Raju K. Mandal

Polymorphic Variants of DNA Repair Gene XRCC3 and XRCC7 and Risk of Prostate Cancer: A Study from North Indian Population

DNA repair gene alterations may cause a reduction in DNA repair capacity and influence an individuals susceptibility to carcinogenesis. We hypothesized that single nucleotide polymorphisms of DNA repair genes may be a risk factor for prostate cancer (PCa) susceptibility, influencing expression of homologous recombination (XRCC3) and nonhomologous end-joining (XRCC7) genes and conferring predisposition to PCa. In a case-control study, genotyping was done in 192 patients with PCa and 224 age matched unrelated healthy controls of similar ethnicity to determine variants in XRCC3 Exon 7 (C18067T, rs861539), IVS5-14 (A17893G, rs1799796), and XRCC7 Intron 8 (G6721T, rs7003908) by polymerase chain reaction-restriction fragment-length polymorphism methods. Variant genotype GG (odds ratio [OR], 2.23; p=0.003) and combined genotype TG+GG (OR, 1.541; p=0.049), G allele of XRCC7 Intron 8 (G>T), demonstrated significant risk for PCa (OR, 1.529; p=0.002). Stratification on bases of Gleason grade and bone metastasis, significant risk with high Gleason grade for CT genotype of XRCC3 Exon 7, and variant genotype GG of XRCC7 Intron 8 were observed. Our results strongly support that common sequence variants (GG) genotype of XRCC7 may increase risk of PCa. G allele being a risk allele in our study also suggests that this polymorphism be used as a marker for the PCa susceptibility.

DNA Repair Gene X-Ray Repair Cross-Complementing Group 1 and Xeroderma Pigmentosum Group D Polymorphisms and Risk of Prostate Cancer: A Study from North India

Interindividual variation in prostate cancer (PCa) susceptibility may be modulated in part through genetic polymorphisms in the DNA repair genes, especially the genes involved in the base excision repair and nucleotide excision repair pathway. Two of the common single-nucleotide polymorphisms X-ray repair cross-complementing group 1 (XRCC1) and Xeroderma pigmentosum group D (XPD) genes in PCa, which is one of the most common neoplasias in men all over the world, have been studied. In a case-control study of 171 PCa patients and 200 age-matched healthy controls, of similar ethnicity, genotyping was done to determine XPD exon 10 (G23592A), exon 23 (A35931C), and XRCC1 exon 6 (C26304T), exon 9 (G27466A), exon 10 (G23591A) gene polymorphisms by amplification refractory mutation-specific and polymerase chain reaction-restriction fragment length polymorphism methods, respectively. We observed that XPD exon 10 variant AA genotype was associated with increased risk for PCa (adjusted odds ratio [OR] 2.63, 95% confidence interval [95% CI] 1.40-4.92, p = 0.003), and XRCC1 exon 9 GA genotype was also statistically associated with PCa (adjusted OR 2.61, 95% CI 1.53-4.43, p < 0.001). However, XPD exon 23 (A>C) and XRCC1 exon 6 (C>T) and exon 10 (G>A) did not have significantly increased risk for PCa. The haplotype analysis of XPD exon 10 and exon 23 G-C (OR 3.44, 95% CI 2.15-5.51, p < 0.0001) and A-A (OR 4.96, 95% CI 3.08-7.98, p < 0.0001) was associated with a significant increase in PCa risk. Similarly, the combined analysis of XRCC1 exon 6, exon 9, and exon 10 C-G-A (OR 2.93, 95% CI 1.91-4.50, p < 0.001) and C-A-G (OR 2.48, 95% CI 1.62-3.80, p < 0.001) demonstrated statistically significant risk in PCa. XRCC1 exon 9 GA genotype showed protective association with high grade of PCa. Our results suggest a positive association of XRCC1 exon 9 and XPD exon 10 genotypes that may play an important role in the pathophysiology and may modulate the risk of PCa.

