Effects of Gly71Arg mutation in UGT1A1 gene on neonatal hyperbilirubinemia: a systematic review and meta-analysis.

OBJECTIVE: The associations between Gly71Arg polymorphism in the coding region of uridine diphosphate glucuronosyl transferase 1A1 (UGT1A1) gene and the risk of neonatal hyperbilirubinemia remained controversial. Therefore, a meta-analysis of observational studies has been conducted to assess the relationship between UGT1A1 gene polymorphism of Gly71Arg and neonatal hyperbilirubinemia susceptibility. METHODS: An electronic literature search from online databases, such as PubMed, Embase, Cochrane, and Scopus was conducted to identify eligible studies. The effect summary odds ratio (OR) with 95% confidence interval (CI) was used to estimate the strength of association in the fixed or random effects model, based on the absence or presence of heterogeneity. RESULTS: A total of 32 eligible studies involving 2634 cases of neonatal hyperbilirubinemia and 4996 controls were enrolled in this meta-analysis. The combined results showed that UGT1A1 Gly71Arg polymorphism was associated with an increased risk of neonatal hyperbilirubinemia in all genetic models (homozygote model: OR = 6.12, 95% CI = 4.42-8.46; heterozygote model: OR = 2.06, 95% CI = 1.82-2.33; dominant model: OR = 2.44, 95% CI = 2.03-2.93; recessive model: OR = 4.79, 95% CI = 3.48-6.59, and allelic model: OR = 2.37, 95% CI = 1.98-2.82). Subgroup analysis by ethnicity strongly validated this correlation in Asians but slightly in Caucasian population. CONCLUSIONS: This meta-analysis confirms that UGT1A1 Gly71Arg polymorphism significantly increases the risk of neonatal hyperbilirubinemia in Asian population, but results from the Caucasians were conflicting and further well-designed epidemiological studies are, therefore, required to more adequately assess this correlation.

Clinicopathological and prognostic value of lncRNA PANDAR expression in solid tumors: Evidence from a systematic review and meta-analysis.

PANDAR (promoter of CDKN1A antisense DNA damage activated RNA) has been shown to be aberrantly expressed in many types of cancer. Considering conflicting data, the current study was aimed to assess its potential role as a prognostic marker in malignant tumors. A comprehensive literature search of PubMed, Medline, and Web of Science was performed to identify all eligible studies describing the use of PANDAR as a prognostic factor for different types of cancer. Data related to overall survival (OS) and clinicopathologic features were collected and analyzed. The pooled hazard ratio (HR) and odds radio (OR) with a 95% confidence interval (CI) were used to estimate associations. Ten original studies containing 1,231 patients were included. The results showed that in patients with cancer, high PANDAR expression is correlated with lymph node metastasis (LNM; OR = 2.57; 95% CI, 1.76-3.81; p < 0.001), tumor stage (OR = 2.90; 95% CI, 1.25-6.75; p = 0.013), and tumor size (OR = 1.79; 95% CI, 1.11-2.91; p = 0.018). However, sensitivity analysis further demonstrated a significant association between high PANDAR expression and OS, both in multivariate and univariate analysis models (pooled HR 2.01; 95% CI, 1.17-3.44 and pooled HR 2.62; 95% CI, 1.98-3.47, respectively), after omitting one study. These results suggested that PANDAR expression might be indicative of advanced disease and poor prognosis in patients with cancer. Further studies are necessary to determine the value of this risk stratification biomarker in clinical management of patients with cancer.

MIR196A2 rs11614913 contributes to susceptibility to colorectal cancer in Iranian population: A multi-center case-control study and meta-analysis.

