Association of polymorphism rs10841855 in the glycogen synthase 2 gene with hypercholesterolemia and type 2 diabetes mellitus

Background: Glycogen synthase 2 (GYS2) catalyzes a key step in glycogenesis in the liver. Loss-of-function mutations in the GYS2 gene are associated with type 0a glycogenosis with characteristic fasting hypoglycemia and postprandial hyperglycemia. The association of the single nucleotide polymorphism rs10841855 (G>T) with the risk of type 2 diabetes mellitus (T2D) was first established in the European population, but data on the effect of this variant on the predisposition to T2D in the inhabitants of the Slavic ethnic group of Central Russia are not available in the literature. The aim of the study: To investigate the association of polymorphism rs10841855 (G>T) GYS2 with the risk of T2D in residents of Central Russia. Materials and methods: The study included 2668 unrelated individuals of Slavic origin, including 1387 patients with T2D and 1281 healthy volunteers. Genotyping of the rs10841855 polymorphism of the GYS2 gene was performed by the MassArray Analyzer-4 genetic analyzer. SNPStats software was used for statistical analysis of the data. Results: Linear regression established an association of the alternative rs10841855-T allele (OR 1.25; 95% CI 1.09-1.43; P=0.001) and the rs10841855-G/T genotype (OR 1.37; 95% CI 1, 13-1.66; P=0.0064) of GYS2 with an increased risk of T2D. The sex- and BMI-stratified analysis showed that the association of the rs10841855-G/T genotype (OR 1.71; 95% CI 1.32-2.22; P=0.0001) occurred only in females with BMI>25 kg/m2. In addition, carriage of the rs10841855-T allele was associated with a higher level of total cholesterol in the blood plasma of T2D patients (P=0.0068). According to the Roadmap Epigenomic Consortium, the rs10841855-T allele is associated with H3K4 histone methylation in the enhancer and promoter regions of the GYS2 gene in the liver. Conclusion: The association of rs10841855 of the GYS2 gene with an increased risk of T2D in residents of Central Russia was validated for the first time. The association may be explained by the low transcriptional activity of the glycogen synthase 2 gene in the carriers of the alternative allele of this polymorphism.