High Serum Level of Matrix Metalloproteinase 9 and Promoter Polymorphism − 1562 C:T as a New Risk Factor for Metabolic Syndrome

The altered matrix metalloproteinases (MMPs) have been suggested in the pathophysiology of metabolic syndrome (MetS). Genetic variants in the promoter region of MMP1 and MMP9 genes may modulate an individuals susceptibility to MetS. The aim of this study was to determine the frequency of MMP1 -519 A:G and MMP9 -1562 C:T polymorphisms and the correlation with serum levels of MMP1 and MMP9 in MetS susceptibility. On the basis of anthropometric profile and laboratory investigations, 180 confirmed MetS patients and 190 unrelated healthy controls of similar ethnicity were genotyped for MMP1 -519 A:G and MMP9-1562 C:T polymorphisms by using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methods. In addition, serum levels of MMP1 and MMP9 were quantified by ELISA. We found that the serum level of MMP9 was significantly higher in MetS patients. Variant genotype TT of MMP9 -1562 demonstrated increased risk (odds ratio [OR]=3.70, p=0.015) of MetS. Similarly, variant allele T (OR=1.77, p=0.002) and combined genotype CT+TT (OR=1.81, p=0.057) also showed a significantly higher risk. The CT and TT genotypes of MMP9 -1562 polymorphism contributed to high serum levels of MMP9 in MetS patients. However, no such association was observed with the MMP1 serum level and -519 A:G polymorphism. Our results suggest that a higher serum level of MMP9 in the presence of MMP9 polymorphism -1562 C:T might be a risk factor for the development of MetS. The MMP9 enzyme activity might be a significant indicator in the screening of MetS patients.

Meta-analysis reveals PTPN22 1858C/T polymorphism confers susceptibility to rheumatoid arthritis in Caucasian but not in Asian population

Abstract The PTPN22 1858C/T polymorphism is associated with rheumatoid arthritis (RA). However, reports from the Asian populations are conflicting in nature and lacks consensus. The aim of our study was to evaluate the association between the PTPN22 1858C/T polymorphism and RA in Asian and Caucasian subjects by carrying out a meta-analysis of Asian and Caucasian data. A total of 27 205 RA cases and 27 677 controls were considered in the present meta-analysis involving eight Asian and 35 Caucasian studies. The pooled odds ratios (ORs) were performed for the allele, dominant, and recessive genetic model. No statistically significant association was found between the PTPN22 1858C/T polymorphism and risk of RA in Asian population (allele genetic model: OR = 1.217, 95% confidence interval (CI) = 0.99–1.496, p value 0.061; dominant genetic model: OR = 1.238, 95% CI = 0.982–1.562, p value 0.071; recessive genetic model: OR = 1.964, 95% CI = 0.678–5.693, p value 0.213). A significant association with risk of RA in Caucasian population suggesting that T–– allele does confer susceptibility to RA in this subgroup was observed (allele genetic model: OR = 1.638, 95% CI = 1.574–1.705, p value < 0.0001; dominant genetic model: OR = 1.67, 95% CI = 1.598–1.745, p value < 0.0001; recessive genetic model: OR = 2.65, 95% CI = 2.273–3.089, p value < 0.0001). The PTPN22 1858C/T polymorphism is not associated with RA risk in Asian populations. However, our meta-analysis confirms that the PTPN22 1858C/T polymorphism is associated with RA susceptibility in Caucasians.

Association of Caspases with an Increased Prostate Cancer Risk in North Indian Population

Dysregulation of apoptosis plays a crucial role in carcinogenesis. Thus, genetic alterations within caspase genes would be expected to provoke a deficient apoptotic signaling thereby facilitating the development of prostate cancer (PCa). In the present study we investigated whether three different polymorphisms in the caspase-5 and -3 genes are differentially expressed in PCa. In a hospital-based case control study in northern India, we genotyped 192 PCa patients and 225 unrelated healthy controls for caspase-5 (G>C) (T>C) and caspase-3 (G>A) polymorphisms using amplification refractory mutation system and polymerase chain restriction fragment length polymorphism methods. Data were statistically analyzed and variant genotype GG of caspase-3 demonstrated increased risk for PCa (odds ratio [OR]=2.72, p=0.005). Similarly variant allele carrier (AG+GG) (OR=1.53, p=0.034) and G allele (OR=1.54, p=0.005) were also statistically associated with PCa risk. High risk for PCa was also observed with respect to caspase-5 (CC) diplotypes (OR=21.67, p=0.012, Pc=0.048). We observed significantly enhanced risk for PCa due to interaction between caspase-3 and -5 gene polymorphisms. In association of genotypes with clinical characteristics, heterozygous TC genotype of caspase-5 (T>C) conferred risk with high Gleason grade tumor (OR=2.35, p=0.042). In case-only analysis, interaction of environmental risk factors and genotypes did not further modulate the risk for PCa. Our observations suggested positive association of caspase-3 and diplotype analysis of caspase-5 to be associated with PCa risk. Interaction of caspase-3 and -5 genotypes also modulated the PCa risk.

