The roles of ANRIL polymorphisms in periodontitis: a systematic review and meta-analysis.

OBJECTIVES: The aim of this study is to investigate the potential role of ANRIL polymorphisms in susceptibility to periodontitis. METHODS: The authors searched Pubmed, Web of Science, and Scopus up to April 2021 to identify all published studies without any language restriction on the association between ANRIL and periodontitis. A meta-analysis of all ANRIL variants replicated by three or more studies was performed by testing multiple genetic models of association. Pooled odds ratios and 95% confidence intervals (CI) were used to estimate associations. Tests for sensitivity and publication bias were performed. RESULTS: Twenty-two variants in the ANRIL gene were examined for their potential association with the risk of periodontitis. However, only 4 (rs1333048, rs1333042, rs2891168, rs496892) are replicated at least three or more studies. The ANRIL rs1333048 was the most replicated polymorphisms with five articles, seven different populations comprising of 1331 cases, and 2624 controls. The pooled overall analysis showed that rs1333048, rs1333042, rs2891168, and rs496892 polymorphisms were associated with susceptibility to periodontitis in the whole population in allele contrast and dominant models. Moreover, similar to the overall analysis, rs1333048 polymorphism showed a significant association with grade C periodontitis (known as aggressive periodontitis in 1999 classification) in allele contrast (OR = 1.16) and dominant models (1.19). Interestingly, subgroup analysis also showed rs1333048 polymorphism might influence predisposition to a slowly progressive form of periodontitis (known as chronic periodontitis in 1999 classification). CONCLUSION: Our findings suggest that the ANRIL rs1333048, rs1333042, rs2891168, and rs496892 polymorphisms might influence predisposition to periodontitis, particularly in Caucasians. CLINICAL SIGNIFICANCE: ANRIL gene may represent a potential risk marker for periodontitis.

Xenobiotic/drug metabolizing enzyme and TP53 polymorphisms and clinical outcome in advanced nonsmall cell lung cancer patients.

BACKGROUND/AIM: The association between polymorphisms of xenobiotic/drug metabolizing enzymes and TP53 and response to chemotherapy and survival of patients with nonsmall cell lung cancer (NSCLC) are limited and inconclusive. In this study, CYP2E1*5B, CYP2E1*6, CYP2E1*7B, GSTO1 (A140D), and TP53 (Arg72Pro) polymorphisms and response to platinum-based chemotherapy and survival in 137 advanced stage NSCLC patients were investigated. MATERIALS AND METHODS: Genetic polymorphism analyses were determined by polymerase chain reaction (PCR) coupled with restriction fragment length polymorphism (RFLP). RESULTS: The patients with TP53 Pro/Pro variant were more likely to be resistant to chemotherapy than those with Arg/Arg variants with marginal significance (P = 0.066). We also analyzed these gene variants in combination with CYP1A1 (Ile462Val), CYP1B1 (Asn453Ser), GSTM1, GSTP1 exon 5 (Ile105Val), and GSTP1 exon 6 (Ala114Val) and GSTT1 polymorphic genes that we have previously genotyped in the same patients (Ada et al., Neoplasma, 57, 512-527, 2010). The multivariate analysis revealed that adjusted hazard ratio (HR) of death of the combined variant genotypes of TP53 (Arg72Pro, Pro72Pro) and CYP1A1 (Ile462Val, Val462Val) increased significantly as compared to wild-type genotypes (HR, 6.03; 95% CI, 1.39-26.04, P = 0.016). CONCLUSION: These results show that combined variant genotypes of TP53 (Arg72Pro, Pro72Pro) and CYP1A1 (Ile/Val, Val/Val) are associated with worsening of survival in NSCLC patients.

Polymorphisms and Protein Expressions of Glutathione S-Transferase M1 and T1 in Non-Small Cell Lung Cancer.

