Association of Intelectin 1 Gene rs2274907 A > T Polymorphism with Obesity, Type 2 Diabetes, Serum Intelectin-1 Levels and Lipid Profiles in Turkish Adults.

The anti-inflammatory adipokine intelectin-1, which is encoded by the ITLN1 gene, is hypothesized to be linked to the pathogenesis of type 2 diabetes (T2DM) and obesity. The purpose of this study was to examine the effect of the ITLN1 gene polymorphism rs2274907 on obesity and T2DM in Turkish adults. The impact of genotype on lipid profiles and serum intelectin levels in the obese and diabetes groups was also investigated. Randomly selected 2266 adults (mean age, 55.0 ± 11.7 years; 51.2% women) participating in the population-based Turkish adult risk factor study were cross-sectionally analyzed. The genotyping of rs2274907 A > T polymorphism was performed by using the hybridization probe based LightSNiP assay in real-time PCR. T2DM were defined using the criteria of the American Diabetes Association. Obesity was described as Body mass index ≥ 30 kg/m2. Statistical analyses were used to investigate the association of genotypes with clinical and biochemical measurements. According to findings, there was no vital connection between the rs2274907 polymorphism and obesity, T2DM, or serum intelectin-1 level. The TA+AA carriers had significantly higher triglyceride levels (p = 0.007) compared with the TT carriers in both obese and T2DM women when adjusted for relevant covariates. ITLN1 rs2274907 polymorphism is not correlated with the risk of obesity and T2DM and not affect serum ITLN1 levels in Turkish adults. However, this polymorphism appears to be important in regulating triglyceride levels in obese and diabetic women.

Cholesterol-related gene variants are associated with diabetes in coronary artery disease patients.

Coronary artery disease (CAD) which is a complex cardiovascular disease is the leading cause of death worldwide. The changing prevalence of the disease in different ethnic groups pointing out the genetic background of CAD. In this study, we aimed to evaluate the contribution of selected cholesterol metabolism-related gene polymorphisms to CAD presence. A total of 493 individuals who underwent coronary angiography were divided into 2 groups: normal coronary arteries (≤ 30% stenosis) and critical disease (≥ 50% stenosis). Individuals were genotyped for APOC1 (rs11568822), APOD (rs1568565), LIPA (rs13500), SORL1 (rs2282649), and LDLR (rs5930) polymorphisms using hydrolysis probes in Real-Time PCR. Blood samples were drawn before coronary angiography and biochemical analyses were done. The results were statistically evaluated. When the study group was stratified according to CAD, the minor allele of APOD polymorphism was found related to decreased risk for T2DM in the non-CAD group. In logistic regression analysis adjusted for several confounders, LDLR rs5930 polymorphism was found associated with T2DM presence in the male CAD group [OR = 0.502, 95%CI (0.259-0.974), p = 0.042]. Besides, APOD and LIPA polymorphisms were shown to affect serum lipid levels in non-CAD T2DM patients (p < 0.05). The minor allele of APOC1 was found associated with triglyceride levels in males independent of CAD status. Besides, LDLR minor allele carrier females had elevated HbA1c and glucose levels independent from CAD status in the whole group. The cholesterol metabolism-related gene polymorphisms were found associated with T2DM and biochemical parameters stratified to sex, CAD, and T2DM status.

Peripheral TREM2 mRNA levels in early and late-onset Alzheimer disease's patients.

'Triggering receptor expressed on myeloid cells 2' (TREM2) gene is involved in Alzheimer's disease (AD) and TREM2 mRNA expression is known to be increased in the peripheral blood cells of AD patients. In this study, we examined the expression levels of TREM2 mRNA in peripheral leukocytes of early and late-onset AD patients. We have also investigated the effect of the presence of APOE ε4 allele on TREM2 expression. TREM2 mRNA expression was analyzed in 30 early-onset AD (EOAD) patients, 38 late-onset AD (LOAD) patients, and in their age-matched controls by using quantitative real-time polymerase chain reaction. TREM2 levels in LOAD patients were higher than EOAD. Also, in elderly controls significantly higher TREM2 levels were found compared with young controls. Moreover, APOE ε4 carriers in LOAD patients exhibited significantly higher TREM2 expression levels than APOE ε4 non-carriers and elderly controls. Also, correlation analysis showed that TREM2 mRNA expression was increased by age. The differential expression of TREM2 mRNA levels between EOAD and LOAD patients might be independent of the AD disease status and results from an age-related increase in TREM2 expression. In LOAD patients, increased age and the presence of APOE ε4 allele further increase TREM2 expression. Taken together, we can suggest that age is a factor that increases TREM2 expression, and TREM2 and APOE ε4 may interact together in the pathogenesis of LOAD.

