Single Nucleotide Polymorphisms Rs12255372 Research Articles

Frequency of Transcription Factor 7-like 2 rs12255372 Mutation among Bangladeshi Adult Type 2 Diabetes Patients

ABSTRACT Background: While the etiology of type 2 diabetes mellitus (T2DM) is complex, genetic markers for T2DM are surfacing fast, and amidst such markers, the transcription factor 7-like 2 (TCF7L2) gene has been emerged as the most promising T2DM-causing gene. The intronic variant rs12255372 of the TCF7L2 gene has been found to be strongly associated with T2DM in different ethnic populations. Objectives: The objectives of this study were to determine the frequency of rs12255372 polymorphism in the TCF7L2 gene in Bangladeshi adult population with T2DM. Materials and Methods: This cross-sectional study was conducted in the Department of Endocrinology, Bangabandhu Sheikh Mujib Medical University. Eighty T2DM patients were recruited consecutively by nonrandom sampling, who signed the informed consent, history, and clinical features including height, weight, and waist circumferences were recorded. Blood samples were collected. Genomic DNA was extracted and single-nucleotide polymorphisms rs12255372 (G>T) were determined by the restriction fragment length polymorphism (RFLP) method. Statistical Analysis: RFLP results were analyzed by the gel electrophoresis to get the frequency of rs12255372 polymorphism. The independent segregation of alleles was tested for Hardy–Weinberg equilibrium using the Chi-square test of goodness of fit. P ≤0.05 was considered statistically significant. Results: The minor (T) allele frequencies (MAF) for rs12255372 (G>T) among T2DM was 28%. The observed genotype frequencies of rs12255372 (G>T) were different than those expected from the Hardy–Weinberg equation. Conclusion: The minor T allele frequency of rs12255372 (G>T) among T2DM participants was about one-fourth.

Genetic determinants of obesity in adolescent girls

Significant progress in understanding the genetic contribution in obesity and its prevalence at all ages has been achieved since existing methods of treatment and preventive measures aimed at combating obesity are not effective enough.Purpose. To study the prevalence of pathologic single nucleotide polymorphisms rs6265 of the brain neutrophic factor gene BDNF; rs1137101 of the leptin receptor gene LEPR; rs9939609 of the gene, associated with fat mass, FTO; rs4762 and rs699 of angiotensinogen AGT gene; rs1799883 of fatty acid transporter gene FABP2; rs1801282 of PPARG2 gene in obese adolescent girls.Material and methods. 72 teenage girls aged 12–17 years were examined. Group 1 consisted of 36 obese children (standard deviation coefficient SDS BMI ≥ 2.0), group 2 — 36 non-obese children (SDS BMI <1.0). Anthropometric, molecular genetic, and statistical methods were used.Results. In obese adolescent girls, an association was detected with only one gene — PPARG2, a polymorphic locus (Pro/Pro). The prevalence rate of the C allele in group 1 was 80%, in group 2 — 3% (p<0.05). No statistically significant differences in the frequencies of genotypes and alleles of other genes in children with obesity and normal body weight were established.Conclusion. Further large-scale studies, including biochemical and hormonal parameters, are needed to establish the influence of specific polymorphic loci of various genes contributing in obesity and metabolic processes.

Type 2 diabetes linked FTO gene variant rs8050136 is significantly associated with gravidity in gestational diabetes in a sample of Bangladeshi women: Meta-analysis and case-control study.

