Adiponectin gene single-nucleotide polymorphisms in patients with type 2 diabetes mellitus and nonalcoholic fatty liver disease

Abstract

Background. It is generally believed that environmental and genetic factors interact with the formation of nonalcoholic fatty liver disease (NAFLD) phenotype and determine its progression. Both NAFLD and type 2 diabetes (T2D) are heterogeneous diseases with common pathogenic pathways. Adiponectin is an adipokine, which increases the sensitivity of hepatocytes and muscle to insulin, modulates energy homeostasis, glucose/lipid metabolism, and inflammatory response. A number of significant adiponectin gene polymorphisms are known in this area. The purpose of the study was to evaluate the possible association between two adiponectin gene (ADIPOQ) variants, +276 G/T (rs1501299) and –11391 G/A (rs17300539), and susceptibility to NAFLD in T2D patients of Ukrainian population. Materials and methods. Case-control study included a total of 155 persons with T2D (males/females: 77/78, age 54.55 ± 0.73 years, T2D duration 6.66 ± 0.49 years, body mass index 32.20 ± 0.43 kg/m², waist/hip circumference 0.98 ± 0.01 m, HbA_1c 7.26 ± 0.11 %) for biochemical characteristics (lipid profile, non-esterified fatty acids (NEFA), insulin, total adiponectin, etc.), including 90 T2D patients with NAFLD, 245 — with rs1501299 genotyping, 155 — with rs17300539 genotyping, and 51 sex and age-matched control subjects. The +276 G/T and –11391 G/A were determined by polymerase chain reaction — restriction fragment length polymorphism method with endonucleases Mva1269I (BsmI) and MspI (HpaII). Insulin resistance (IR) was assessed using homeostasis model assessment (HOMA) algorithm and as adipose IR (Adipo-IR, NEFA^xinsulin). Unpaired Student’s t test, c² test and Spearman’s rank order were used. To predict the probabilities of genetic risk in NAFLD, the odds ratio (OR) and 95% confidence interval (CI) were calculated. Results. T2D patients were characterized by overweight and obesity, which were more significant in the presence of NAFLD (p < 0.01). It was accompanied by an increase in НОМА-IR (p < 0.05) and triglycerides (p < 0.001) levels. We found that Adipo-IR was higher in patients with T2D as compared to the controls (p < 0.001), and this index was significantly increased in T2D patients with NAFLD in contrast to obesity-matched persons without NAFLD (190.18 ± 22.15 vs 133.32 ± 13.58 mmol/L·pmol/L, p < 0.02), with negative correlation between Adipo-IR and adiponectin level in T2D patients with NAFLD only (r_s = –0.350, p = 0.021). Stratification of non-NAFLD patients by +276G/T genotype suggests the prevalence of GT- and TT-genotypes. Thus, the rs1501299 G-allele increased the risk of NAFLD in comparison with T-allele (OR = 4.44, 95% CI = 2.89–6.81, p < 0.05). We also found a significant difference in the frequency of –11391G/A between T2D and control groups, but not between the patients with and without NAFLD. We observed that the haplotype of GT/GG had been more common in T2D with NAFLD, and twice less often detected in patients without hepatic disease (33 and 16.49 %, respectively, p < 0.05). Conclusions. We can recommend Adipo-IR index as a predictive marker for the NAFLD development and the indicator for therapy success in T2D patients. We established new genetic markers (rs1501299 G-allele, rs17300539 and rs1501299 GG/GG and GT/GG haplotypes, respectively) for the risk of NAFLD development in T2D patients.