The rs2175898 Polymorphism in the ESR1 Gene has a Significant Sex-Specific Effect on Obesity.

Polymorphisms in the ESR1 gene have been associated with obesity and lipid metabolism. There are also important sex-related differences in the prevalence of obesity and related phenotypes. Therefore, we aimed to interrogate the association of the ESR1 rs2175898 gene polymorphism with obesity, obesity-related variables, and lipid levels in men and women as separate groups. Two thousand twenty-two randomly selected middle-aged and elderly Turks were genotyped for ESR1 rs2175898 polymorphism using real-time polymerase chain reaction with hybridization probes. We found sex-related differences of the ESR1 rs2175898 polymorphism in obesity. Logistic regression analysis after adjustment for age, smoking status, physical activity, diabetes mellitus, and the presence of menopause status in women demonstrated significantly decreased risk for obesity in female AG genotype carriers (OR 0.69; 95% CI 0.52-0.91; p = 0.010), and in male GG genotype carriers (OR 0.49; 95% CI 0.25-0.96; p = 0.039), Furthermore, carriers of the rs2175898 G allele exhibited a lower body mass index in both sexes and decreased waist circumference in women but not in men. Our findings also showed significantly higher serum total-C levels (p = 0.007) in the carriers of the AG+GG/AG genotype compared with the AA genotype in men. The AG genotype of the ESR1 rs2175898 polymorphism in women and GG genotype in men were found to have a decreased likelihood for obesity compared with the other rs2175898 genotypes.

Loss of VPS13C Function in Autosomal-Recessive Parkinsonism Causes Mitochondrial Dysfunction and Increases PINK1/Parkin-Dependent Mitophagy.

Autosomal-recessive early-onset parkinsonism is clinically and genetically heterogeneous. The genetic causes of approximately 50% of autosomal-recessive early-onset forms of Parkinson disease (PD) remain to be elucidated. Homozygozity mapping and exome sequencing in 62 isolated individuals with early-onset parkinsonism and confirmed consanguinity followed by data mining in the exomes of 1,348 PD-affected individuals identified, in three isolated subjects, homozygous or compound heterozygous truncating mutations in vacuolar protein sorting 13C (VPS13C). VPS13C mutations are associated with a distinct form of early-onset parkinsonism characterized by rapid and severe disease progression and early cognitive decline; the pathological features were striking and reminiscent of diffuse Lewy body disease. In cell models, VPS13C partly localized to the outer membrane of mitochondria. Silencing of VPS13C was associated with lower mitochondrial membrane potential, mitochondrial fragmentation, increased respiration rates, exacerbated PINK1/Parkin-dependent mitophagy, and transcriptional upregulation of PARK2 in response to mitochondrial damage. This work suggests that loss of function of VPS13C is a cause of autosomal-recessive early-onset parkinsonism with a distinctive phenotype of rapid and severe progression.

Association between selected cholesterol-related gene polymorphisms and Alzheimer's disease in a Turkish cohort.