Gestational diabetes mellitus (GDM) is a growing public health concern that has not been extensively studied. Numerous studies have indicated that a variant (rs8050136) of the fat mass-associated gene, FTO, is associated with both GDM and Type 2 diabetes mellitus(T2DM). We conducted a meta-analysis on the association between the FTO single nucleotide polymorphism (SNP) rs8050136 and T2DM, followed by a case-control study on the association of the said SNP and GDM in a sample of Bangladeshi women. A total of 25 studies were selected after exploring various databases and search engines, which were assessed using the Newcastle-Ottawa Scale (NOS). The MetaGenyo web tool was used to conduct this meta-analysis. A case-control study was performed on 218 GDM patients and 284 controls to observe any association between FTO rs8050136 and GDM. Genotyping was performed using the tetra-primer amplification refractory mutation system-polymerase chain reaction (T-ARMS) method, and statistical analyses were performed using various statistical softwares. In the meta-analysis 26231 cases and 43839 controls were examined. Pooled association analyses revealed a statistically significant relationship between the FTO rs8050136 polymorphism and an elevated risk of T2DM under all genetic models (P<0.05). In the case-control study, synergistic analyses of the SNP and gravida with GDM revealed a significant (P<0.01) association with an increase in odds by 1.6 to 2.4 folds in multigravida and decrease in odds by 2 folds in primigravida. A positive family history of diabetes and the minor allele of this SNP collectively increased the risk of developing GDM by many-fold (1.8 to 2.7 folds). However, after accounting for family history of diabetes and gravidity, analyses showed no significant association with GDM. Our meta-analysis revealed a significant association between SNP rs8050136 of FTO with T2DM, and this variant was substantially associated with an increased risk of GDM in a sample of Bangladeshi multigravida women.

Relationship between BDNF gene polymorphisms and alcohol-related liver cirrhosis

Background and aimBrain-derived neurotrophic factor (BDNF) functions not only in the brain but also in peripheral tissues such as the liver. Genetic factors determine the development of alcohol dependence and somatic consequences of chronic intoxication, especially liver cirrhosis. The BDNF gene polymorphisms are associated with alcohol dependence; however, their relationship with the development of alcohol-related liver cirrhosis (ALC) has not yet been established. This study evaluated the association between single-nucleotide polymorphisms (SNPs) within the BDNF gene and liver cirrhosis in heavy drinkers.MethodsBDNF-related SNPs rs925946, rs6265, rs10835210, rs7103411, and rs75945125 were determined using real-time PCR in heavy drinkers with and without liver cirrhosis. Single SNPs and defined haplotypes within the BDNF gene were tested for association with ALC.ResultsAccording to both codominant and recessive genetic models, carriers of the rs925946 TT genotype have an elevated risk of liver cirrhosis development with odds ratios (confidence intervals) 6.287 (1.286–30.738) and 6.321 (1.317–30.348), respectively. BDNF SNPs rs6265, rs10835210, rs7103411, and rs75945125 do not associate with risk of ALC. One block of haplotypes consisting of rs10835210 and rs7103411 demonstrated linkage disequilibrium (D′ = 1 and r2 = 0.228). The revealed haplotypes do not associate with the development of liver cirrhosis in alcohol heavy drinkers.ConclusionThus, the BDNF rs925946 SNP is associated with the risk of ALC in heavy drinkers. Future investigations of the BDNF gene-related genetic markers of ALC will help to objectively assess the risk and severity of liver damage and correct the corresponding therapy.

High blood levels of brain-derived neurotrophic factor (BDNF) mRNA in early psychosis are associated with inflammatory markers

The brain-derived neurotrophic factor (BDNF) single nucleotide polymorphism (SNP) rs6265C > T, Val66Met, affects BDNF secretion and has been related to inflammatory processes. Both the rs6265 and BDNF protein levels have been widely investigated in neuropsychiatric disorders with conflicting results. In the present study we examined BDNF mRNA expression in blood considering the SNP rs6265 and its relationship with inflammatory markers in the early stages of psychosis. The rs6265 genotype and blood BDNF mRNA levels were measured in 34 at-risk mental states (ARMS) individuals, 37 patients with first-episode psychosis (FEP) and 42 healthy controls (HCs) by quantitative PCR and reverse transcription (RT)-qPCR using validated TaqMan assays. We also obtained measures of interleukin-6 (IL6) mRNA levels, fibrinogen, neutrophil-to-lymphocyte ratio (NLR) and high-sensitivity C-reactive protein. We identified that BDNF mRNA levels were associated with the rs6265 genotype in an allele-dose-dependent manner, with low expression levels associated with the T allele (Met substitution). Thus, we controlled for the rs6265 genotype in all analyses. Blood BDNF mRNA levels differed between diagnostic groups: patients with FEP exhibited higher blood BDNF mRNA levels than ARMS individuals, and the lowest levels were observed in HC. In addition, we observed significant correlations between BDNF mRNA levels and inflammatory markers (IL6 mRNA levels and NLR), controlled by the rs6265 genotype, in ARMS and FEP groups. This exploratory study suggests that the rs6265 genotype is associated with differential blood mRNA expression of BDNF that increases with illness progression and correlated with inflammation in the early stages of psychosis.

