Association of Interleukin-10 -592 C > A gene polymorphism with coronary artery disease: A case-control study and meta-analysis.

BACKGROUND: Coronary-artery-disease (CAD) is the leading cause of death worldwide, and hence there is a need to identify reliable markers for identifying individuals at high risk of developing CAD. Interleukin-10 (IL-10) is an anti-inflammatory cytokine that is associated with an increased risk of developing both atherosclerosis and acute coronary events. The study aimed to explore the association of a genetic variant in IL-10 with the risk of developing CAD and the severity of the disease. To further explore, a systematic review and meta-analysis was performed. The cumulative results of the relationship between IL and 10 -592 C > A polymorphism and CAD in Iranian population have also been presented. METHODS: In this cross sectional study, a total of 948 individuals including 307 healthy controls and 641 patients that among cases, four hundred and fifty-five of the patients had > 50% stenosis (angiogram positive group) and 186 patients had < 50% stenosis (angiogram negative group) were recruited from the Mashhad-Stroke and Heart-Atherosclerotic-Disorders cohort. Genotyping for the IL-10 -592 C > A polymorphism was performed using a PCR-RFLP technique, and statistical analysis undertaken by univariate and multivariate analyses. PubMed, Google Scholar and Scopus were searched for papers related to this polymorphism up to October 2019. The Meta-analysiswas done based on the random effect model using a Meta-analysis. RESULTS: In our study, the frequency of the variant A allele of the IL-10 -592 C > A was significantly higher in CAD patients than the control group (P value = 0.043). Moreover, subjects carrying AA genotype had a significantly higher risk of CAD (OR: 1.8, 95%CI: 1.04-3.16), p = 0.03), compared to those with the wild type genotype. The results of meta-analysis of 9336 cases and 8461 controls did not also show any significant association between IL and 10 -592 C > A and CAD in dominant and recessive genetic models but only in co-dominant model when fix effect was applied. CONCLUSION: Although our research findings support a significant association of genetic polymorphism in the IL10 gene with cardiovascular diseases, this finding cannot be confirmed in meta-analysis. Further functional analysis and evaluation of this marker in a multicenter setting are needed to establish its value as a risk stratification marker.

Association of neuropeptide Y gene rs16147 polymorphism with metabolic syndrome in patients with documented coronary artery disease.

BACKGROUND AND AIMS: There have been few epidemiological studies that have investigated genetic susceptibility to cardiovascular risk associated with the prevalence of metabolic syndrome (MetS). Neuropeptide Y (NPY) is a strong candidate gene for coronary artery disease (CAD). Therefore, the aim of this study was to investigate the association between the NPY gene rs16147 polymorphism and the presence of MetS in a well defined group of Iranian subjects with angiographically-defined CAD. METHODS: A cross-sectional study design was used in which a total of 364 patients were recruited; 143 patients with MetS and 221 without MetS were genotyped using the ARMS-PCR technique. Logistic regression analyses were performed to determine the odds ratios (ORs) for the association of specific genotypes with the presence of MetS and related phenotypes. RESULTS: The frequency of the variant G allele of the NPY gene was significantly higher in CAD patients without MetS (p = 0.032). Compared to the AA genotype of the NPY gene, individuals carrying the GG genotype had a reduced risk of MetS (OR = 0.51, 95% CI = 0.27-0.95, p = 0.034). CONCLUSION: The rs16147 polymorphism may be associated with presence of MetS among subjects with documented CAD. Carriage of NPY A allele in patients with CAD is associated with a higher prevalence of MetS.

Associations between C1431T and Pro12Ala variants of PPARγ gene and their haplotypes with susceptibility to metabolic syndrome in an Iranian population.

Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear hormone receptor that regulates a number of genes involved in lipid and carbohydrate metabolism. The aim of this study was to investigate the association of C1431T and Pro12Ala polymorphisms of PPARγ gene and their haplotypes and diplotypes with risk of metabolic syndrome (MetS) in an Iranian population. A total of 340 unrelated Iranian subjects, including 175 MetS patients and 165 normal controls were enrolled. Each group was then divided into two subgroups according to the genotype (Pro/Pro and Pro/Ala+Ala/Ala for Pro12Ala, CC and CT+TT for C1431T). Genotypes were determined using a TaqMan method. Anthropometric indices, fasting plasma glucose and fasting lipid profile were measured by routine methods. A significant difference in the frequencies of the C1431T genotypes was observed between MetS and control subjects (P=0.014), whereas no association was found for the Pro12Ala. The T allele carriers had a significantly increased risk of MetS compared to the CC genotype (P=0.016) even after correction for multiple-testing and adjustment for age, sex and genotype. The T allele may therefore be considered as a risk factor for MetS (P=0.003). Analysis of combined groups showed that X/Ala-CC and Pro/Pro-X/T diplotypes were associated with a higher body weight, waist circumference and waist to hip ratio among the individuals with MetS. Moreover the Ala-T haplotype was weakly associated with a higher level of triglyceride and lower level of HDL, suggesting the possibility of an interaction between Ala and T alleles. This study suggests that the PPARγ C1431T polymorphism is related to an increased risk of MetS in an Iranian population and interacts with the Pro12Ala polymorphism, further increasing the risk of MetS.

Lack of an association between a functional polymorphism in the neuropeptide Y gene promoter and the presence of coronary artery disease in an Iranian population.

BACKGROUND/AIMS: Several genetic factors have been identified that may contribute to the risk of coronary artery disease (CAD). Variants of the neuropeptide Y (NPY) gene, whose products play an important role in regulating several physiological functions, have been associated with the risk of CAD in some populations. The purpose of this study was to investigate the relationship between the NPY gene rs16147 polymorphism and the presence of CAD in an Iranian population. METHODS: DNA samples of 922 subjects, including 433 with angiographically defined CAD (CAD+), 196 without angiographically defined significant CAD (CAD-) and 293 controls, were genotyped using polymerase chain reaction based on the amplification-refractory mutation system. Logistic regression analyses were performed to assess the association of rs16147 genotypes with the presence of significant CAD. RESULTS: Although logistic regression analysis indicated that the NPY polymorphism rs16147 was nominally associated with an increased risk of CAD (p < 0.05), after adjustment for confounding factors, there was no evidence for any significantly increased or decreased risk of CAD with this polymorphism. However, in stratified analyses, the C allele was significantly associated with a reduced risk of CAD in males and subjects who were <50 years of age. CONCLUSIONS: This study suggests that the rs16147 polymorphism in the NPY gene may not be a potential contributor to the risk of CAD in an Iranian population.

Association of LXRα polymorphisms with obesity and obesity-related phenotypes in an Iranian population.

BACKGROUND: Obesity is a multifactorial disorder due to the complex interaction between genetic and environmental factors. Liver X receptor alpha (LXRα), encoded by the gene NR1H3, is involved in lipoprotein metabolism and its genetic variations may also play a role in the aetiology of obesity. AIM: To assess the association of two NR1H3 polymorphisms (rs11039155 and rs2279238) and their haplotypes with obesity in an Iranian population. SUBJECTS AND METHODS: A total of 447 unrelated subjects (including 206 overweight, 162 obese and 79 controls) were enrolled in the study and were genotyped by TaqMan assay using DNA from peripheral blood. The association of these two LXRα polymorphisms with the presence of obesity and overweight was assessed. RESULTS: There was no significant association between the two SNPs and obesity, even after adjustment for age and sex. By logistic regression using a dominant model, the odds ratios for obesity were: 1.32 (0.85-2.74) for rs11039155 and 0.77 (0.30--1.99) for rs2279238. Haplotype analyses identified three common haplotypes GC, GT and AC with frequency greater than 1%, but none of the haplotypes was associated with the risk of obesity. CONCLUSIONS: This study revealed that there was no significant association between LXRα polymorphisms and the presence of obesity in an Iranian population and suggests that these two SNPs are not major contributors to obesity risk in this population.

