Genetic Polymorphisms of Xenobiotic Metabolizing Genes (GSTM1, GSTT1, GSTP1), Gene-Gene Interaction with Association to Lung Cancer Risk in North India; A Case Control Study

Aim: In this case control study involving, 220 human subjects; polymorphisms in xenobiotic metabolizing genes (GST-M1, -T1 and -P1) and their association to lung cancer risk is being analysed among smokers and non-smokers. GSTM1 or GSTT1 gene polymorphism and amino acid changes in GSTP1 have been correlated and may be associated to lung cancer risk. Other factor includes exposure to environmental pollutants and life style choices. We have explored gene-gene and gene-environment interaction in the aetiology of lung cancer risk among north Indian population. Patients and Methods: For the study we have collected 120 lung cancer patient blood samples from Kamala Nehru Memorial Cancer Hospital, Allahabad, Uttar Pradesh and 100 matched controls. DNA was isolated and GST-M1 and - T1 genotyping were assessed by multiplex PCR whereas the GSTP1 polymorphism was analysed using restriction fragment length polymorphism. The risk of lung carcinogenesis was assessed using logistic regression analysis calculating the odd ratio (OR) with 95% confidence interval (CI). Results: The risk of lung carcinogenesis was three fold higher for null GSTT1 (OR=3.045, 95%CI=1.750-5.301, p-value <0.001) genotype; whereas other two types; GSTM1 (OR= 1.342, 95% CI=0.788-2.284, p-value=0.270) and GSTP1 (OR=0.806, 95% CI=0.526-1.236, p-value=0.323) showed no association to lung cancer susceptibility respectively. Smokers diagnosed with lung cancer had more null genotypes for GSTT1 (OR=4.773, 95%CI=1.939-11.751, p<0.001). The ‘at risk’ genotype combination GSTM1 (null) /GSTT1 (null) (OR=1.76, 95%CI; 0.920-3.370, p-value=0.03) showed increased susceptibility to lung cancer risk. The genotype combination of GSTT1 (null)/GSTP1 (Ile/Ile) (p=0.009) was associated with increased lung cancer risk. Conclusion: The results of this study suggest that; GSTT1 null genotype were more susceptible for lung cancer risk and smoking increases the susceptibility for lung cancer several folds among the North Indian population. Gene-gene interaction for null genotypes of GSTM1 and GSTT1 were correlated with higher risk of having lung cancer.     

Association of PON2 and PON3 polymorphism with risk of developing cataract

PurposeParaoxonases (PON) are calcium bound enzymes offering protection against oxidative stress by working as endogenous free-radical scavenging molecules. Oxidative stress has been implicated in pathophysiology of many diseases including cataract. Lens opacity is an age related disorder which is a principal cause of blindness in Pakistani population. Relationship of PON2 and PON3 polymorphism with genetic predisposition for incidence of cataract has not been investigated till date. Objective of the current study was to explore possible association between PON2 and PON3 polymorphism with incidence of cataract in local population.MethodsOur study design comprised of fifty-one cataractous and fifty-nine healthy individuals. Identification of single nucleotide polymorphism (SNP) at positions (C311S and G148A) for PON2 and C133A for PON3 was conducted using restriction fragment length polymorphism (RFLP).ResultsStatistical analysis revealed significant association of PON2 G148 allele with incidence of cataract. GG allele was found to be higher in cataract patients as compared to control (p < 0.001) suggesting distribution of PON2 G148A genotype and allele frequency is linked with cataractogenesis. There was no noticeable association between PON2 C311S and PON3 C133A. Significant difference was observed in distribution of 311CS/148A combined genotype with highest frequency in control individuals (88.89%), while 311S/148G combined genotypes showed the highest frequencies among the cataract patients (71.42%).ConclusionOur data suggests mutation at G148A might be related with incidence of cataract in studied population.     

Association of ACE I/D and AGTR1 A1166C Gene Polymorphisms and Risk of Uterine Leiomyoma: A Case-Control Study

Objective: Uterine leiomyoma (UL) can be considered as the most common benign gynecological tumors of the smooth muscle cells in the myometrium. They are likely to be associated with infertility and recurrent abortion as well as obstructed labor and post-partum hemorrhage. Moreover, altered vascular-related genes can be linked to developing leiomyoma. Polymorphisms of the angiotensin-converting enzyme (ACE) gene are associated with some vascular diseases. The present study was carried out to investigate the association of ACE I/D and AGTR1 A1166C gene polymorphisms and the risk of uterine leiomyoma in a sample of Iranian population. Methods: The study was carried out on a total of 413 women divided into 202 patients with diagnosed uterine leiomyomas and a control group of 211. Genotyping was performed using the PCR or PCR-RFLP methods. Results: The ID and DD genotypes of ACE I/D polymorphism were associated with 2 and 2.9 fold higher risk of UL compared to II genotype (OR, 2 [95% CI, 1.3 to 3.2]; P = 0.004 and OR, 2.9 [95% CI, 1.6 to 5]; P = 0.0002). The frequencies of ACE D alleles were 53.7% in women with UL and 40.3% in controls, which were observed to be statistically different (P < 0.0001). The alleles and genotypes of AGTR1 A1166C polymorphism were not different between UL and control women (P=0.9). Conclusion: The ACE ID and DD genotypes were associated with a higher risk of UL. No relationship was found between AGTR1 A1166C polymorphism and UL.     