Vascular Endothelial Growth Factor 936 C>T Polymorphism Increased Oral Cancer Risk: Evidence from a Meta-Analysis

AIM The vascular endothelial growth factor (VEGF) plays a major role in angiogenesis. The association between VEGF 936 C>T (rs3025039) gene polymorphisms and oral cancer (OC) risk is still contentious and ambiguous. To assess the relationship between the VEGF 936 C>T genotype and the risk of developing OC, we performed a meta-analysis to summarize the possible association. METHODOLOGY We assessed published studies of the association between 936 C>T polymorphisms and OC risk from four studies with 440 controls and 556 OC cases. We calculated pooled odds ratios (ORs) and 95% confidence interval (CI), considering the frequency of allele, homozygous, heterozygous genotypes and comparison of dominant and recessive genetic models. RESULTS The combined results showed that the T allele was significantly associated with increased OC risk (T vs. C: p=0.001; OR=1.521, 95% CI=1.194-1.938). The heterozygous genotype CT had a 1.5-fold increased risk (CT vs. CC: p=0.002; OR=1.582, 95% CI=1.184-2.114). In addition the dominant genetic model demonstrated a 1.6-fold increased risk of developing OC (TT+CT vs. CC: p=0.001; OR=1.621, 95% CI=1.226-2.143). CONCLUSION Our results suggest that the VEGF gene polymorphism (936 C>T) contributes increased susceptibility to OC. However, larger studies with a stratified case-control population and biological characterization are needed to validate this finding.

Prevalence of drug resistance in clinical isolates of tuberculosis from GCC: a literature review from January 2002 to March 2013

INTRODUCTION The prevalence of drug resistance in clinical isolates of Mycobacterium tuberculosis from the Gulf Cooperation Council (GCC; Saudi Arabia, Qatar, Bahrain, Kuwait, Oman, United Arab Emirates [UAE]) countries was appraised using reports published between January 2002 and March 2013. METHODOLOGY A total of 11,393 tuberculosis (TB) isolates from the GCC were studied through published literature and were analyzed statistically. RESULTS Most of the isolates were resistant to isoniazid, followed by streptomycin, rifampin, ethambutol, and pyrazinamide. The highest prevalence rate of multidrug-resistant-TB (MDR-TB) was found in UAE (9.2%), followed by Kuwait (5.9%) and Saudi Arabia (4.3%). The overall MDR-TB prevalence rate was recorded as 4.0% in the entire GCC region. Automated linear modeling revealed that isoniazid resistance had a strong relationship with the prevalence of MDR-TB in all the GCC countries and was found to be the strongest predictor for MDR-TB. Interestingly, rifampicin resistance was significantly associated with the prevalence of MDR-TB in Oman, Kuwait, and Saudi Arabia, while isoniazid was identified for UAE. On the basis of a number of reports and isolates, the principal component analysis showed that, among all GCC member countries, the highest burden of TB was in Saudi Arabia and Kuwait, and maximum drug resistance was present in UAE. CONCLUSION The study demonstrates that the prevalence of MDR-TB in GCC countries is almost equal to other developing and developed countries, and requires immediate attention for surveillance and control.

Association of P2X7 A1513C (rs3751143) gene polymorphism with risk of tuberculosis: evidence from a meta-analysis.

AIM Many case-control studies have been performed in the past to elucidate the association between the P2X7 receptor 1513 A>C (rs3751143) polymorphism and tuberculosis (TB) risk. However, their data interpretation was difficult due to scattered and inconsistent results that led to limited power. In this study, a quantitative summary assessment has been done through meta-analysis to appraise the association between the 1513 A>C polymorphism and TB susceptibility. METHODOLOGY Systematic assessment was performed for the published studies related with the association between the P2X7 1513 A>C polymorphism and TB risk retrieved from PubMed (Medline), EMBASE search. A meta-analysis was done using a statistical program to evaluate the said association. Pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated for allele contrast, homozygous, heterozygous, dominant, and recessive genetic models. RESULTS A total of 2710 controls and 2521 TB cases were included in this meta-analysis. Meta-analysis results showed that C allele carrier status was significantly associated with increased TB risk (C vs. A: p=0.001; OR=1.382, 95% CI=1.248-1.531). Significant risk of TB was associated with the homozygous mutant CC (CC vs. AA: p=0.001; OR=1.676, 95% CI=1.251-2.247) and heterozygous AC (AC vs. AA: p=0.001; OR=1.429, 95% CI=1.260-1.621) comparisons. Similarly, dominant (CC vs. AA+AC: p=0.008; OR=1.481, 95% CI=1.109-1.978) and recessive (CC+AC vs. AA: p=0.001; OR=1.458, 95% CI=1.292-1.645) genetic models also revealed increased risk of developing TB. CONCLUSION We found that the P2X7 1513 A>C gene polymorphism is significantly associated with increased susceptibility to TB. Also, future well-designed epidemiological studies with stratified case-control and biological characterization may be beneficial to validate these findings.