Association of COMT Val158Met Polymorphism with Fibromyalgia in Khartoum State, Sudan.

Fibromyalgia (FM) is a disorder characterized by chronic musculoskeletal pain, fatigue, and cognitive problems. Neurotransmitters, mainly catecholamines, appear to be involved in regulating the etiology of FM. Catechol-O-methyltransferase (COMT) is involved in catabolizing catecholamines such as norepinephrine. The most common variant studied in the COMT gene is the valine (Val) to methionine (Met) substitution at codon 158. This is the first study in Sudan addressing FM cases and genetic susceptibility to the disease. We aimed in this study to investigate the frequency of COMT Val 158 Met polymorphism among patients with FM, rheumatoid arthritis, and in healthy individuals. Genomic DNA from forty female volunteers was analyzed: twenty were from primary and secondary FM patients, ten were from rheumatoid arthritis patients, and ten were from healthy control. FM patients' age was ranging from 25 years to 55 with a mean of 41.14 ± 8.90. The mean age of the rheumatoid arthritis patients and healthy individuals was 31.3 ± 7.5 and 38.6 ± 11.2, respectively. Samples were genotyped for COMT single nucleotide polymorphism rs4680 (Val158Met), using the amplification-refractory mutation system (ARMS-PCR). Genotyping data have been analyzed using the Chi-square and Fisher exact test. The most common genotype among the study participants was the heterozygous Val/Met found in all participants. It was the only genotype found in the healthy participants. The genotype Met/Met was found only in FM patients. The genotype Val/Val was found only in rheumatoid patients. Analyses have shown no association between the Met/Met genotype and FM, and this could be due to a small sample size. In a larger sample size, a significant association could be found as this genotype was shown only by FM patients. Moreover, the Val/Val genotype, which is shown only among rheumatoid patients, might protect them from developing FM symptoms.

Single Nucleotide Polymorphism at rs7903146 of Transcription Factor 7-like 2 gene Among Subjects with Type 2 Diabetes Mellitus in Myanmar.

To investigate the association between the single nucleotide polymorphism (SNP) rs7903146 in the transcription factor 7-like 2 (TCF7L2) gene and type 2 diabetes mellitus (T2DM) and to examine the impact of this variant on pancreatic beta-cell function in the Myanmar population. A case-control study was undertaken in 100 subjects with T2DM and 113 controls. The SNP rs7903146 was genotyped using the allele-specific polymerase chain reaction method. Plasma glucose and serum insulin levels were determined using the enzymatic colorimetric method and ELISA respectively. Beta-cell function was calculated by the HOMA-β formula. The frequencies of carrier genotypes (CT and TT) were higher in subjects with T2DM than in controls. The minor T alleles of rs7903146 were found to statistically increase type 2 diabetes risk than the C allele with an allelic odds ratio of 2.07 (95% CI 1.39-3.09, p=0.0004). The mean HOMA-β level of the group with non-carrier genotype (CC) was significantly higher than that of the groups with carrier genotypes (CT and TT) in subjects with T2DM and controls with a p-value of 0.0003 and less than 0.0001, respectively. The rs7903146 variant of the TCF7L2 gene was found to be associated with T2DM and low β-cell function among Myanmar subjects.

Apoprotein-E gene polymorphism in an Iraqi population with type 2 diabetes and cardiovascular disease