Numerous genetic evidence has pointed out that variations in cholesterol-related genes may be associated with an Alzheimer's disease (AD) risk. We aimed to investigate the association between polymorphisms in several cholesterol-related genes [APOA5 (rs662799), APOC1 (rs11568822), APOD (rs1568565), CH25H (rs13500), LDLR (rs5930), SORL1 (rs2282649)] and AD in a cohort of Turkish patients. The study group consisted of 257 AD patients (mean age: 75.9 years ± 10.4) and 414 controls (mean age: 62.2 years ± 13.1). Genotyping was performed by quantitative real-time polymerase chain reaction using hydrolysis probes. Our results showed that the 'TT' genotype of CH25H rs13500 polymorphism was significantly more frequent in the AD group (p < 0.001) and individuals carrying the CH25H 'T' allele had an increased risk for AD (OR 3.07, 95% CI 2.13-4.44, p = 2.20e-09) independently from age, gender and APOE ε4 allele. Moreover, this risk was excessively increased (OR 14.04, 95% CI 6.99-28.23, p = 9.78e-14) in the presence of APOE ε4 allele. The 'ins/ins' genotype of APOC1 rs11568822 was significantly more frequent in the AD group compared to controls (p = 1.95e-08). However, this increased AD risk in 'ins/ins' carriers was found to be dependent on their APOE ε4 carrier status. No significant associations were found in allele and genotype distributions of APOA5, APOD, LDLR and SORL1 gene polymorphisms. Our results suggest that the association between APOC1 'ins/ins' genotype and AD risk can be explained by linkage disequilibrium with the APOE locus. CH25H rs13500 polymorphism is associated with an AD risk in the Turkish population and CH25H might have a role in the pathogenesis of AD together with, and independently from APOE.

HPCA confirmed as a genetic cause of DYT2-like dystonia phenotype.

BACKGROUND: HPCA (hippocalcin) is one of the underlying genetic causes of autosomal-recessively inherited forms of dystonia. Here, we describe two consanguineous Turkish DYT-HPCA families carrying the novel HPCA mutations. METHODS: After detailed clinical and neurological examination, whole-exome sequencing was performed. RESULTS: Whole-exome sequencing analysis revealed two homozygous novel truncating mutations (p.W103* and p.P10PfsTer80) in the HPCA gene in two unrelated Turkish dystonia families presenting with complex dystonia. CONCLUSIONS: After identification of HPCA as a genetic cause of DYT-HPCA-like dystonia by Charlesworth et al, this is the second report in the scientific literature that describes dystonia families harboring HPCA mutations. Our findings confirm that HPCA leads to recessively inherited dystonia. © 2018 International Parkinson and Movement Disorder Society.

Identification of potential target genes of ROR-alpha in THP1 and HUVEC cell lines.

ROR-alpha is a nuclear receptor, activity of which can be modulated by natural or synthetic ligands. Due to its possible involvement in, and potential therapeutic target for atherosclerosis, we aimed to identify ROR-alpha target genes in monocytic and endothelial cell lines. We performed chromatin immunoprecipitation (ChIP) followed by tiling array (ChIP-on-chip) for ROR-alpha in monocytic cell line THP1 and endothelial cell line HUVEC. Following bioinformatic analysis of the array data, we tested four candidate genes in terms of dependence of their expression level on ligand-mediated ROR-alpha activity, and two of them in terms of promoter occupancy by ROR-alpha. Bioinformatic analyses of ChIP-on-chip data suggested that ROR-alpha binds to genomic regions near the transcription start site (TSS) of more than 3000 genes in THP1 and HUVEC. Potential ROR-alpha target genes in both cell types seem to be involved mainly in membrane receptor activity, signal transduction and ion transport. While SPP1 and IKBKA were shown to be direct target genes of ROR-alpha in THP1 monocytes, inflammation related gene HMOX1 and heat shock protein gene HSPA8 were shown to be potential target genes of ROR-alpha. Our results suggest that ROR-alpha may regulate signaling receptor activity, and transmembrane transport activity through its potential target genes. ROR-alpha seems also to play role in cellular sensitivity to environmental substances like arsenite and chloroprene. Although, the expression analyses have shown that synthetic ROR-alpha ligands can modulate some of potential ROR-alpha target genes, functional significance of ligand-dependent modulation of gene expression needs to be confirmed with further analyses.

CYP19A1, MIF and ABCA1 genes are targets of the RORα in monocyte and endothelial cells.

