Associations of SLC30A8 polymorphisms with metabolic and dietary parameters in a Brazilian obesity cohort

Interleukin 37 (IL-37) is an anti-inflammatory cytokine expressed in foam cells located in the atherosclerosis plaques. The present study aimed to evaluate the association of the IL-37 polymorphisms with premature coronary artery disease (pCAD), cardiovascular risk factors, metabolic parameters, and levels of liver enzymes. Three IL-37 polymorphisms (rs6717710, rs2708961, and rs2708947) were determined in 1161 patients with pCAD and 951 healthy controls. IL-37 polymorphisms were not associated with the presence of pCAD. The association of the polymorphisms with cardiovascular risk factors, metabolic parameters, and levels of liver enzymes was evaluated independently in pCAD and healthy controls. In pCAD patients, under different models, the rs6717710 was associated with low risk of having elevated alkaline phosphatase (ALP) (padditive = 0.020; pdominant = 0.02; pheterozygous = 0.04; pcodominant1 = 0.040). On the other hand, in healthy controls, the rs6717710 was associated with low risk of having elevated levels of alanine aminotransferase (ALT) (padditive = 0.04, precessive = 0.01, pcodominant2 = 0.01) and aspartate aminotransferase (AST) (padditive = 0.02, pdominant = 0.02). The IL-37 polymorphisms were not associated with the risk of pCAD. In pCAD patients, the rs6717710 was associated with low risk of having elevated ALP levels, whereas in controls was associated with low risk of having elevated ALT and AST levels.

The association of the rs738409 polymorphism of patatin-like phospholipase-3 (PNPLA3) with nonalcoholic fatty liver disease (NAFLD) has been suggested in other populations, but not in Asian Indians. We investigated the association of the rs738409 polymorphism of PNPLA3 with clinical, anthropometric, and biochemical profiles in Asian Indians with NAFLD. In this case-control study, 162 cases and 173 controls were recruited. Abdominal ultrasound, clinical, anthropometry, and biochemical profiles were determined. Fasting insulin levels and values for homeostasis model assessment of insulin resistance (HOMA-IR) were determined. Polymerase chain reaction and restriction fragment length polymorphism of the PNPLA3 gene were performed. The associations of this polymorphism with clinical, anthropometric, and biochemical profiles were investigated. A higher frequency of C/G and G/G genotypes of the rs738409 polymorphism was obtained in cases as compared to controls (P=0.04), and as a consequence the frequency of the minor allele G was significantly higher in cases (P=0.003). In this study, the G allele was associated with significantly higher fasting insulin (P=0.002), HOMA-IR (P=0.05), alanine transaminase (P=0.003), and aspartate transaminase (P=0.04) values only in cases, but not in the controls. The values of serum triglycerides and total cholesterol were slightly higher in cases with G/C+G/G genotypes but statistically not significant (P>0.05). Using a multivariate logistic regression model after adjusting for age, sex, body mass index, and fasting insulin, subjects with the G/G genotype showed higher risk of NAFLD [odds ratio (OR), 1.98, 95% confidence interval (CI) 1.43-2.73, P=0.04). The relationships of the rs738409 polymorphism with the metabolic parameters were not significant after adjustment for multiple comparisons. Asian Indians in north India carrying the allele rs738490 of PNPLA3 is predispose to develop NAFLD.

The purpose of this study was to explore the association of the MCT1 gene Glu490Asp polymorphism (rs1049434) with athletic status and performance of endurance athletes. A total of 1,208 Brazilians (318 endurance athletes and 890 non-athletes) and 867 Europeans (315 endurance athletes and 552 non-athletes) were evaluated in a case–control approach. Brazilian participants were classified based on self-declared ethnicity to test whether the polymorphism was different between Caucasians and Afro-descendants. Moreover, 66 Hungarian athletes underwent an incremental test until exhaustion to assess blood lactate levels, while 46 Russian athletes had their maximum oxygen uptake ( ) compared between genotypes. In the Brazilian cohort, the major T-allele was more frequent in Caucasian top-level competitors compared to their counterparts of lower competitive level (P = 0.039), and in Afro-descendant athletes compared to non-athletes (P = 0.015). Similarly, the T-allele was more frequent in European athletes (P = 0.029). Meta-analysis of the Brazilian and European cohorts confirmed that the T-allele is over-represented in endurance athletes (OR: 1.48, P = 0.03), especially when Afro-descendant athletes were included in the meta-analysis (OR: 1.58, P = 0.005). Furthermore, carriers of the T/T genotype accumulated less blood lactate in response to intense effort (P < 0.01) and exhibited higher (P = 0.04). In conclusion, the Glu490Asp polymorphism was associated with endurance athletic status and performance. Our findings suggest that, although ethnic differences may exist, the presence of the major T-allele (i.e., the Glu-490 allele) favours endurance performance more than the mutant A-allele (i.e., the 490-Asp allele).