Introduction and Aim: The ApoE gene polymorphisms are considered as risk factors for developing atherosclerosis and related cardiovascular disease (CVD) in humans. There exists no study pertaining to ApoE gene polymorphism and its association to these disorders among the Iraqi population. Hence in this study, we aimed to investigate the possible relationship between single nucleotide polymorphisms (SNPs) in the ApoE gene with the prevalence of diabetes (T2DM) and cardiovascular disease among the Iraqi population. Materials and Methods: This cross-sectional investigation involved 76 patients (50 with diabetics and 26 with cardiovascular disease) and 73 otherwise healthy individuals. The ApoE gene fragment corresponding to the SNPs rs429358 and rs7412 was amplified using conventional polymerase chain reaction (PCR) with a specific pair of primers. Genotyping was performed by direct sequencing. Results: Differences in genotypic and allelic frequencies were seen in SNPs rs429358 and rs7412 of the ApoE gene. Significant higher frequency was seen for the CT genotype in SNP rs429358 when compared to healthy controls. Among the epsilon alleles, the E3/E3 was the most common genotype, accounting for 76% and 69.23% of patients with diabetes and CVD, respectively. E2/E4 was the least common genotype, accounting for 2% and 0% of diabetes and CVD patients, respectively. When DM patients were compared to controls, the genotype E 3 E 4 was found to be more common in T2DM patients (10%) than in controls (1.34%), with a significant difference (OR= 4.32, 95%CI=0.02-0.98, p= 0.050). At the allelic level, the E2 allele was significantly more common in patients than in controls (OR= 12.73, 95%CI= 1.38-116.87). Conclusion: Data in this study indicate ApoE gene polymorphisms in SNPs rs429358 and rs7412 could be risk factors for T2DM and CVD in Iraqi patients.

FTO genotypes (rs9939609 T>A) are Associated with Increased Added Sugar Intake in Healthy Young Adults

Introduction: Single-nucleotide polymorphism (SNP) rs9939609 in the FTO gene has been associated with dietary intake and appetite traits, mainly in participants with obesity; however, it remains widely unexplored in normal weight participants. Thus, the aims of this study were (1) to compare the changes in subjective appetite sensations, ghrelin, and insulin concentrations according to the SNP rs9939609 T>A in FTO and (2) to compare dietary intake between rs9939609 genotype groups in normal weight young participants. Methods: We conducted a quasi-experimental study involving 88 normal weight participants to analyze subjective perception of appetite, hormonal response for hunger and satiety, and dietary intake according to the rs9939609 SNP. Participants received a standardized single breakfast. Visual analogue scales (VAS) were utilized for assessing the subjective perception of appetite at fasting and immediately after breakfast and at 30, 60, 90, and 120 min postprandially. Glucose, lipid profile, ghrelin, and insulin were measured at fasting and at 120 min after breakfast. Dietary intake was assessed with a 3-day food record. The SNP was determined by allelic discrimination with TaqMan probes. To compare dietetic, biochemical, and the subjective appetite sensations, Student t test, ANCOVA test, and the repeated measures ANOVA were used. The linear regression model and the linear mixed model were used for the association analysis. Pearson correlation was used to test the correlation between two quantitative variables. Results: A total of 88 people participated, 81.8% were female, with a mean body mass index of 21.8 ± 2.0 kg/m² and a mean age of 20.6 ± 2.0. Genotype frequencies of the rs9939609 SNP were 52% for the TT allele and 48% for the TA/AA. The subjective perception of appetite named hunger, fullness, satiety, desire to eat, and prospective food consumption were similar between genotypes of the rs9939609. Participants with the TA/AA genotype showed a higher intake of added sugar (p = 0.039) than TT participants. No differences were found in ghrelin, insulin, glucose, or lipid parameters between genotypes. Conclusion: Carriers of the A allele from FTO gene SNP rs9939609 may have an increased preference for foods, specifically for added sugars.

Association of the apolipoprotein E ε4 allele in a Serbian population with Alzheimer’s dementia

Although single nucleotide polymorphisms rs429358 and rs7412 in the apolipoprotein E gene (APOE) are widely investigated to analyze APOE alleles, there are no data on their association with Alzheimer?s disease (AD) dementia in a Serbian population. This study aimed to investigate the distribution of APOE ?2/?3/?4 alleles in patients with dementia due to AD and cognitively unimpaired subjects and to assess the association of the APOE ?4 allele with disease risk in the Serbian population. A case-control study included patients with dementia due to AD and cognitively unimpaired individuals. APOE rs429358 and rs7412 were analyzed using the Real-Time PCR method with allele-specific TaqMan assays, followed by APOE ?2/?3/?4 allele carrier status analysis. Patients had a significantly higher frequency of the APOE ?4 allele than the control group (P&lt;0.001). The APOE ?4 allele was found to be associated with a 3-fold higher risk of AD dementia compared to the reference ?3 allele (P&lt;0.001). In conclusion, this is the first study to suggest that carriers of the APOE ?4 allele have a higher risk of developing dementia due to AD than those who carry the APOE ?3 allele in the Serbian population.