RORα is a member of nuclear receptor superfamily of transcription factors, which has a vital role in the regulation of various physiological processes. Cholesterol is a known ligand of RORα and is one of the key components that take part in cardiovascular diseases such as atherosclerosis. Therefore, it is possible that RORα might have a role in the development of atherosclerosis. To test this hypothesis, we investigated the presence of novel RORα response elements (ROREs) located in the promoter of CYP19A1, MIF and ABCA1 genes. Briefly, the occupancy of RORα in the promoter regions of these genes was demonstrated in THP-1 and HUVEC cell lines by ChIP analysis. In order to modulate RORα activity, THP-1 and HUVEC cells were treated with specific RORα ligands (CPG 52608 and SR1001) and then the expression levels of target genes were analysed. In the next step, we tested whether RORα activity in THP-1 macrophages was influenced by the presence of simvastatin, a cholesterol lowering drug. We found that in the presence of simvastatin the expression of the investigated target genes were down regulated and that this regulation was partially prevented by CPG 52608 and SR1001. Results of this study suggest that CYP19A1, MIF and ABCA1 are the direct target genes of RORα. In conclusion, it is important to demonstrate that certain genes involved in the development of atherosclerosis could be modulated by an inducible transcription factor. Therefore, these results offer a potential therapeutic approach for the treatment of atherosclerosis.

Risk of obesity and metabolic syndrome associated with FTO gene variants discloses clinically relevant gender difference among Turks.

Gene variations in the fat mass- and obesity-associated gene (FTO) have shown controversial associations with obesity and metabolic syndrome (MetS) in several populations. We explored the association of FTO gene with obesity, MetS, and insulin-related parameters separately in men and women. Two SNPs in the FTO, gene rs9939609 and rs1421085, were genotyped by the Taqman System in 1967 adults (mean age of the whole group 50.1 ± 12.0; 48.4 % male). A random sample of the Turkish Adult Risk Factor cohort was cross-sectionally analyzed. Both SNPs exhibited strong linkage disequilibrium (r(2) = 0.85) and minor alleles were associated with risk of obesity in women and of MetS in men. Carriers of the rs1421085 C-allele exhibited higher body mass index (BMI) in each gender. Adjusted fasting insulin and HOMA index were significantly higher in C-allele carriers in men alone. Logistic regression analysis demonstrated significantly increased likelihood for obesity in female C-risk allele carriers (OR 1.61; 95 % CI 1.19-2.18), after adjustment for age, smoking status, alcohol usage, physical activity grade and presence of diabetes mellitus. Male C-allele carriers were at increased risk for MetS (OR 1.44; 95 % CI 1.07-1.95), adjusted for age, smoking status, alcohol consumption, and physical activity. Further adjustment for BMI attenuated the MetS risk, indicating interaction between C-allele, gender and BMI. The FTO gene in Turkish adults contributes independently to obesity in women and-by interacting with BMI-to MetS and insulin resistance in men.

A new F-box protein 7 gene mutation causing typical Parkinson's disease.

BACKGROUND: Recessive mutations in the F-box protein 7 gene (FBXO7; PARK15) have been identified as a cause of the parkinsonian-pyramidal syndrome. Here, we report clinical and genetic findings in a Turkish family with novel FBXO7 mutations. METHODS: Whole exome and targeted Sanger sequencing were performed for genetic analysis in a family with two members affected by Parkinson's disease (PD). All family members underwent detailed clinical, mental, and neurological examination. RESULTS: The new p.L34R (c.101 T>G) FBXO7 mutation was detected in a homozygous state in two Turkish sibs with typical levodopa-responsive PD. CONCLUSION: This is the first time a FBXO7 mutation has been identified that causes a phenotype compatible with typical idiopathic PD and presents with some of its common nonmotor features, such as rapid eye movement sleep behavior disorder, depression, and anxiety.

Prevalence of Prader-Willi syndrome among infants with hypotonia.

OBJECTIVE: To investigate the prevalence of Prader-Willi syndrome (PWS) in infants with hypotonia between the ages of 0 and 2 years. STUDY DESIGN: Karyotyping studies were performed in all infants with hypotonia. The study group was composed of infants with hypotonia for whom the karyotyping was found to be normal. Fluorescence in situ hybridization and methylation analysis were performed simultaneously in the study group. Molecular studies for uniparental disomy were undertaken in the patients without deletions with an abnormal methylation pattern. RESULTS: Sixty-five infants with hypotonia with a mean age of 8 months were enrolled. A deletion was detected in 6 patients by fluorescence in situ hybridization analysis. Only 1 patient had no deletion but had an abnormal methylation pattern. A maternal uniparental disomy was observed in this patient. PWS was diagnosed in 10.7 % (7/65) of the infants with hypotonia. CONCLUSION: The prevalence of PWS syndrome is high among infants with hypotonia. PWS should be considered by pediatricians and neonatologists in the differential diagnosis of all newborns with hypotonia. Early diagnosis of PWS is important for the management of these patients.