OBJECTIVES: The deletion polymorphisms of glutathione S-transferase (GST) GSTM1 and GSTT1 genes result in the absence of the corresponding protein, which decreases the detoxification of carcinogens. Studies evaluating polymorphisms and protein expressions in the same patients are limited. Therefore, in this study, we aimed to investigate the association between polymorphisms and protein expressions of GSTM1 and GSTT1 in lung tissues of patients with non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: For protein expression and gene deletion studies, tumor and surrounding tumor free (normal) tissue of 33 patients with NSCLC were used. In paraffin-embedded tissues, immunohistochemistry was used to detect protein expressions, and multiplex polymerase chain reaction amplification was used to identify gene deletions. RESULTS: GSTM1 and GSTT1 protein expressions were not detected in patients with GSTM1 and GSTT1 gene deletions, whereas protein expressions were detected in lung tissues of all patients carrying GSTM1 and GSTT1 genes. The protein expression level of GSTT1 was 2.0-fold higher in tumors of patients lacking GSTM1 genes than those with GSTM1 genes (p=0.018). Protein expression of GSTM1 was statistically higher in tumor tissues than in normal tissues of patients with GSTM1 genes (p=0.001). CONCLUSION: These results show that a) there is an association between gene deletions and protein expressions of GSTM1 and GSTT1 in patients with NSCLC, b) in the absence of GSTM1 genes, enhancement of expression of GSTT1 in tumors is likely to show that GSTT1 increases its capacity to detoxify the toxic electrophiles in tumors, and c) GSTM1 protein expression is higher in tumors compared with normal lung tissues of patients with NSCLC.

Cytochrome P-450 Polymorphisms and Clinical Outcome in Patients with Non-Small Cell Lung Cancer.

Lung cancer is an increasing worldwide public health problem. Most patients with lung cancer have non-small cell lung cancer (NSCLC). These patients are mainly treated with standard platinum-based chemotherapy. Poor response and great inter-individual variety in treatment response occurs among these patients. There is accumulating evidence to support the hypothesis that genetic polymorphisms alter the drug response and survival. Cytochrome P450 (CYP) enzymes metabolize antineoplastic drugs and are involved in drug resistance. Polymorphic CYPs have altered enzyme activities and thus they may influence the response to chemotherapy and survival in patients with lung cancer. In the current review, recent findings with respect to the role of mainly CYP1A1, CYP1B1, CYP2D6, CYP2E1 and CYP3A4 gene polymorphisms in response to chemotherapy and survival in patients with NSCLC have been provided, which could be useful for clinicians in the prognosis of these patients who are mainly treated with platinum-based chemotherapy.

Association between the TP53 and CYP2E1*5B gene polymorphisms and non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) is the most common form of lung cancer. Genetic polymorphisms in tumour suppressor genes and genes encoding xenobiotic metabolising enzymes alter the activity of their corresponding enzymes and are important individual susceptibility factors for NSCLC. Because of the lack of information in literature, the aim of our study was to investigate the role of the tumour suppressor gene TP53 (Arg72Pro) and the xenobiotic metabolising CYP2E1*5B gene polymorphisms on the risk of NSCLC development. The study population consisted of 172 patients and 172 controls (156 men and 16 women in each group). Genetic polymorphisms were determined with real-time polymerase chain reaction (PCR) and PCR restriction fragment length polymorphism (PCR-RFLP). Multivariate analysis showed a significant association with NSCLC for the combination between the TP53 codon72 Arg/Pro and the Pro/Pro genotypes (OR 2.21, 95 % CI 1.390-3.51; p=0.001). We also analysed whether combinations of these gene variants with GSTM1, GSTT1, GSTP1 exon 5 (Ile105Val), and GSTP1 exon 6 (Ala114Val) gene polymorphisms were associated with the NSCLC risk. A significant increase in the risk was observed for the following combinations: TP53 codon72 variant with GSTM1 null (OR 2.22, 95 % CI 1.23-4.04; p=0.009), GSTT1 null (OR 2.98, 95 % CI 1.49-5.94; p=0.002), and GSTP1 (Ala114Val) variant genotypes (OR 3.38, 95 % CI 1.54-7.41; p=0.002). Further studies with larger samples are needed to verify these findings.