Relationship between Saturated Fatty Acid Intake and Blood Pressure in Healthy Japanese Women with the Fat Mass and Obesity-Associated Gene Variant.

Hypertension is one of the most prevalent diseases and a risk factor for stroke and cardiovascular disease. Our previous study indicated a negative correlation between fat intake and blood pressure in subjects with a fat mass and obesity-associated gene variant. We investigated the effects of four fatty acid groups on blood pressure in healthy Japanese women with the gene variants, including the involvement of body mass index. A total of 227 Japanese women aged 18-64 years completed a 3-day nutritional intake diary and their blood pressure was measured. The single nucleotide polymorphism rs9939609 of the gene was genotyped, and the participants were divided into two genetic groups (those with or without at least one minor allele). Spearman's rank correlation coefficient was applied to investigate the relationships between the fatty acids and blood pressure. A path analysis was performed to determine the effect of fatty acids on blood pressure including the involvement of body mass index. In the group with the gene variant, a significant negative correlation was detected between saturated fatty acid intake and systolic and diastolic blood pressures, and between monounsaturated fatty acid intake and only diastolic blood pressure. In a path analysis of both systolic and diastolic blood pressures, the path from only saturated fatty acid intake to blood pressure was significant, but the path from saturated fatty acids to body mass index was not significant. These results suggest that saturated fatty acid intake, without the involvement of body mass index, may be associated with the lower systolic and diastolic blood pressures in healthy Japanese women with a fat mass and obesity-associated gene variant.

Inverse Association of APOE ε4 and Glaucoma Modified by Systemic Hypertension: The Canadian Longitudinal Study on Aging.

Studies examining the apolipoprotein E (APOE) ε4 allele and glaucoma are inconsistent, which could be due to interactions with other factors. We examined the relationship between the APOE ε4 allele and glaucoma and intraocular pressure in a large, population-based random sample and explored whether the APOE ε4 allele interacted with systemic hypertension. Data came from the Canadian Longitudinal Study on Aging, a population-based study that included 24,655 adults ages 45 to 85 years old in the European ancestry cohort. APOE genotypes were derived from single-nucleotide polymorphisms rs429358 and rs7412. Participants were asked about a prior diagnosis of glaucoma from a doctor. Corneal compensated intraocular pressure (IOP) was measured using the Reichart Ocular Response Analyzer. Having an APOE ε4 allele was associated with a lower odds of glaucoma after adjusting for age, sex, IOP, and the top 10 population structure principal components (odds ratio [OR] = 0.83; 95% confidence interval [CI], 0.69-0.98; P = 0.033). A novel statistically significant interaction was found in that having an APOE ε4 allele was only associated with glaucoma in those without systemic hypertension (OR = 0.62; 95% CI, 0.46-0.85) although it was not associated in those with it (OR = 0.97; 95% CI, 0.79-1.21) (interaction term P value = 0.017). APOE ε4 was not associated with IOP (β = -0.01; 95% CI, -0.13 to 0.10). Evidence increasingly points to the APOE ε4 allele having protective benefits against glaucoma, but this association was limited to those without systemic hypertension. Further research is needed to understand the biological mechanisms for these findings and the treatment potential they hold.

Association between single nucleotide polymorphisms rs2200733 and rs10033464 at chromosome 4q25 and thyrotoxic atrial fibrillation

Background. Thyrotoxic atrial fibrillation (TAF) genesis does not exclude a genetic component due to the difference in thyroid hormones effects on the cardiovascular system in similar patients. According to genomewide association studies (GWAS), the first locus associated with non-thyrotoxic atrial fibrillation (AF) was locus 4q25, and the first single-nucleotide polymorphisms in it identified as risk factors for AF were polymorphisms rs2200733 and rs10033464. Their connection with TAF remains unclear.Objective. To investigate the possible association of the two single nucleotide polymorphisms rs2200733 and rs10033464 with TAF.Design and methods. The association of TAF and other thyrotoxic cardiomyopathy manifestations with the studied polymorphisms was examined in a sample of 150 patients with Graves’ disease and overt thyrotoxicosis, 18.7 % of whom had TAF. Genotyping was preformed using real time PCR.Results. A significant predominance of TT genotype for both polymorphisms was revealed: p=0.038 for rs10033464, p&lt;0.001 for rs2200733. TT genotype frequency in TAF patients compared with non-TAF participants: 7.4 % vs 1.6 % for rs10033464, 17.9 % vs 0.8 % for rs2200733. When assessing the frequency of genotypes depending on the presence of other thyrotoxic cardiomyopathy manifestations, TT genotype was more common in patients with ventricular premature beats, p=0.001.Conclusion. TT genotype of rs2200733 and rs10033464 polymorphisms at 4q25 locus is associated with a higher incidence of TAF and ventricular extrasystole in thyrotoxic patients.