Distribution and genotype frequency of the C1431T and pro12ala polymorphisms of the peroxisome proliferator activator receptor gamma gene in an Iranian population.

BACKGROUND: Peroxisome proliferator activator receptor gamma (PPARγ) is a nuclear transcription factor regulating multiple genes involved in cell growth, differentiation, carbohydrate and lipid metabolism and energy production. Several genetic variations in the PPARγ gene have been identified to be associated with diabetes, obesity, dyslipidemia, insulin resistance, metabolic syndrome and coronary artery disease. The present study was designed to explore the distribution of two common single nucleotide polymorphisms of the PPARγ gene (C1431T and Pro12Ala) in an Iranian population. MATERIALS AND METHODS: Genotype frequencies for these two polymorphisms were compared for 160 healthy Iranian individuals with reports from other populations. The Genotyping was performed using real-time polymerase chain reaction. RESULTS: The genotype distribution of the C1431T PPARγ polymorphism was 0.869 for the CC genotype, 0.119 for the CT genotype and 0.013 for uncommon TT genotype. Allelic frequencies were 0.93 for C and 0.07 for T allele respectively. For the Pro12Ala polymorphism of PPARγ gene, genotypic distributions and allelic frequencies were, 0.813 for CC, 0.181 for CG and 0.06 for GG and 0.903 for C and 0.097 for G respectively. Allelic and genotypic frequencies for both polymorphisms of PPARγ gene were in Hardy-Weinberg equilibrium. CONCLUSIONS: Iran is a country with an ethnically diverse population and a comparison of allelic and genotypic frequencies of PPARγ C1431T and Pro12Ala polymorphisms between our population and others showed significant differences.

Partially folded conformations of bovine liver glutamate dehydrogenase induced by mild acidic conditions.

The acid-induced unfolding of bovine liver glutamate dehydrogenase (GDH) was studied using various spectroscopic methods such as far- and near-UV circular dichroism (CD), intrinsic and 1-anilino naphthalene-8-sulphonate (ANS) extrinsic fluorescence spectroscopy, light scattering and fluorescence quenching in 20 mM mixed buffer at various pHs. CD spectra show that at pH 3.5, GDH retains its secondary structure substantially, whereas its tertiary structure content is reduced considerably. Intrinsic fluorescence of GDH and ANS binding suggest that, at pH 3.5, the hydrophobic surface of enzyme is more exposed in comparison to the native form. Acrylamide quenching indicates more exposure of tryptophan residues of enzyme at pH 3.5 in comparison to pH 7.5. Another partially unfolded intermediate was detected at pH 5.0, which with its ANS binding capacity lies between the pH 3.5 intermediate and the native form of the enzyme. Gel filtration results revealed that the enzyme at pH 3.5 is dissociated into trimeric species whereas it exists as hexamer at pH 7.5 and 5.0. All the data taken together suggest the existence of two partially unfolded states of GDH at moderate acidic pHs which may be considered as molten and pre-molten globule-like states.

An imbalance in serum concentrations of inflammatory and anti-inflammatory cytokines in hypertension.

Hypertension is an important risk factor for cardiovascular disease and there is increasing evidence that inflammation and abnormal immune responses are involved in the pathogenesis of hypertension. However, the data on the association between specific cytokine concentrations and hypertension are inconsistent. We have evaluated the association between 12 cytokines/growth factors and the presence of different degrees of hypertension, comparing these concentrations to values in a healthy group of subjects. The concentrations of interleukin (IL)-1α, -1ß, -2, -4, -6, -8, -10, tumor necrosis factor (TNF-α), interferon-γ (IFN-γ), monocyte chemoattractant protein (MCP-1), epidermal growth factor, and vascular endothelial growth factor were measured in 155 hypertensive patients and 148 healthy subjects, using EV-3513 cytokine biochip arrays, a competitive chemiluminescence immunoassay. Univariate and multivariate analyses were used to evaluate the association of specific cytokines and growth factors with systolic blood pressure (SBP) and diastolic blood pressure (DBP). Hypertensive subjects had higher serum concentrations of IL-1α, -2, -8, vascular endothelial growth factor, IFN-γ, TNF-α, MCP-1, and epidermal growth factor; and lower concentrations of anti-inflammatory cytokine, IL-10 (P < .05), compared with the healthy individuals. The serum concentrations of IL-4, -6, and -1ß did not differ between the hypertensive subjects and control group. Univariate and multivariate analyses revealed that IL-1α and IFN-γ were independent predictors of a high SBP, while IFN-γ, IL-1α, TNF-α, and MCP-1 remained statistically significant for DBP after correction for age, gender, Body mass index, smoking, fasting blood glucose, and triglycerides. There was a significant association between the concentrations of several cytokines and hypertension. These associations may either be related to common underlying factors that cause hypertension and may also be proinflammatory or because these inflammatory cytokines might directly be involved in the etiology of hypertension.