Carcinogen Metabolism Pathway and Tumor Suppressor Gene Polymorphisms and Gallbladder Cancer Risk in North Indians: A Hospital-Based Case-Control Study

Background: Carcinogen metabolism pathway and tumor suppressor gene polymorphisms have been reported to be associated with increased gallbladder cancer risk. However, the association of genetic variants and gallbladder cancer risk in Indians are not well studied. We examined whether genetic polymorphisms of metabolic enzymes cytochrome P450 1A1 and glutathione S-transferase and tumor suppressor gene p53 (TP53) are associated with an increased risk of gallbladder cancer in North Indians. Methods: This hospital-based case-control study was conducted in 96 gallbladder cancer patients with gallstones (cases) and 93 cholelithiasis patients (controls) at the Sanjay Gandhi Postgraduate Institute of Medical Sciences in Lucknow, India from July 2014 through May 2017. Genomic DNA was extracted from white blood cells of each patient using a simple salting-out procedure. The genotypic frequencies of CYP1A1 rs4646903, CYP1A1 rs1048943, and TP53 rs1042522 polymorphisms were investigated using TaqMan SNP Genotyping Assay and GSTM1 and GSTT1 polymorphisms were analyzed using the multiplex PCR assay. Results: The frequency of CC genotype of TP53 rs1042522 polymorphism was 27.1% (26/96) in cases and 12.9% (12/93) in controls. The CC genotype was associated with an increased risk of gallbladder cancer in North Indians (age- and sex-adjusted odds ratio, 2.81; 95% confidence interval, 1.19–6.61; P = 0.02). No significant differences in genotypic and allelic frequencies of the metabolic pathway gene polymorphisms were found between cases and controls. Conclusions: Our data provide preliminary evidence that the CC genotype of the TP53 rs1042522 polymorphism may be associated with an increased risk of gallbladder cancer in North Indians.     

Association of IL-12B rs3212227 and IL-6 rs1800795 Polymorphisms with Susceptibility to Cervical Cancer: A Systematic Review and Meta-Analysis

Background: Primary studies have shown that the IL-12B rs3212227 and IL-6 rs1800795 polymorphisms are associated with an increased risk of cervical cancer. However, conflicting results warrant a meta-analysis to obtain more precise estimates. Methods: A comprehensive literate search on PubMed, Web of Science, Scopus, CNKI, and SciELO was performed to collect all eligible studies up to November 10, 2019. The pooled odds ratios (OR) and 95% confidence intervals (CI) were used to calculate the risk. This meta-analysis was carried out by utilizing CMA software. Results: A total of eleven case-control studies including four studies on IL-12B rs3212227 and seven studies on IL-6 rs1800795 were selected. Pooled ORs revealed that the IL-6 rs1800795 polymorphism was significantly associated with an increased risk of cervical cancer (C vs. G: OR = 1.294, 95% CI 1.071-1.564, p= 0.007; CC vs. GG: OR = 1.633, 95% CI 1.059-2.520, p= 0.027; CC+CG vs. GG: OR = 1.312, 95% CI 1.048-1.643, p= 0.018; and CC vs. CG+GG: OR = 1.592, 95% CI 1.268-1.999, p≤0.001), but not IL-12B rs3212227 polymorphism. Stratified analysis by ethnicity revealed that both IL-12B rs3212227 and IL-6 rs1800795 polymorphisms were associated with risk of cervical cancer in Asian women. Conclusions: Our pooled data revealed that the IL-12B rs3212227 and IL-6 rs1800795 polymorphisms may be used to identify individuals at high risk of cervical cancer in Asian women.     

Matrix metalloproteinase 9 (MMP9) level and MMP9 -1562C>T in patients with obstructive sleep apnea: a systematic review and meta-analysis of case-control studies