Висока частота гомозиготного генотипу 472АА COMT (Val158) гена катехол-О-метилтрансферази (COMT) у дітей із синдромом подразненого кишечника

Following the biopsychosocial model of medicine, the pathophysiological basis of irritable bowel syndrome (IBS) is a combination of biological, psychoemotional, and psychosocial factors, the contribution of each of them to the development of this disorder remains unclear. Psychoemotinal factors, which are involved in the pathogenesis of IBS, are caused not only by the environment but also by the metabolism of catecholamines, particularly by the functional activity of catechol-O-methyltransferase (COMT). Purpose - to determine the role of Val158Met COMT polymorphism in development of IBS in children; to identify associations between genotype and clinical variant of the disorder and the nature of the provoking factor. Materials and methods. The material for the molecular genetic study were DNA samples obtained from nuclear cells of venous blood of 54 patients aged 6-12 years with diagnosed IBS. In 48 practically healthy children of the same age DNA samples were isolated from buccal epithelial cells. Molecular genetic study of single nucleotide polymorphism rs4680 of COMT gene was performed by polymerase chain reaction followed by analysis of restriction fragment length polymorphism. Microsoft Excel 2016 and GraphPad Prism 5 software were used for statistical analysis. Results. We have revealed significant differences in the distribution of Val158Met COMT genotypes in children with IBS in comparison with the control group. There was established that the 472GА COMT is more prevalent in healthy children and has a protective role in the development of IBS. In contrast, homozygous genotypes 472GG and 472AA, which are associated with changes in functional activity of enzyme COMT, may be considered as the risk factors for IBS (p≤0.0001). Conclusions. Genotype 472АА COMT was mostly detected in сhildren with stress-associated IBS, which is more related to dysnociception, disorders of cognition, and emotional disturbances. The higher prevalence of 472GA COMT heterozygotes among children with postinfectious IBS and IBS associated with antibiotic therapy indicates a less important role for the psychoemotional component and nociceptive disorders in the onset of this disorder (p=0.03). The research was carried out in accordance with the principles of the Helsinki Declaration. The study protocol was approved by the Local Ethics Committee of all participating institutions. The informed consent of the patient was obtained for conducting the studies. No conflict of interests was declared by the authors.

Association between risk polymorphisms for neurodegenerative diseases and cognition in colombian patients with frontotemporal dementia.

Frontotemporal dementia (FTD) is a heterogeneous neurodegenerative disease of presenile onset. A better characterization of neurodegenerative disorders has been sought by using tools such as genome-wide association studies (GWAS), where associations between single nucleotide polymorphisms (SNPs) and cognitive profiles could constitute predictive biomarkers for these diseases. However, in FTD, associations between genotypes and cognitive phenotypes are yet to be explored. Here, we evaluate a possible relationship between genetic variants and some cognitive functions in an FTD population.MethodologyA total of 47 SNPs in genes associated with neurodegenerative diseases were evaluated using the Sequenom MassARRAY platform along with their possible relationship with performance in neuropsychological tests in 105 Colombian patients diagnosed with FTD.Results and discussionThe SNPs rs429358 (APOE), rs1768208 (MOBP), and rs1411478 (STX6), were identified as risk factors for having a low cognitive performance in inhibitory control and phonological verbal fluency. Although the significance level was not enough to reach the corrected alpha for multiple comparison correction, our exploratory data may constitute a starting point for future studies of these SNPs and their relationship with cognitive performance in patients with a probable diagnosis of FTD. Further studies with an expansion of the sample size and a long-term design could help to explore the predictive nature of the potential associations we identified.