Association of 8q24.21 rs10505477-rs6983267 haplotype and age at diagnosis of colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) is the fourth most common cause of cancer death in the world. Genetic variants in 8q24.21 including rs10505477 and rs6983267 have been hypothesized to be involved in susceptibility to CRC. This study aims to investigate the possible association between these loci and their haplotypes with CRC risk in Iranian population. MATERIALS AND METHODS: Subjects were recruited from two hospitals in Tehran. The rs10505477 and rs6983267 polymorphisms were genotyped by TaqMan real time PCR using subject genomic DNA, extracted either from formalin-fixed, paraffin-embedded tissue of patients or from blood of the controls by standard methods. RESULTS: A total of 715 subjects (380 CRC patients and 335 matched controls) were genotyped in this study. Allele and genotype analysis of the rs10505477 and rs6983267 polymorphisms by gender, age at diagnosis, tumor location, tumor grade, and tumor node metastasis (TNM) showed no significant association with CRC risk. There was a significant relationship between GG haplotype and susceptibility to age at diagnosis for both <60 and ≥60 (p=0.0005 and p=0.000004, respectively) and between GT and CRC in the age at diagnosis ≥ 60 (Table 3: p=0.031). The GG haplotype was less frequent in CRC patients with the age at diagnosis <60, but was more common in subjects with the age at diagnosis ≥ 60. CONCLUSIONS: Results of this study suggests that the rs6983267 and rs10505477 polymorphisms alone may not be relevant to CRC risk, but their GG haplotype plays a notable role in age at diagnosis of CRC in the Iranian population.

Lack of association between LXRα and LXRß gene polymorphisms and prevalence of metabolic syndrome: a case-control study of an Iranian population.

The metabolic syndrome (MetS) is considered to be a major risk factor for type 2 diabetes mellitus and cardiovascular diseases. It is characterized by central adiposity, high blood pressure, glucose intolerance and abnormalities of lipoprotein metabolism. The cause of MetS is likely to be due to a complex interaction between genetic and environmental factors. Liver X receptors alpha (NR1H3) and beta (NR1H2) play a key role in lipid and carbohydrate metabolism. The aim of this study was to investigate the contribution of genetic polymorphisms in the LXRs to risk of MetS and related traits. Two common SNPs in NR1H3 (rs11039155 and rs2279238) and in NR1H2 (rs17373080 and rs2695121) were genotyped using TaqMan assays in MetS patients (n=265) and controls (n=219). Logistic regression analyses were performed to calculate the odds ratios (ORs) as a measure of association of genotypes with the presence of MetS and related phenotypes. Although The NR1H2 polymorphism rs2695121 was nominally associated with MetS but correction for multiple-testing and adjustment for age, sex and number of MetS criteria, failed to identify any significant interactions associated with prevalence of MetS. However in the haplotype analysis, a LXRα haplotype AC, was more common in controls and was associated with a significant protective effect for MetS (OR [95% CI]=0.25 [0.07-0.88], p=0.031). In conclusion, this study suggests that the above-named variants in LXRα and LXRß genes are not potential contributors to the risk of MetS and related traits in an Iranian population.