Cytogenetic damage in Turkish coke oven workers exposed to polycyclic aromatic hydrocarbons: Association with CYP1A1, CYP1B1, EPHX1, GSTM1, GSTT1, and GSTP1 gene polymorphisms.

The aim of this study was to determine the frequencies of chromosomal aberrations (CA) and cytochalasin-blocked micronuclei (CBMN) in peripheral blood lymphocytes from Turkish coke oven workers and the influence of CYP1A1, CYP1B1, EPHX1, GSTM1, GSTT1, and GSTP1 gene polymorphisms on these biomarkers. Cytogenetic analysis showed that occupational exposure significantly increased the CA and CBMN frequencies. Gene polymorphisms, on the other hand, did not affect CA or CBMN in either exposed or control subjects. However, due to the limited sample size, our findings need to be verified in future studies with a larger sample.

Association between glutathione S-transferase omega 1 A140D polymorphism in the Turkish population and susceptibility to non-small cell lung cancer.

Recent years have seen a growing evidence of ethnic differences in the frequency of glutathione S-transferase omega 1 (GSTO1) A140D gene polymorphism, which is associated with various cancers such as breast and liver. Until now however, no association has been investigated between the GSTO1 A140D polymorphism and lung cancer. The aim of our study was to see if there was one in the Turkish population. To do that, we identified GSTO1 A140D polymorphism in 214 unrelated healthy individuals and 172 patients with non-small cell lung cancer (NSCLC) using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. The frequencies of A/A (wild type), A/D (heterozygous mutant), and D/D (homozygous mutant) GSTO1 A140D genotypes in healthy subjects were 48%, 41%, and 11%, respectively. In NSCLC patients they were 48%, 45%, and 7%, respectively. We found no significant association between the GSTO1 A140D gene polymorphism and NSCLC or its histological subtypes, namely squamous cell carcinoma or adenocarcinoma. Furthermore, this polymorphism did not correlate with smoking. Our study is the first to show that the frequency of GSTO1 A140D gene polymorphism in the Turkish population is similar to other Caucasian populations and that this polymorphism is not associated with susceptibility to NSCLC.

Cytochrome P450 (CYP) and glutathione S-transferases (GST) polymorphisms (CYP1A1, CYP1B1, GSTM1, GSTP1 and GSTT1) and urinary levels of 1-hydroxypyrene in Turkish coke oven workers

Genetic polymorphisms of xenobiotic metabolizing enzymes have been associated with cancer risk. We evaluated the influences of genetic polymorphisms of polycyclic aromatic hydrocarbon (PAH) metabolizing enzymes on urinary 1-hydroxypyrene (1-OHP) excretion in Turkish coke oven workers. Urinary 1-OHP was analyzed by HPLC after enzymatic hydrolysis. Lymphocyte DNA was used for PCR-based genotyping of cytochrome P450 (CYP) polymorphisms (CYP1A1 and CYP1B1) and glutathione S-transferases (GST) polymorphisms (GSTM1, GSTT1 and GSTP1). The mean urinary 1-OHP levels of coke oven workers were significantly higher than that of controls. No significant difference was detected in the mean urinary 1-OHP levels of smokers and non-smokers either for coke oven workers or controls. Genetic polymorphisms of the CYPs and GSTs studied had no significant influence on 1-OHP excretion in coke oven workers, but in the control group the urinary 1-OHP levels of individuals carrying the GSTT1- genotype were significantly higher than those of individuals carrying GSTT1+ genotype. The duration of occupational exposure and metabolic genotype for GSTT1 were the significant predictors of urinary 1-OHP levels. The control individuals carrying combined GSTM1-/GSTT1- genotypes also had significantly higher levels of urinary 1-OHP than those of individuals carrying GSTM1+/GSTTI+, GSTM1-/GSTT1+, and GSTM1+/GSTT1- genotypes. These results indicate that urinary 1-OHP is a sensitive indicator of recent human exposure to PAHs and that genetic polymorphism of GSTT1 may also to some extent reflect the interindividual variation in susceptibility to PAHs only at low PAH exposure.