Negative results in screening for possible new sequence variations on ATP-binding cassette transporter A1 gene in Turkish adults with metabolic syndrome.

OBJECTIVES: ATP binding cassette transporter A1 (ABCA1) plays a pivotal role in the reverse cholesterol transport. Some mutations in the ABCA1 gene have correlation with changes in serum high-density lipoprotein-cholesterol (HDL-C) and other lipids concentrations. The role of genetic factors in susceptibility to metabolic syndrome (MetS) is not clear. The aim of this study was to explore the relationship between ABCA1 gene and the MetS. STUDY DESIGN: Therefore, to investigate probable new mutations in the functional regions of the ABCA1 gene, 14th, 19th and 49th exons were analyzed using single strand conformational polymorphism method in 220 subjects, 110 of whom had MetS, selected from the Turkish Adults Risk Factor study. RESULTS: No significant relationship was found between the functional region of ABCA1 and MetS. The risk for low HDL-C-high triglyceride levels and MetS are not associated with selected functional regions of the gene, 14th, 19th and 49th exons, which code for the first extracellular loop, the nucleotide binding domain and the C-terminal region, respectively. CONCLUSION: These data indicate that the mutations and polymorphisms in ABCA1 gene are not associated with MetS in Turks.

Isolation and analysis of genes mainly expressed in adult mouse heart using subtractive hybridization cDNA library.

Subtractive hybridization cDNA library (SHL) is one of the powerful approaches for isolating differentially expressed genes. Using this technique between mouse heart and skeletal muscle (skm) tissues, we aimed to construct a cDNA-library that was specific to heart tissue and to identify the potential candidate genes that might be responsible for the development of cardiac diseases or related pathophysiological conditions. In the first step of the study, we created a cDNA-library between mouse heart and skm tissues. The homologies of the randomly selected 215 clones were analyzed and then classified by function. A total of 146 genes were analyzed for their expression profiles in the heart and skm tissues in published mouse microarray dataset. In the second step, we analyzed the expression patterns of the selected genes by Northern blot and RNA in situ hybridization (RISH). In Northern blot analyses, the expression levels of Myl3, Myl2, Mfn2, Dcn, Pdlim4, mt-Co3, mt-Co1, Atpase6 and Tsc22d1 genes were higher in heart than skm. For first time with this study, expression patterns of Pdlim4 and Tsc22d1 genes in mouse heart and skm were shown by RISH. In the last step, 43 genes in this library were identified to have relationships mostly with cardiac diseases and/or related phenotypes. This is the first study reporting differentially expressed genes in healthy mouse heart using SHL technique. This study confirms our hypothesis that tissue-specific genes are most likely to have a disease association, if they possess mutations.

Minor allele of the APOA4 gene T347S polymorphism predisposes to obesity in postmenopausal Turkish women.

The aim of this study was to examine the relationship between APOA4 gene T347S polymorphism with obesity measures and serum lipids in Turkish adults. Randomly selected sample of 1,554 adults (754 men, mean age 50.4 ± 11.9 years and 800 women, mean age 49.6 ± 11.8 years) were included in the study. 346 Women (43.2 %) were postmenopausal. Genotyping was performed by using hybridization probes in real-time PCR. Not men but postmenopausal women, carrying the S347 allele, were associated with 1.5 kg/m(2) higher BMI (P = 0.016) and 3.6 cm wider waist circumference (P = 0.005) than postmenopausal T347 homozygotes, controlled for covariates. Logistic regression analyses of this polymorphism, adjusted for age, fasting triglyceride, smoking status, alcohol consumption and physical activity disclosed the rare allele to be associated with obesity in postmenopausal women at an odds of 1.80 (95 % CI 1.09-2.97; P = 0.021). Serum apoB level was lower in S347 allele carriers (110.9 ± 2.9 mg/dL) than in T347 homozygotes (119.0 ± 2.4 mg/dL; P = 0.035) in men but not women. APOA4 T347S polymorphism was unrelated to lipids and other lipoproteins in either gender. The APOA4 S347 allele predisposes to obesity and high waist circumference in Turkish postmenopausal women. ApoB levels are lower only in men in S347 allele carriers.