Aim The aetiopathogenesis of the multigenic multifactorial endocrinopathy, polycystic ovary syndrome (PCOS) has been explored using linkage, candidate gene and genome-wide association studies. Contradictory reports of replication studies attributed to phenotypic, ethnic and geographic variations are available. In this study, we investigated the association of Han Chinese GWAS polymorphism (rs13429458) in thyroid adenoma-associated gene (THADA) with PCOS susceptibility and its related traits in Indian women. Methods We genotyped rs13429458 of THADA by direct sequencing and investigated its association with PCOS and its related traits in controls (N = 150) and PCOS women (N = 348). All women were extensively phenotyped in terms of anthropometric, hormonal and metabolic parameters. Association of polymorphism with PCOS risk and its related traits was carried out by regression analysis. Results Genotypic and allele frequencies for rs13429458 were not different between controls and PCOS. Women with PCOS carrying variant allele showed significantly reduced fasting glucose levels, and decreased free and bioavailable testosterone and free androgen index. Conclusion To our knowledge, this is the first study to demonstrate that although this polymorphism does not alter PCOS susceptibility, it favorably impacts glucose metabolism and hyperandrogenism in Indian women with PCOS only. This study highlights that genetic predisposition markers for PCOS may differ with ethnicity and phenotypic variations.

Previous studies conducted in adult obese patients have shown that glucocorticoid receptor and corticosteroid-binding globulin gene polymorphisms influence cortisol-driven obesity and metabolic parameters. We investigated the impact of these polymorphisms in prepubertal obese children that were thoroughly examined for hypothalamic-pituitary-adrenal axis activity and for metabolic and obesity parameters. Obese children carrier of the allele G of the BclI polymorphism within glucocorticoid receptor gene tend to present a higher percentage of fat mass as well as a decreased cortisol suppression after low-dose dexamethasone as found in adult studies. Additionally, these allele G carriers show a strong correlation between truncal fat mass distribution and cortisol response to a standardized lunch, whereas this correlation is weak in allele C carriers. No differences were found for obesity or metabolic parameters between genotypes at the corticosteroid-binding globulin locus. However, allele 90 carriers present increased 24-h free urinary cortisol. Overall, this study provides new data showing the influence of glucocorticoid receptor and corticosteroid-binding globulin genes in obesity and/or cortisol action in prepubertal obese children.

Hyperandrogenism is the most common endocrine disorder in women, characterized by an imbalance of normal estrogen and androgen levels in the blood. Androgens play an important role in the female body because they influence bone mineral density (BMD), body mass composition, muscle mass, mental state, and the regulation of sexual function. The reduced activity of aromatase, due to mutations in the CYP19A1 gene, reduces the estrogen pool in favor of androgens. Clinically, aromatase deficiency causes hyperandrogenism in women. Therefore, the aim of the study was to assess the effect of the CYP19A1 gene polymorphism on selected markers of bone metabolism and hormonal parameters in women with hyperandrogenism. The study group was comprised of 80 young women with hyperandrogenism who underwent measurements of bone mineral density (BMD), and determination of hormonal and metabolic parameters. Enzyme immunoassays were used to measure leptin, total sRANKL (free and bound RANKL), osteoprotegerin, and total 25-OH Vitamin D. An analysis of the CYP19A1 gene polymorphisms was performed using the real-time PCR method. The GG genotype of the CYP19A1 rs700518 polymorphism turned out to be associated with: FEI (Free Estradiol Index), SHGB concentration, estradiol concentration, and insulin concentration determined in the glucose tolerance test 60’ compared to AG and AA genotypes. Patients with the AG genotype had a higher ratio of android to gynoid fat and a greater content of visceral adipose tissue. Higher visceral tissue content may reduce BMD. In conclusion, the study showed that the CYP19A1 rs700518 polymorphism may be associated with the distribution of adipose tissue in young women with hyperandrogenism. These results suggest that patients with the AG genotype may develop osteoporosis.