Association of SNPs in the FK-506 binding protein (FKBP5) gene among Han Chinese women with polycystic ovary syndrome

BackgroundPolycystic ovary syndrome (PCOS) is a common endocrine disorder in premenopausal women, whose etiology remains uncertain, although it is known to be highly heterogeneous and genetically complex. PCOS often presents with hyperandrogenism symptoms. The present study aimed to determine whether polymorphisms in the FK-506 binding protein 5 (FKBP5) gene (androgen target gene) are associated with an association for PCOS and hyperandrogenism.MethodsThis is a case–control study, and association analyses were conducted. A total of 13 single-nucleotide polymorphisms (SNPs) in the FKBP5 gene were evaluated in 775 PCOS patients who were diagnosed based on the Rotterdam Standard and 783 healthy Chinese Han women. Associations between FKBP5 SNPs and hormone levels were investigated. These 13 SNPs were genotyped using the Sequenom MassARRAY system, and an association analysis between the phenotype and alleles and genotypes were conducted.ResultsThe genotype frequencies for the rs1360780 and rs3800373 SNPs differed significantly between the PCOS cases and healthy controls (p = 0.025, OR is 1.63 (1.05–2.53) and p = 0.029, OR is 1.59 (1.03–2.45) respectively under co-dominant model). Moreover, the genotype frequencies and genetic model analysis for the SNPs rs1360780, rs9470080, rs9296158, rs1043805 and rs7757037 differed significantly between the hyperandrogenism and non-hyperandrogenism groups of PCOS patients. The TT genotype of rs1360780, the TT genotype of rs9470080, the TT genotype of rs1043805 or the GG genotype of rs7705037 (ORs are 2.13 (1.03–4.39), 1.81 (1.03–3.17), 2.94 (1.32–6.53) and 1.72 (1.04–2.84) respectively) were correlated with androgen level of PCOS patients.ConclusionOur study showed that FKBP5 gene polymorphisms are associated with PCOS generally (rs1360780 and rs3800373) and with the hyperandrogenism subtype specifically (rs1360780, rs9470080, rs9296158, rs1043805 and rs7757037).

Brain‐derived Neurotrophic Factor in Duchenne Muscular Dystrophy Myopathy

Brain‐derived neurotrophic factor (BDNF) and its receptor tropomyosin receptor kinase B (TrkB) are crucial for neuronal growth and survival, and loss of this signaling nexus invariably leads to neurodegeneration. In a small cohort of Duchenne muscular dystrophy (DMD) patients we found that BDNF blood levels positively correlated with better heart function, and carriers of the common BDNF single nucleotide polymorphism rs6265 (Val66‐Met) exhibited significantly worse skeletal muscle function and earlier loss of ambulation, compared to non‐carriers. We thus hypothesized that BDNF/TrkB signaling delays progression of myopathy in DMD. To test this hypothesis, we administered the TrkB agonist 7,8‐dihydroxyflavone (DHF) to mdx mice in their drinking water for 26 weeks, beginning at 8 weeks of age. Based on functional assessment using the hang test, DHF treatment preserved skeletal muscle function compared to vehicle‐treated controls. Trichrome staining of gastrocnemius and cardiac tissues also showed reduced levels of fibrosis, which correlated with BDNF expression levels. Using humanized BDNF polymorphic mice, which have the Val66‐Met mutation, and mice with a point mutation in the equivalent position of murine BDNF (Val68‐Met), we found that skeletal muscle strength was significantly reduced in mice with the Met allele, compared to Val/Val littermate controls. Although Val/Met and Met/Met mice weighed considerably more than control mice, they exhibited significantly increased activity, as measured by voluntary wheel running. Based on transmission electron microscopy, individual gastrocnemius muscle fibers of Met/Met mice were smaller and less organized compared to those of Val/Val. Finally, we crossed Val66‐Met mice with mdx mice to assess the effects of the BDNF polymorphism on the dystrophic background. As was found for DMD patients who harbor the BDNF rs6265 polymorphism, dystrophic mice with the Met allele exhibited worse skeletal muscle function compared to noncarriers. Considered together, our results indicate that BDNF plays a protective role in dystrophic muscle and might represent a novel therapeutic candidate for DMD myopathy.