Association of polymorphisms in the sex hormone genes with the presence and severity of coronary artery disease.

OBJECTIVE: Coronary artery disease (CAD) is an important public health problem worldwide. Therefore, it is important to identify the molecular mechanisms and the candidate gene polymorphisms involved in the development of CAD. In this study, we focused on 2 polymorphisms of the atherosclerosis-related genes, ESR1 and CYP19A1. METHODS: Unselected 339 individuals who underwent coronary angiography were divided into 2 groups: those with normal coronary arteries (≤30% stenosis) and those with critical disease (≥50% stenosis). Individuals were genotyped for CYP19A1 rs10046 C/T and ESR1 rs2175898 A/G polymorphisms using hybridization probes in real-time PCR. In addition, Gensini and SYNTAX scores were assessed. RESULTS: ESR1 polymorphism was significantly associated with CAD in men (p=0.036) via G allele carriage. Multiple logistic regression analyses showed that ESR1 rare allele carriage was associated with CAD presence (Odds ratio=2.12, 95% confidence interval 1.01-4.1, p=0.025), adjusted for age, HDL-C, LDL-C and smoking status in the male group. CYP19A1 rs10046 T allele carriers had a 2.84-fold increased risk for complex CAD in multiple logistic regression analysis (p=0.016). Furthermore, the univariate analysis of variance indicated that T allele carriage of rs10046 polymorphism was associated with increased SYNTAX and Gensini scores (p<0.05). Female patients who were ESR1 G allele carriers with CAD had higher adiponectin levels (p=0.005), whereas HbA1c levels were associated with T allele of CYP19A1 in the CAD group (p=0.004) and male CAD group (p=0.018). CONCLUSION: The CYP19A1 and ESR1 polymorphisms were associated with the presence and severity of CAD. These gene polymorphisms warrant further studies for the elucidation of their contribution to CAD development.

Examining the effects of the CLU and APOE polymorphisms' combination on coronary artery disease complexed with type 2 diabetes mellitus.

AIMS: Coronary artery disease (CAD) and type 2 diabetes mellitus (T2DM) are important and increasing public health problems. This study aimed to identify the impact of APOE and CLU gene polymorphisms on the prevalence of both diseases, along with the effect of these polymorphisms on lipid profile and glucose metabolism. METHODS: 736 CAD patients (≥50 stenosis) and 549 non-CAD subjects (≤30 stenosis) were genotyped for APOE (rs429358 and rs7412) and CLU (rs11136000) gene polymorphisms using hydrolysis probes in real-time PCR. Blood samples of the individuals were drawn before coronary angiography and biochemical analyses were done. The associations between the polymorphisms and the selected parameters were assessed using statistical analysis. RESULTS: In this study, the ε2 and ε4 isoforms of apoE were associated with serum lipid levels and TC/HDL-C and LDL-C/HDL-C ratios in analysis adjusted for several confounders and in crude analysis. It was observed that CLU T allele carrier non-CAD subjects had lower glycosylated hemoglobin levels. Furthermore, the effects of APOE and CLU polymorphisms were assessed on CAD and T2DM presence. In crude and multiple logistic regression analyses, the ε2 isoform carriers had a lower risk for CAD complexed with T2DM. When the combinational effects of APOE and CLU polymorphisms were examined, the ε2 and T allele carriers had decreased risk for CAD complexed with T2DM compared to non-carriers. CONCLUSIONS: In conclusion, the combination of APOE and CLU polymorphisms is associated with CAD-DM status along with the APOE ε2 isoform by itself, and the apoE isoforms are strongly associated with serum lipid levels.

Gender- and obesity-specific effect of apolipoprotein C3 gene (APOC3) -482C>T polymorphism on triglyceride concentration in Turkish adults.

