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.

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.

Targeting c-MET/HGF signaling pathway in upper gastrointestinal cancers: rationale and progress.

Aberrant activation of receptor-tyrosine kinase c-Met/HGF pathway is shown to be associated with cell proliferation, invasion, metastasis and poor-prognosis in several tumor types, including upper gastrointestinal-malignancies. The interaction of c-Met with multiple signalling-pathways involved in tumorigenic-properties and invasive-phenotype has gained substantial attention, suggesting its role as an intriguing-target for cancer-therapy. In recent years, there have been considerable efforts in the development of effective c-Met inhibitors with potential clinical-applications and one of them, crizotinib (dual c-Met/ALK inhibitor), has recently been approved for lung-cancers with ALKrearrangement. However several important questions remain to be answered on the molecular mechanisms underlying the antitumor effects of crizotinib, as well as on its possible role in the treatment of different tumor types, including uppergastrointestinal- cancers. The aim of this review is to give an overview on critical role of the c-Met/HGF pathway in cancer, and the preclinical/clinical studies on c-Met inhibitors. There are accumulating evidences on therapeutic potential of c-Met inhibitors for the treatment of other malignancies, such as gastric and pancreatic cancers. However, further investigations are needed to identify determinants of the activity of c-Met inhibitors, through the analysis of genetic/ environmental alterations affecting c-Met and parallel pro-cancer pathways; mechanisms result in developing resistance to anti-c-Met agents; and selection of patients that might benefit from therapy. These studies will be essential to improve the selectivity/efficacy of future anticancer strategies of c-Met targeted-therapies in the treatment of upper gastrointestinal- cancers.

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.