Different studies have shown that -238 G>A polymorphism in promoter region of tumor necrosis factor alpha (TNF-α) gene is associated with increased risk of non-alcoholic fatty liver disease (NAFLD). The current study investigates the association between metabolic parameters and nutritional intakes with -238 G>A of TNF-α promoter gene polymorphism among the Iranian patients with NAFLD. In this study, 75 patients with NAFLD and 76 individuals as control were enrolled. Dietary intakes were assessed using a semi-quantitative food-frequency questionnaire. Body mass index and waist to hip ratio were calculated. Biochemical assays were measured after 12h fasting. -238 G>A Polymorphism of TNF-α gene was determined by using sequencing method. We observed no significant difference in frequency of different genotypes of this polymorphism between NAFLD and control groups (P>0.05). Among biochemical parameters, TAC showed significant decrease in NAFLD patients with GG genotype when compared to controls (P=0.001). The comparison of macro and micronutrient intakes between groups according to genotypes showed no statistically significant difference (P>0.05). Although the data were not statistically significant, further studies with larger sample size are needed to determine the effect of dietary compounds in NAFLD.

Cirrhosis is the fourteenth leading cause of death globally and significantly increases the risk of hepatocellular carcinoma (HCC). Polymorphisms in the vitamin D receptor (VDR) can influence inflammation, fibrosis progression and cancer susceptibility. We analysed the association of genetic polymorphisms of the VDR (VDR-rs2228570, VDR-rs731236 and VDR-rs7975232) in cirrhosis with or without HCC, considering clinical, biochemical profiles and survival. A total of 158 patients with cirrhosis, with or without HCC, were studied and distributed into Group 1 (G1 = 60): cirrhosis and HCC; Group 2 (G2 = 98): isolated cirrhosis and control group (G3 = 225): without liver disease. Genetic polymorphisms were analysed by real-time polymerase chain reaction; clinical and biochemical profiles were obtained from medical records. A significance level of α = 5% was adopted. The homozygous mutant for VDR-rs731236 and rs7975232 predominated in G1 compared to other groups (p < 0.05). For VDR-rs2228570, the homozygous mutant predominated in patients, while heterozygotes were found in controls (p > 0.05). A positive correlation between vitamin D and parathyroid hormone was observed in patients (R² = 0.3273). VDR-rs2228570 emerged as a protective factor for G2 (p = 0.0057) and was associated with increased survival, as was rs7975232. In conclusion, VDR-rs731236 and VDR-rs7975232 are associated with cirrhosis and HCC, with VDR-rs7975232 identified as independent predictors for isolated cirrhosis. VDR-rs2228570 confers protection and is associated with increased survival in cirrhosis, as well as a better clinical profile for both conditions in the Brazilian cohort. These findings highlight the potential clinical relevance of VDR polymorphisms as biomarkers for risk assessment and prognosis in cirrhosis and HCC.

Oxidative stress is involved in the pathophysiology of diabetic nephropathy. The superoxide-generating nicotinamide adenine dinucleotide phosphate-oxidase 2 (NOX2, encoded by the CYBB gene) and the antioxidant enzyme glutathione peroxidase 4 (GPX4) play opposing roles in the balance of cellular redox status. In the present study, we investigated associations of single nucleotide polymorphisms (SNPs) in the regulatory regions of CYBB and GPX4 with kidney disease in patients with type 1 diabetes. Two functional SNPs, rs6610650 (CYBB promoter region, chromosome X) and rs713041 (GPX4 3'untranslated region, chromosome 19), were genotyped in 451 patients with type 1 diabetes from a Brazilian cohort (diabetic nephropathy: 44.6%) and in 945 French/Belgian patients with type 1 diabetes from Genesis and GENEDIAB cohorts (diabetic nephropathy: 62.3%). The minor A-allele of CYBB rs6610650 was associated with lower estimated glomerular filtration rate (eGFR) in Brazilian women, and with the prevalence of established/advanced nephropathy in French/Belgian women (odds ratio 1.75, 95% CI 1.11–2.78, p = 0.016). The minor T-allele of GPX4 rs713041 was inversely associated with the prevalence of established/advanced nephropathy in Brazilian men (odds ratio 0.30, 95% CI 0.13–0.68, p = 0.004), and associated with higher eGFR in French/Belgian men. In conclusion, these heterogeneous results suggest that neither CYBB nor GPX4 are major genetic determinants of diabetic nephropathy, but nevertheless, they could modulate in a gender-specific manner the risk for renal disease in patients with type 1 diabetes.

