Parkinson's disease and polymorphisms of the glutamatergic system genes GRIN2A, SLC1A2, and GRIK4

Parkinson's disease (PD) is now increasingly considered as a multi-system disorder associated with multi-neurotransmitter dysfunction, so it is important to search for genetic risk factors that determine different clinical types of this disease.

Objective: to investigate the associations of PD with the polymorphic variants of glutamatergic system genes, such as GRIN2A encoding the N-methyl-D-aspartate (NMDA) receptor; SLC1A2 encoding the glial glutamate transporter; and GRIK4 encoding the ionotropic glutamate kainate receptor.

Patients and methods. Examinations were made in 222 patients diagnosed with Parkinson's disease and 318 healthy individuals, who were an ethnic Russian population from the Siberian Region. Genotyping using one single-nucleotide polymorphism was performed in three glutamatergic system genes: the polymorphisms were rs2650427 in the GRIN2A gene, rs4354668 in the SLC1A2 gene, and rs1954787 in the GRIK4 gene. The results were statistically processed using the SPSS Statistics 23.0.

Results and discussion. In the group of patients with tremor-dominant PD, the GRIK4 polymorphism rs1954787 showed a considerable increase in frequency of the T allele (66.7%) and a reduction in that of the C allele (33.3%) as compared to their distribution in the control group (42.1 and 57.9%, respectively; χ2 =7.70; p=0.006). The odds ratio (OR) was calculated for all of the genotypes and alleles of the investigated polymorphisms; the ratio showed that the C allele of the GRIK4 polymorphism rs1954787 had a protective effect (OR, 0.36; 95% CI, 0.17–0.76), whereas the T allele (OR, 2.75; 95% CI, 1.32–5.75) and the homozygous TT genotype (OR, 3.40; 95% CI, 1.21–9.53) were found to predispose to the development of tremor-dominant PD.

Conclusion. The found significant association of the GRIK4 polymorphism rs1954787 with the tremor-dominant PD may suggest that abnormalities in the glutamatergic system play a role in the pathophysiological processes of the disease.

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