Lack of association between fat mass and obesity-associated genetic variant (rs8050136) and type 2 diabetes mellitus.

Objectives:To study the genotype and allele frequency of the fat mass and obesity-associated (FTO) rs8050136 A>C genetic variant and investigate its association with type 2 diabetes mekkitus (T2DM) parameters.Methods:This study was carried out on 118 diabetic patients and 106 healthy individuals (control) from Prince Mohammed bin Abdulaziz Hospital, Al Madinah Al Munawarah, Saudi Arabia. The TaqMan single-nucleotide polymorphism (SNP)genotyping assay was used for rs8050136 genotyping.Results:The frequency of the genotype AA was the same among T2DM and healthy control groups (21%). However, the frequency of genotype CC was 19.5% in T2DM patients and 24.5% in control individuals. There was no significant association between FTO SNP rs8050136 and an increased risk of T2DM. Furthermore, there was no association between the risk AA genotype and fasting blood glucose (p=0.092), glycated hemoglobin (p=0.177), or body mass index (p=0.561).Conclusion:Our findings show that the FTO rs8050136 A>C variant is not associated with T2DM in the Saudi population.

Differential Effect of Fat Intake on Blood Pressure in Healthy Japanese Women with and without the Variant of Fat Mass and Obesity-Associated Gene.

A high-fat diet is believed to be a risk factor for hypertension through inducing obesity. It has been reported that variants of the fat mass and obesity-associated (FTO) and beta-3 adrenergic receptor (B3AR) genes are associated with obesity and blood pressure. The purpose of this study was to investigate the effect of dietary fat on blood pressure with or without the variant of the FTO and B3AR genes. A total of 227 healthy Japanese women aged 18 to 64 years were recruited for measurement of nutrient intake and blood pressure. The single nucleotide polymorphism rs9939609 of the FTO gene and rs4994 of the B3AR gene were genotyped. Spearman's rank correlation coefficient was applied to investigate the relationship between fat intake and blood pressure. A hierarchical multiple regression analysis was performed to determine whether the genotype interacts with fat intake to affect blood pressure. No significant correlations were found between fat intake and either systolic or diastolic blood pressure. A significant negative correlation was found between fat intake and both blood pressures in the FTO-gene-variant group, but not in the normal-FTO-gene group. In hierarchical multiple regression analysis, the interaction of fat intake and the gene variant showed significance, and the change in coefficient of determination (R 2) was significantly increased with increases of the interaction variable. These results indicate that the effect of fat intake on blood pressure may be modified by the variant of the FTO gene such that a high-fat diet intake may be associated with a decrease of systolic and diastolic blood pressure in healthy Japanese women with the FTO variant. Our results did not support the hypothesis that a high-fat diet increases blood pressure.

Epigenetic modifications of tumor necrosis factor-alpha in joint cartilage tissue from osteoarthritis patients - CONSORT.

Background:Osteoarthritis (OA) remains one of the most common osteopathy for centuries, which can be attributed to multiple risk factors including mechanical and biochemical ones. More and more studies verified that inflammatory cytokines play important roles in the progression of OA, such as tumor necrosis factor-alpha (TNF-α). In this study, we aimed to investigate the relationship between epigenetic manifestations of TNF-? and the pathogenesis of OA.Methods:Totally, 37 OA patients’ cartilage was collected through the knee joint and 13 samples of articular cartilage as healthy control was collected through traumatic amputation. Real-time PCR, Western blot and ELISA analysis were performed to observe the expression of target genes and proteins in collected samples.Results:Compared with the healthy control group, TNF-? was over-expressing in cartilage which was collected from OA patients. DNA hypomethylation, histone hyperacetylation and histone methylation were observed in the TNF-? promoter in OA compared with normal patients, and we also studied series of enzymes associated with epigenetics. The results showed that by increasing DNA methylation and decreasing histone acetylation in the TNF-? promoter, and TNF-? over-expression in OA cartilage was suppressed, histone methylation has no significant correlation with OA.Conclusion:In conclusion, the changes of epigenetic status regulate TNF-α expression in the cells, which are pivotal to the OA disease process. These results may give us a better understanding of OA and may provide new therapeutic options.