ObjectiveThe aim of the study was to investigate whether the Gln223Arg in the leptin receptor may influence body weight, leptin concentration, and metabolic parameters in children.Materials and methodsThe examined group included 101 obese children (58 girls and 43 boys) with BMI 31.41 ± 5.03 kg/m2 (BMI ≥ 2 SDS) and the control group consisted of 41 children with BMI 20.0 ± 0.80 kg/m2 (BMI < 1.0 SDS). Polymorphism identification was performed in total genomic DNA using PCRRFLP method.ResultsThe distribution of genotypes LEPR was the following: in the obese group: AA - 20.8%, AG-55.4%, GG-23.8%; in the control group AA-31.7%, AG-53.65%, GG-14.65%. Comparative analyses between AA homozygous children and carriers of G alleles did not confirm any relation between the analyzed polymorphism and BMI, leptin concentrations, and metabolic disturbances in children with obesity.ConclusionIn children with obesity we did not observe association of the LEPR Gln223Arg gene polymorphism with obesity, leptin, insulin resistance, and metabolic abnormalities.

BackgroundPrevious studies have suggested that fat mass-and obesity-associated (FTO) gene is associated with body mass index (BMI) and the risk of obesity. This study aims to assess the association of five FTO polymorphisms (rs9939609, rs8050136, rs1558902, rs3751812 and rs6499640) with obesity and relative parameters in Han Chinese adolescents.MethodsWe examined a total of 401 adolescents, 223 normal weights (58.7% boys, 41.3% girls), 178 overweight (60.1% boys, 39.9% girls), aging from 14 to 18-years-old, recruited randomly from public schools in the central region of Wuxi, a southern city of China. DNA samples were genotyped for the five polymorphisms by Sequenom Plex MassARRAY. Association of the FTO polymorphisms with BMI, serum fasting plasm glucose (FPG), fasting insulin (FIns), triglyceride (TG) and cholesterol (TC) were investigated.Results1) Serum FPG, FIns, TG and TC were statistically significant higher than that in normal control group. 2) We found that BMI was higher in the rs9939609 TA+AA, rs8050136 AC+AA, rs1558902 TA+AA and rs3751812 GT+TT genotypes than in wild TT genotypes (rs9939609: P = 0.038; rs1558902: P = 0.038;), CC genotypes(rs8050136: P = 0.024) and GG genotypes (rs3751812: P = 0.024), which were not significant on adjusting for multiple testing. 3) In case-control studies, five polymorphisms were not significantly associated with overweight (p>0.05), haplotype analyses showed non-haplotype is significantly associated with a higher risk of being overweight (p>0.05). 4) There existed no significant statistical difference about FPG, FIns, TG and TC in genotype model for any SNP.ConclusionsOur study has conducted a genetic association study of the FTO polymorphisms with BMI, serum fasting plasm glucose (FPG), fasting insulin (FIns), triglyceride (TG) and cholesterol (TC). Our study found BMI of subjects with A allele of FTO rs9939609 is higher than that with T allele. Further studies on other polymorphisms from FTO and increasing the sample size are needed.

Introduction: It is well-known that there is an association between rs9939609 polymorphism of fat mass and obesity-associated (FTO) gene with obesity in people from different ethnic background. Objectives: This study aimed to assess the association of common polymorphism on adiposity indexes and type 2 diabetic mellitus (T2DM) and its association with adiponectin level in Iranian women. Patients and Methods: A sample population of 83 obese patients was investigated in a study with case-control design. The patients’ age, body mass index (BMI), systolic blood pressure (SBP), diastolic blood pressure (DBP), fasting blood sugar (FBS), insulin, insulin resistance, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), glycated hemoglobin, triglycerides (TG) and adiponectin level were measured. The genotype of FTO rs9939609 was considered using specific primers via PCR and sequencing. Results: There was a significant difference between two groups (diabetic and non-diabetic) in terms of their age, FBS, HbA1c, LDL-C, SBP and DBP. The mean ± standard error (SE) of these parameters except for DBP and SBP were higher in diabetic group. The frequency of the TA genotype (48.27%) was higher in the diabetic group. The levels of FBS, HbA1c and insulin resistance index (HOMA-IR) were high in mutant group in comparison with wild group. There was no significant correlation between adiponectin level and anthropometric and metabolic parameters. However, in diabetic patients significant moderate positive correlation was found between HDL-C and adiponectin level (r = 0.473, P = 0.01). Conclusion: The association of rs9939609 FTO polymorphism was significant with FBS, HbA1c, TG, insulin, HOMA and adiponectin level in obese diabetic women who harbored the mutant A allele.