BACKGROUND: Apolipoprotein C3 (APOC3) gene polymorphisms are associated with cardiometabolic risk factors, varying in ethnicities. This study aimed to investigate such association between the APOC3 -482C>T polymorphism and cardiometabolic risk factors in the turkish adult risk factor (TARF) study cohort, stratifying by gender and obesity. METHODS: Randomly selected 1548 individuals (757 male and 791 female, mean age 49.9±11.8 years) were genotyped for -482C>T polymorphism using hybridization probes in a Real-Time PCR LC480 device. RESULTS: The -482TT genotype prevailed 9.9% in men and 11.5% in women. Association between 482C>T polymorphism and dyslipidemia (p=0.036, OR=1.42, 95%Cl=1.02-1.97) was found only in men. Analysis of variance showed that anthropometric and metabolic variables were not differently distributed in APOC3 -482C>T genotypes in the study population. In relation to dyslipidemia and obesity, the -482C>T polymorphism showed significant gender-by-genotype interactions (p<0.01). When the study population was stratified according to gender and obesity, homozygotes for the T allele were associated strongly with (by 45%) elevated fasting triglyceride concentrations in obese men (p=0.009) and homeostatic model assessment (HOMA) index in non-obese women (p=0.013). Furthermore, in the same subgroups, the associations of the fasting triglyceride concentrations and HOMA index with the TT genotype remained after adjustment for risk factors (p<0.05). CONCLUSIONS: APOC3 -482TT genotype is independently associated with elevated fasting triglyceride concentrations in obese men. Presence of obesity seems to be required for this genotype to induce markedly elevated triglycerides. Furthermore, it is associated with the dyslipidemia in men, without requirement of obesity.

Niemann-Pick type C fibroblasts have a distinct microRNA profile related to lipid metabolism and certain cellular components.

MicroRNAs (miRNAs) are non-coding RNAs that regulate gene expression at post-transcriptional level. Dysregulation of miRNA expression may lead to severe pathophysiologies in human cells. Niemann-Pick type C (NPC) disease is a complex lipid storage disease characterized by late endosomal-lysosomal accumulation of multiple lipid molecules. Our aim was to characterize the miRNA profile in NPC fibroblasts as they may play an active role in the NPC disease associated changes in the cellular physiology. To investigate the miRNA expression, total RNAs were isolated from cultured human NPC fibroblasts and healthy fibroblasts and then, TaqMan Low-Density Array system containing 365 mature human miRNAs was used. Expression differences between the healthy and NPC cells were detected according to the relative quantification values. Target genes were predicted by using three different algorithms and classified regarding NPC related biological processes and cellular components. We found that three miRNAs, miR-196a, miR-196b and miR-296 were up-regulated (>3.5-fold increase, p<0.05) whereas 38 miRNAs were significantly down-regulated in NPC cells (>3.5-fold decrease, p<0.05). Among these non-coding RNAs, miR-98 was the most down-regulated (-33.3-fold) miRNA and miR-143, the lipid biosynthesis associated miRNA, had a 20-fold decreased expression in the NPC cells. Additionally, gene ontology analyses of the target genes suggested a distinct role for each miRNA. Our results show that NPC fibroblasts have an altered miRNA expression profile and certain miRNAs have importance in disease pathogenesis as well as the therapeutic capacity to correct lipid related pathophysiologies in the NPC cells.

Pretreatment with octreotide modulates iNOS gene expression, mimics surgical delay, and improves flap survival.

We aimed to evaluate the role of a synthetic somatostatin analogue in delay procedure of experimental skin flaps. Thirty-six rats were randomly divided into 2 groups of 18 each to compare the possible local ischemic effect of octreotide with that of surgical delay in the dorsal random pattern skin flap model. The inducible nitric oxide synthase gene expression was assessed in the flap territory at intervals of immediate, 24 and 48 hours after preconditioning. Histologic analysis was performed in rats at 48th hour and 3 additional rats were used for microangiography. A gradual increase of daily transcript levels was detected in both groups (P < 0.05). The differences of molecular and histologic findings between the groups were not distinctive. Pharmacologically preconditioned rat displayed relevant microvascular features. Forty rats were further grouped randomly into 4 groups of 10 each. In group 1 rats, flaps were raised and reinserted without any prior intervention. Group 2 rats underwent surgical delay procedure, whereas flap territories of the others received either saline solution or octreotide 1 week before the ultimate flap harvest. After another 7-day period, both delay procedures were found effective in improving flap viability (P < 0.01). Ischemia induced by octreotide favored to investigate its utility in delay phenomenon. Although it was not as effective as the surgical delay procedure, it may be a safe pharmacologic alternative to improve the flap survival.