BackgroundThe peripheral level of matrix metalloproteinase (MMP)-9 and polymorphism of MMP9 -1562C>T in patients with obstructive sleep apnea (OSA) remains controversial. Therefore, the aims of this systemic review and meta-analysis are to assess the MMP9 level in OSA patients and identify the relationship between MMP9 -1562C>T and OSA susceptibility.MethodsThis systematic review was performed following the PRISMA guideline. We searched for studies in major databases, identifying those indexed from inception to July 3, 2019 which related to MMP9 level, MMP9 -1562C>T and OSA. The pooled standardized mean differences (SMDs) and 95% confidence interval (CI) of MMP9 levels were calculated. In addition, the relationship between MMP9 -1562C>T and OSA susceptibility was assessed by three genetic models. The heterogeneity analysis and calculation of the pooled odds ratio (OR) were also performed, followed by quality assessment using the Newcastle-Ottawa Scale (NOS).ResultsIn sum, our review included 15 eligible studies regarding MMP9 level and three regarding MMP9 -1562C>T. The pooled results showed that peripheral level of MMP9 was increased in OSA patients (SMD = 1.37; 95% CI = 1.15–1.59). Furthermore, significant difference of MMP9 level can be found between severe and mild-to-moderate OSA patients (SMD = 28.17; 95% CI = 4.23–52.11) or between moderate-severe and mild OSA (SMD = 36.62; 95% CI = 12.19–61.04). However, no relationship was observed between MMP9 -1562C>T and OSA susceptibility in three genetic models (Homozygote model, OR = 1.37; 95% CI = 0.87–2.18); (Recessive model, OR = 1.42; 95% CI = 0.83–2.42); (Allele model, OR = 1.07; 95% CI = 0.96–1.18).ConclusionsThis systemic review and meta-analysis indicated that the level of MMP9 was increased in patients with OSA and this increase is relevant to OSA severity. Moreover, the relationship between MMP9 -1562 C>T and OSA susceptibility has currently not been proven by current merging values. Further analyses with larger sample size are required to verify these associations.     

A Study of Ser217Leu and Ala541Thr Polymorphism in the Men Afflicted with Prostate Cancer and in the Men being Suspicious of Prostate Cancer

Background and objective: Prostate cancer is one of the most widespread cancers among men throughout the world. In addition, it is the second cause of death after lung cancer. Occurrence of the prostate cancer is variable in various regions of the world. Solely, there are three known risk factors for the prostate cancer, including: Age, inheritance and ethnic origin. ELAC2 protein is a phosphodiesterase enzyme encoded by ELAC2 gene in human. This gene is placed on chromosome 17, and it is believed that product of the mentioned gene is an endonuclease contributed in puberty of mitochondrion’s tRNA. From clinical viewpoint, variables of ELAC2 gene such as Ser217Leu and Ala541Thr Missense mutations which are accompanied by hereditary prostate cancer (HPC2).Objective of this study is to investigate Ser217Leu (rs4792311) and Ala541Thr (rs5030739) polymorphisms in the individuals with prostate cancer or those who are suspicious of prostate cancer with family past record/history. Study method: In this study conducted by case-control method in 2018, 102 men with prostate cancer and 98 men being suspicious of prostate cancer out of 10 families referred to shahid Rajaei Hospital in Tonekabon county to study and check were investigated. After collection of data using questionnaire, sampling from individuals and performance of the rest steps, study of polymorphism was carried out by PCR sequencing technique, and the results were analyzed by Chromas software. Finding: Of the total studied 102 individuals, 44 individuals (43.1%) were homozygote for Ser217Leu mutation, 36 individuals (35.2%) were heterozygote and 22 individuals (21.5%) lacked Missense mutation. for Ala541Thr mutation, 18 ones (17.6%) were heterozygote and 84 ones (82.3%) lacked Missense mutation. For Ser217Leu mutation, out of 98 suspicious individuals, 21 individuals (21.4%) were homozygote. 6 individuals (6.1%) were heterozygote and 71 individuals (72.4%) lacked the mutation. For Ala541Thr mutation, 15 ones (15.3%) were homozygote and 84 ones (84.6%) lacked the studied mutation. Conclusion: Results of this research showed that, in the individuals with the prostate cancer, there is a relationship between Ser217Leu and Ala541Thr polymorphism of ELAC2 gene and/with prostate cancer, and the suspicious individuals gotten involved in the mutation must take action to prevent this cancer.     

Polymorphisms of insulin-like growth factor binding protein-3 as a predictor for risk and patient survival in esophageal squamous cell carcinoma

Background and purposeGenetic single nucleotide polymorphisms (SNP) play a critical role in the development of esophageal squamous cell carcinoma (ESCC). The aim of this study is to investigate the associations between insulin-like growth factor binding protein-3 (IGFBP-3) gene polymorphisms and ESCC patients risk and survival after definitive chemoradiotherapy (CRT).Materials and methodsWe undertook a case-control study to analyze two IGFBP-3 polymorphisms (rs2854744 A > C and rs2854746 G > C) in an Han Chinese population, by extraction of genomic DNA from the peripheral blood of 110 ESCC patients treated with CRT and 128 control participants, and performed IGFBP-3 genotyping using DNA sequencing.ResultsThe obtained results indicated that overall, no statistically significant association was observed in rs2854746 G > C. However, rs2854744 A > C genotype was at increased risk of ESCCs (P = 0.032; odds ratio (OR) = 1.201, CI 95%:1.014–1.423). Moreover, rs2854744 A > C genotype ESCCs were more significantly common in patients with tumor size of >6 cm than A allele ESCC and in cases of lower T stage. Furthermore, ESCC patients with rs2854744CC genotype have the poorer CRT response and shorter survival time than GG + GC genotype ESCC.ConclusionsIn conclusion, polymorphism in IGFBP-3 rs2854744 A > C might be a potential predictor of ESCC risk and patient survival. Nevertheless, further investigation with a larger sample size is needed to support our results.