Maturation of MIR196A2 as a gene regulator with a high potential for targeted cancer therapy can be modulated by the rs11614913 polymorphism. Several studies evaluating the association between this variant and pathogenesis of colorectal cancer (CRC) found significant results in various ethnic groups. This study aimed at investigating this relationship in a large sample size of Iranians as well as in a systematic review and meta-analysis of the pooled data of the current study with previous reports from Iran and other populations. After extraction of genomic DNA from the formalin-fixed paraffin-embedded tissues and whole blood of 2150 subjects (42% CRC patients), the rs11614913 was genotyped in both cases and controls. Furthermore, we conducted a meta-analysis of the present case-control study together with a previous report from Iranian population. The results of case-control study identified significant association between the rs11614913 and susceptibility to CRC [TT vs. CC: 1.58 (1.26-1.98), p < 0.01; TT vs. CT: 3.94 (3.07-5.05), p < 0.01; TT vs. CC + CT: 0.70 (0.59-0.83), p < 0.01; and CT + TT vs. CC: 1.43 (1.21-1.70), p < 0.01]. After correction of the meta-analysis results by using Bonferroni protocol, no significant association was observed in overall and in Asians [T vs. C: 1.19 (1.00-1.43), p = 0.05 and 1.14 (0.83-1.56), p = 0.43, respectively], whereas association was significant in Caucasians [T vs. C: 1.14 (1.04-1.25), p = 0.004] influenced by the data from Iran [T vs. C: 1.15 (1.03-1.29), p = 0.02 and TT vs. CC + CT: 0.73 (0.60-0.87), p = 0.003]. In conclusion, MIR196A2 rs11614913 might play a potential role in the pathogenesis of CRC in Iranian population.

Lack of association of CASC8 rs1447295 with colorectal cancer in Iranian population: A multicenter case-control study.

Several studies reported the potential role of the rs1447295 polymorphism in susceptibility to cancer. This variant located in the cancer susceptibility candidate 8 (CASC8) is a long noncoding RNA (lnRNA) gene and does not code protein. LnRNA transcripts play a potential regulatory role in the expression of key genes involved in multiple cellular pathways, including cell cycle, pluripotency, and immune response. The aim of this study is to evaluate this association with colorectal cancer (CRC) in a large case-control study of the Iranian population. After extraction of genomic DNA by the standard protocols, the rs1447295 was genotyped in 2416 subjects (46% patients). Results of this case-control demonstrated no significant association between the rs1447295 polymorphism and risk of CRC or its characteristics under allele or alternative genotype models. In conclusion, it is unlikely that the rs1447295 polymorphism is a risk variant for the development of CRC in Iranian population.

MTRR rs1801394 and its interaction with MTHFR rs1801133 in colorectal cancer: a case-control study and meta-analysis.

AIM: This study aims to evaluate the association between the MTRR rs1801394 alone or in interaction with the MTHFR rs1801133 and susceptibility to colorectal cancer (CRC) and its characteristics in Iranian population. Additionally, both a systematic review and meta-analysis were performed to derive a more precise assessment of this association. MATERIALS & METHODS: Genomic DNA of 2332 subjects was genotyped for rs1801394. These data were pooled with 17 eligible studies for meta-analysis. RESULTS: No significant association was found between the rs1801394 or rs1801394-rs1801133 and CRC risk. Meta-analysis results also demonstrated no significant relationship between the rs1801394 and CRC risk. CONCLUSION: Results of this study showed that the rs1801394 alone or together with the rs1801133 is not a risk factor for CRC in Iranian population.

MTHFR rs1801133 polymorphism and susceptibility to colorectal cancer in Iranian population: evidence of a case-control study and meta-analysis.

Several studies have investigated whether MTHFR rs1801133 polymorphism contributes to risk of colorectal cancer (CRC), however the results are inconclusive. AIM: The purpose of this study was to investigate this hypothesis in a case-control study and meta-analysis in Iranian population. MATERIALS & METHODS: This polymorphism was genotyped in the 2421 subjects (46% CRC patients) from Tehran. Meta-analysis was performed for determining the risk effect size of this polymorphism on CRC. RESULTS: Both case-control study and meta-analysis showed no association between rs1801133 and CRC risk or its features. CONCLUSION: This study failed to identify an association between the rs1801133 and susceptibility to CRC in Iranian population.

KCNJ11: Genetic Polymorphisms and Risk of Diabetes Mellitus.

