Polymorphic variant rs4430796 at HNF1B gene: sex-specific, BMI-dependent associations with parameters of glucose metabolism, redox homeostasis and risk of type 2 diabetes

Obesity is a critical risk factor for type 2 diabetes mellitus (T2D). Hepatic nuclear factor 1 β (HNF1B) controls the glucostatic function of pancreatic islets of Langerhans and is associated with the development of T2D in the European and Asian populations. However, studies evaluating the contribution of genetic variants at HNF1B to the pathogenesis of the disease in Russian population have not been conducted to date. The aim of this work was to study the association of the polymorphic variant rs4430796 (A>G) in the intron of the HNF1B gene with parameters of glycemic profile and redox homeostasis, as well as the risk of developing T2D in citizens of Central Russia, taking into account their gender and body mass index. The study included 3206 participants, 1579 patients with T2D and 1627 healthy volunteers. Genotyping was performed using iPLEX technology on a genomic time-of-flight mass spectrometer MassArray 4 (Agena Bioscience). For the first time in the Russian population, the relationship of the rs4430796 polymorphism at the HNF1B gene with an increased risk of developing T2D (OR 1,24, 95CI 1,05-1,47, p=0,011) was established. A gender-stratified analysis found that the association is characteristic only for females with overweight (OR 1,54, 95CI 1,06-2,22, p=0,02) and obesity (OR 2.07, 95CI 1,14-3,77, p=0.047) and is absent in individuals with normal body weight, regardless from the gender. The studied SNP is associated with an increased content of hydrogen peroxide (p=0,012) and a lower level of total plasma glutathione (p=0,041) in females, whereas in diabetic males the G/G genotype is associated with a decrease in the concentration of C-peptide (p=0,004) and an increase in blood glucose concentration (p=0,015). Bioinformatic analysis confirmed the negative effect of the alternative G allele on the expression of the HNF1B gene, as well as its relationship with hypermethylation of the gene at different periods of life, which leads to low expression of HNF1B in carriers of variant rs4430796. Conclusions: It was found for the first time that the polymorphic variant rs4430796 of the HNF1B gene is associated with a predisposition to T2D, whereas its relationship with the disease is sex-specific and depends on body mass index.

type 2 diabetes mellitus, HNF1B, single nucleotide polymorphism, body mass index, glutathione, hydrogen peroxide, C-peptide

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