Relevance. The main component of the metabolic syndrome (MS) is the abdominal obesity (AO) which inevitably leads to insulin resistance (IR). Adiponectin (AN) secreted by the adipocytes protects from the IR development, increases the sensitivity of skeletal muscles to insulin, reduces intake of free fatty acids in a liver and, thus reduces the synthesis of atherogenic lipoproteins. Some investigations prove that the level of the adiponectin in blood plasma correlates back with the mass of the fatty tissue, the waist-hip ratio and IR expressiveness. With obesity, AN secretion decreases, losing its protective role as for the risk of IR development and metabolic violations. It is known that ADIPOQ gene has several polymorphic sites, which influence the production and activity of AN. Allelic options of its polymorphic marker G276T are associated with the development of the AO, IR, and diabetes. The aim of the study was to investigate the association of the genetic polymorphism of the G276T marker of the adiponectin gene with changes in metabolic parameters in patients with arterial hypertension (AH) and concomitant obesity. We examined 300 patients with AH 45 to 55 years old who gave informed written consent to participate in the study and met the inclusion criteria. Group 1 consisted of 200 patients with AH and class I–II obesity, group 2 – 50 patients with AH and normal body weight, group 3 – 50 patients with AH and overweight. The control group consisted of 30 practically healthy individuals, in whom AH and obesity were excluded on the basis of clinical and instrumental examination data. As a result of the study the association of T-allele of the polymorphic marker G276T of the adiponectin gene with the development of comorbidity of AH and obesity was established. It has been proven that adiponectin gene polymorphism influenced changes in metabolic parameters in hypertensive patients with obesity: more pronounced impairment of metabolic parameters in G/T and T/T genotypes as compared to G/G genotype. G/T and T/T genotypes of the polymorphic marker G276T of the adiponectin gene were associated with a significantly higher body mass index, higher triglyceride levels, more pronounced insulin resistance and adipokine imbalance.

Although antipsychotic medication contributed to the improvement of psychotic symptoms and reduced relapse, it induced weight gain and metabolic syndrome during antipsychotic medication treatment, which was seriously concerning. To investigate the association of methylenetetrahydrofolate reductase (MTHFR) gene C677T (rs1801133) polymorphism with antipsychotic-induced weight gain and metabolism parameter change, we employed 1,868 patients with schizophrenia in this study and randomly allocated them to seven antipsychotic medication treatment groups. All patients received antipsychotics monotherapy and were followed up for 6 weeks. Height, body weight, and metabolic parameters of the patients were measured at baseline and at 2, 4, and 6 weeks after antipsychotic treatment. We genotyped blood DNA from patients for MTHFR C677T polymorphisms and performed quantitative analyses using analysis of variance (ANOVA) and the analysis of covariance (ANCOVA) among three genotype groups.We found a predominant association between MTHFR C677T and body weight mass index (BMI) change after 6-week risperidone treatment. After 6-week treatment of risperidone, the BMI change rate (%) of MTHFR C677 carriers was significantly higher than that of MTHFR TT genotype carriers [CC (2.81 ± 6.77)%, CT (3.79 ± 5.22)%, TT (1.42 ± 3.53)%, F = 4.749, P = 0.009]. Some of the abnormal metabolic parameters were found to be associated with the MTHFR 677T, including higher levels of low-density lipoprotein and waist circumference. Validation was performed in an independent cohort, consisting of 252 patients with schizophrenia treated with three atypical antipsychotic drugs. Overall, the MTHFR C677 was associated with high risk of antipsychotic-induced weight gain and metabolism abnormalities.

Association of endothelial lipase Thr111Ile polymorphism with lipid metabolism and microvascular complications in type 2 diabetic patients