrations of Na⁺ and Mg²⁺. The regulation by extracellular factors such as concentrations of Na⁺ and Mg²⁺ in the extracellular fluid and extracellular signaling molecules/hormones (ESM; e.g., insulin, neuritin, PDGF, EGF), which stimulate various receptor tyrosine kinases (RTK) are also equally important. RTK further activate adjacent signaling cascades (represented by dashed red arrow) that merge together in PI3K–Akt/PKB signaling nodes [16]. (ECS) extracellular space; the short red arrow (↑) indicates increased and the short black (↓) decreased experession of A1.

Figure 2

Correlation between age of onset of idiopathic PD and the particular genotypes at each tested A1 SNP: (A) rs11240569, (B) rs708727, (C) rs823156. The correlation for each SNP involved 138 PD patients. Twelve patients out of 150 patients in PD cohort have been excluded from the correlation due to discrepancies about the age of PD onset in their documentation.

Figure 3

Correlation between age of onset of idiopathic PD and the particular genotypes at each tested A1 SNP in the subgroup of female PD patients (A–C; (A) rs11240569, (B) rs708727, (C) rs823156; N = 63, 3 out of 66 patients in subcohort of PD females have been excluded from the correlation due to discrepancies about the age of PD onset in their documentation) and the subgroup of male PD patients (D–F; (D) rs11240569, (E) rs708727, (F) rs823156; N = 75, 9 out of 84 patients in subcohort of PD males have been excluded from the correlation due to discrepancies about the age of PD onset in their documentation).

Figure 4

ROC (receiver operating characteristic) curves with the area under the ROC curve (AUC) for the machine-learning Random Forest algorithm with (A) the three individual A1 SNPs (summarized in Table 1) as joined predictors and (B) with the 27 triplets of the three A1 SNPs (summarized in Table 4) as predictors. Abbreviations: (TPR) true positive rate, (FPR) false positive rate.