Associations of molecular genetic predictors of type 2 diabetes mellitus with hyperglycemia in extremely low birth weight infants

Hyperglycemia in premature newborns is an independent risk factor for death, so blood glucose testing is widely used in the practice of neonatal intensive care units.Objective: to evaluate the associations of the frequency of carriage of allelic variants of polymorphic loci of genes predisposing to type 2 diabetes mellitus in newborns with extremely low body weight and hyperglycemia.Methods. The study design is prospective, controlled, single – center, non-randomized. Genomic DNA samples were studied in newborn infants with extremely low body weight (ELBW) (n = 105). Previously, we compared the distribution of allele frequencies of the studied genes between a group of newborns with ELBW and a population sample of adults (control). Then, the distribution of allele frequencies of the genes was compared depending on the presence of hyperglycemia in newborns with ELBW. For the analysis, loci with already known association with the development of type 2 diabetes mellitus were selected ‒ ADRB2 (rs1042713) and (rs1042714), ADRB3 (rs4994), GNB3 (rs5443), PPARA (rs4253778), PPARD (rs2016520), TCF7L2_IVS3 (rs7903146) and TCF7L2_IVS4 (rs12255372), PPARGC1A (rs8192678), MTHFR (rs1801131), PPARG (rs1801282), MTNR1B (rs10830963), SIRT1 (rs7069102).Results. In newborns with ELBW, we found a more frequent occurrence of the mutant allele A of the polymorphic locus rs8192678 in the PPARGC1A gene and the allele C of the polymorphic locus rs4253778 in the PPARA gene, in contrast to the adult population sample. But in newborns with ELBW, hyperglycemia is most likely associated with the carrier of the allele C rs1801282 of the PPARG gene (χ2 = 18.972, p < 0.001) and the allele T rs7903146 in the TCF7L2 gene (χ2 = 11.496, p < 0.001).Conclusions. The carriage of the allele С rs1801282 of the PPARG gene is characterized by the presence of a strong conjugation with hyperglycemia in newborns with extremely low body weight. It is desirable to monitor the level of glycemia in the conditions of neonatal intensive care units, taking into account the carriage of genes predisposing to hyperglycemia.

Post-Treatment with Amorfrutin B Evokes PPARγ-Mediated Neuroprotection against Hypoxia and Ischemia

In this study, we demonstrate for the first time that amorfrutin B, a selective modulator of peroxisome proliferator-activated receptor gamma—PPARγ, can protect brain neurons from hypoxia- and ischemia-induced degeneration when applied at 6 h post-treatment in primary cultures. The neuroprotective effect of amorfrutin B suggests that it promotes mitochondrial integrity and is capable of inhibiting reactive oxygen species—ROS activity and ROS-mediated DNA damage. PPARγ antagonist and Pparg mRNA silencing abolished the neuroprotective effect of amorfrutin B, which points to agonistic action of the compound on the respective receptor. Interestingly, amorfrutin B stimulated the methylation of the Pparg gene, both during hypoxia and ischemia. Amorfrutin B also increased the protein level of PPARγ during hypoxia but decreased the mRNA and protein levels of PPARγ during ischemia. Under ischemic conditions, amorfrutin B-evoked hypermethylation of the Pparg gene is in line with the decrease in the mRNA and protein expression of PPARγ. However, under hypoxic conditions, amorfrutin B-dependent hypermethylation of the Pparg gene does not explain the amorfrutin B-dependent increase in receptor protein expression, which suggests other regulatory mechanisms. Other epigenetic parameters, such as HAT and/or sirtuins activities, were affected by amorfrutin B under hypoxic and ischemic conditions. These properties position the compound among the most promising anti-stroke and wide-window therapeutics.

MYOSTATIN COORDINATING THE PROLIFERATION AND DIFFERENTIATION OF ADIPOSE AND SKELETAL MUSCLE CELLS AND ENERGY METABOLISM BALANCE BASED ON GENE CHIP TECHNOLOGY

ABSTRACT Myoblasts fuse into multinucleated muscle fibers to form and promote the growth of skeletal muscle. In order to analyze the role of myostatin (MSTN) in body fat, skeletal muscle cell proliferation and differentiation and energy metabolism, this study will use the antisense RNA technology of gene chip technology to study it. The results showed that the MSTN gene regulated the growth and proliferation of myoblasts and affected the development of skeletal muscle by affecting the expression of Cdc42, bnip2, p38 and other genes; knockout or overexpression of the MSTN gene would lead to a trend of fat-related genes from fat synthesis to fat decomposition; after the MSTN gene was knocked down, the expression levels of cpti-b, PPARG and other genes in the cells were corresponding after MSTN overexpression, the relative expression of the PPARG gene decreased. It is suggested that the knockout or overexpression of MSTN may affect lipid accumulation, and cpti-b and PPARG may directly regulate lipid level. It is hoped that this experiment can provide a reference for the study of MSTN effect on fat deposition.

ASSOCIATION ANALYSIS OF PIOGLITAZONE EFFECTIVENESS IN TREATMENT OF NAFLD PATIENTS WITH OBESITY AND PPARG RS1801282 (PRO12ALA) GENOTYPE

The aim: To study the association between the effectiveness of treatment with pioglitazone non-alcoholic fatty liver disease (NAFLD) in patients with obesity and PPARG rs1801282 (Pro12Ala)-polymorphism in Ukrainians. Materials and methods: 123 patients with NAFLD in combination with obesity 1, 2, 3 classes were included in comprehensive weight loss program (5 visits, 12-weeks). The case group was treated with pioglitazone 15 mg / day, while the control group received only program. Ultrasound (US) steatometry and genetic testing rs1801282 polymorphism in PPARG gene were performed. Results: Pioglitazone, PPARG rs1801282 genotype, CAP before treatment, previous weight loss attempts, and duration of obesity were associated with the change in controlled attenuation parameter (CAP) during treatment. There was a significant association between the target CAP reduction achievement and pioglitazone treatment (adjusted odds ratio 0.23, 95% CI 0.07–0.73; p = 0.01) with the CC genotype of PPARG gene (adjusted odds ratio 92.9, 95% CI 7.4–1159; p < 0.001) compared to patients with the CG genotype. Conclusions: Pioglitazone and PPARG rs1801282 polymorphism could influence on dynamics of CAP reduction during treatment.