Diabetes mellitus (DM) is a major worldwide health problem and its prevalence has been rapidly increasing in the last century. It is caused by defects in insulin secretion or insulin action or both, leading to hyperglycemia. Of the various types of DM, type 2 occurs most frequently. Multiple genes and their interactions are involved in the insulin secretion pathway. Insulin secretion is mediated through the ATP-sensitive potassium (KATP) channel in pancreatic beta cells. This channel is a heteromeric protein, composed of four inward-rectifier potassium ion channel (Kir6.2) tetramers, which form the pore of the KATP channel, as well as sulfonylurea receptor 1 subunits surrounding the pore. Kir6.2 is encoded by the potassium inwardly rectifying channel, subfamily J, member 11 (KCNJ11) gene, a member of the potassium channel genes. Numerous studies have reported the involvement of single nucleotide polymorphisms of the KCNJ11 gene and their interactions in the susceptibility to DM. This review discusses the current evidence for the contribution of common KCNJ11 genetic variants to the development of DM. Future studies should concentrate on understanding the exact role played by these risk variants in the development of DM.

Evaluation of association studies and meta-analyses of MTHFR gene polymorphisms in colorectal cancer.

There is a discrepancy between the results of 89 original studies and 15 meta-analyses investigating the association of MTHFR rs1801133 and rs1801131 polymorphisms with colorectal cancer (CRC) risk. We examined this hypothesis through meta-analyses of both loci and their diplotypes as well as evaluation of previous meta-analyses. The present meta-analysis showed that rs1801133 and rs1801131 might be CRC susceptibility variants in Americans and Australians and rs1801133 in Brazilians and Japanese. A strong linkage disequilibrium was observed between both loci and their diplotypes were associated with CRC risk. Evaluation of 15 meta-analyses showed a high discrepancy among their findings, mainly caused by population stratification of original studies and data analysis strategies in meta-analysis. Population stratification was more dominant in the studies from Australia, America and Brazil leading to false positive or negative results. In conclusion, these loci alone might modify the development of CRC in some ethnicities.

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.

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 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.

OPRM1 rs1799971 polymorphism and opioid dependence: evidence from a meta-analysis.

The OPRM1 gene encodes the µ-opioid receptor, which is the primary site of action of most opioids. Several studies and three meta-analyses have examined a possible link between the exonic OPRM1 A118G (rs1799971) polymorphism and opioid dependence; however, results have been inconclusive. Therefore, a systematic review and meta-analysis have been carried out to examine whether this polymorphism is associated with opioid dependence. Thirteen studies (n = 9385), comprising 4601 opioid dependents and 4784 controls, which evaluated association of the OPRM1 rs1799971 polymorphism with susceptibility to opioids, were included in this study. Our meta-analysis showed significant association between this polymorphism and susceptibility to opioid dependence in overall studies under a codominant model, as well as susceptibility to opioid dependence or heroin dependence in Asians under an autosomal dominant model. The nonsynonymous OPRM1 rs1799971 might be a risk factor for addiction to opioids or heroin in an Asian 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.

Association of 8q24.21 loci with the risk of colorectal cancer: a systematic review and meta-analysis.

BACKGROUND AND AIM: Recent genome-wide association studies of colorectal cancer (CRC) have identified rs6983267 and trs10505477 polymorphisms as key loci in the 8q24 region to be associated with CRC. In the present study, we performed a meta-analysis to determine whether these loci are risk factors for susceptibility to CRC. METHODS: We meta-analyzed the 22 included studies (47 003 cases and 45 754 controls) that evaluated the association of rs6983267 and trs10505477 with CRC under alternative genetic models. RESULTS: A meta-analysis of the pooled data showed allelic and genotypic association of the rs6983267 polymorphism with CRC risk in Asians, Europeans, and European-Americans. A subanalysis of the US studies showed negative results in the studies with non-identified ethnicity of the patients. A meta-analysis of included studies of rs10505477 polymorphisms identified allelic and genotypic associations with CRC risk in the US patients. A further meta-analysis of the US studies demonstrated positive results in the studies with non-identified ethnicity of the samples. CONCLUSION: Our data suggested that the rs6983267 G > T polymorphism is a risk factor for CRC in Asians, Europeans, and Americans with European ancestry.