Genetic variants of matrix metalloproteinase (MMP2) gene influence metabolic syndrome susceptibility.

AIM Matrix metalloproteinases (MMPs) are suggested to be involved in the development of various clinical factors of metabolic syndrome (MetS). Allelic variants in the promoter region of the MMP2 gene may modulate an individuals susceptibility to MetS. We performed this study to determine whether single-nucleotide polymorphisms (SNPs) -1575 (G>A) and -168 (G>T) of the MMP2 gene are associated with MetS risk. METHODS In this hospital-based case-control study, 180 confirmed MetS patients and 190 unrelated healthy controls of similar ethnicity were genotyped for MMP2 (-1575 G>A, -168 G>T) polymorphisms using polymerase chain reaction-restriction fragment length polymorphism. RESULTS Variant genotype (AA) of -1575 showed increased risk (odds ratio [OR]=2.72, 95% confidence intervals [CI]=1.19-6.23, p=0.018) of MetS as compared to the wild-type homozygous genotype (GG). Similarly, the variant allele (A) (OR=1.60, 95%CI=1.12-2.26, p=0.009) and combined genotype (GA+AA) (OR=1.51, 95%CI=0.98-2.31, p=0.057) were also significantly associated with MetS risk. High risk of MetS was observed with respect to the haplotype (A-T) (OR=1.83, 95%CI=1.03-3.26, p=0.038) of MMP2 (-1575 and -168) polymorphisms. However, MMP2 (-168 G>T) polymorphism individually did not show any risk with MetS. CONCLUSIONS Our results strongly support the notion that common sequence variants and haplotype of MMP2 (-1575 G>A and -168 G>T) might be a genetic risk for the development of MetS in the North Indian population. Additional studies on larger populations are needed to clarify the role of genetic variants of this gene in MetS.

Matrix metalloproteinase-2 -1306 C>T gene polymorphism is associated with reduced risk of cancer: a meta-analysis.

Matrix metalloproteinase-2 (MMP2) is an endopeptidase, mainly responsible for degradation of extracellular matrix components, which plays an important role in cancer disease. A single nucleotide polymorphism (SNP) at -1306 disrupts a Sp1-type promoter site. The results from the published studies on the association between MMP2 -1306 C>T polymorphism and cancer risk are contradictory and inconclusive. In the present study, a meta-analysis was therefore performed to evaluate the strength of any association between the MMP2 -1306 C>T polymorphism and risk of cancer. We searched all eligible studies published on association between MMP2 -1306 C>T polymorphism and cancer risk in PubMed (Medline), EMBASE and Google Scholar online web databases until December 2013. Genotype distribution data were collected to calculate the pooled odds ratios (ORs) and 95% confidence intervals (95%CIs) to examine the strength of the association. A total of 8,590 cancer cases and 9,601 controls were included from twenty nine eligible case control studies. Overall pooled analysis suggested significantly reduced risk associated with heterozygous genotype (CT vs CC: OR=0.758, 95%CI=0.637 to 0.902, p=0.002) and dominant model (TT+CT vs CC: OR=0.816, 95%CI=0.678 to 0.982, p=0.032) genetic models. However, allelic (T vs C: OR=0.882, 95%CI=0.738 to 1.055, p=0.169), homozygous (TT vs CC: OR=1.185, 95%CI=0.825 to 1.700, p=0.358) and recessive (TT vs CC+CT: OR=1.268, 95%CI=0.897 to 1.793, p=0.179) models did not show any risk. No evidence of publication bias was detected during the analysis. The results of present meta-analysis suggest that the MMP2 -1306 C>T polymorphism is significantly associated with reduced risk of cancer. However, further studies with consideration of different populations will be required to evaluate this relationship in more detail.