Association between genetic variants in metabolic syndrome-related genes and risk of obstructive sleep apnea among a Chinese population

Background Despite the strong epidemiological association between Metabolic syndrome (MetS) and obstructive sleep apnea (OSA), the causal mechanism between the two remains not fully elucidated. We conducted a case-control study to evaluate the genetic association of twelve metabolic syndrome-related genes with OSA in Chinese subjects. Methods Targeted capture sequencing for twelve metabolic syndrome-related genes (EDN1, APOE, LEP, LEPR, IRS1, UCP1, ADIPOQ, PEMT, PPARG, SLC2A4, FABP2 and ADRA2A) were performed in 100 subjects including 50 patients with severe OSA and 50 non-OSA individuals. Possible associations between genetic variants and the risk of OSA were determined by logistic regression analyses. Results From the multiple genes studied, only the rs12486170 variant in PPARG gene was associated with OSA risk after adjusting for potential confounding factors. The PPARG rs12486170 AG/GG genotype was found to decrease the risk for OSA [dominant model: adjusted odds ratio (AOR) = 0.211, 95% confidence interval (CI) = 0.055-0.800, P = 0.022] compared with AA genotype. Moreover, subjects with the rs12486170 AG/GG genotype had a significantly lower apnea-hypopnea index (AHI) (median: 2.50 vs. 50.90 events/h, P = 0.019) and higher lowest oxygen saturation (LSaO2) (median: 87% vs. 75%, P = 0.040) compared with those with the AA genotype. Conclusions We identified a novel variant of PPARG in subjects with OSA, and specifically found an association between rs12486170 polymorphisms and OSA risk in a Chinese population.

THE RS1801282 PPARG POLYMORPHISM DEPENDENT METABOLIC EFFECTS OF PIOGLITAZONE IN PATIENTS WITH OBESITY AND CONCOMITANT NAFLD

The aim: to investigate the metabolic effects of different treatment options in patients with obesity and concomitant non-alcoholic fatty liver disease (NAFLD) based on the presence of CG and GG genotypes PPARG rs1801282 (Pro12Ala) polymorphism in Ukrainians. Materials and methods: 123 patients with NAFLD in combination with obesity 1, 2, 3 classes were included in the motivational weight loss program (5 visits, 3 months). The case group was treated with pioglitazone 15 mg / day, while the control group received only a program. Ultrasound steatometry, anthropometric and laboratory tests before and after treatment, genetic testing rs1801282 polymorphism in PPARG gene were performed. Results: the carriers of CG and GG genotypes PPARG rs1801282 polymorphism had less high stimulated insulin levels compared with groups of different genotypes (p<0.001). It was found pioglitazone effectiveness with significant difference in dynamics of CAP reduction (p<0.001) regardless of polymorphism. Dynamics of BMI decrease was the lowest in control group CC carries – –2.81 (–3.23; –2.39) kg (p<0.001) compared among other groups. Subjects from pioglitazone group with rs1801282 polymorphism carrying of CG and GG genotypes had significant differences in dynamics of fasting С-peptide decrease, serum uric acid reduction – –1.31 (–1.50; –1.13) µg/L and -165.3 (–182.80; –147.80) µmol/L (p<0.001) respectively compared among other groups. Conclusions: Better reduction of metabolic parameters during pioglitazone treatment of patients with obesity and concomitant NAFLD appears to be associated with carrying of CG and GG genotypes PPARG rs1801282 polymorphism.

Impact of Proliferator-Activated Receptor γ Gene Polymorphisms on Risk of Schizophrenia: A Case-Control Study and Computational Analyses

Objective: Schizophrenia (SCZ) is a common psychiatric disorder characterized by a complex mode of inheritance. Peroxisome proliferator-activated receptor-γ (PPARG) mainly regulates lipid and glucose metabolisms while it is constitutively expressed in rat primary microglial cultures. This preliminary study was aimed to investigate the relationship of two polymorphisms in the PPARG gene, rs1801282 C/G, and rs3856806 C/T, to the risk of SCZ in the southeast Iranian population. Method: A total of 300 participants (150 patients with SCZ and 150 healthy controls) were enrolled. Genotyping was done using the amplification refractory mutation system polymerase chain reaction (ARMS–PCR) technique. Computational analyses were carried out to predict the potential effects of the studied polymorphisms. Results: A significant link was found between genotypes of rs1801282 and SCZ susceptibility. The G allele of rs1801282 in CG and GG form of the codominant model increased the risk of SCZ by 2.49 and 2.64 folds, respectively. With regards to rs3856806, enhanced risk of SCZ was also observed under different inheritance models except for the overdominant model. Also, the T allele of rs3856806 enhanced the risk of SCZ by 3.19 fold. Computational analyses predicted that rs1801282 polymorphism might alter the secondary structure of PPARG-mRNA and protein function. At the same time, the other variant created the binding sites for some enhancer and silencer motifs. Conclusion: Our findings showed that PPARG rs1821282 and rs3856806 polymorphisms associate with SCZ susceptibility. Replication studies in different ethnicities with a larger population are needed to validate our findings.