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Increased vascular endothelial growth factor (VEGF) production promotes enhanced endothelial permeability, enhanced leukocyte migration into the allograft, thereby leading to a clinically recognized rejection episode. Interleukin-18 (IL-18), a potent proinflammatory cytokine, may also be involved in mechanisms of kidney allograft rejection. The present study was, therefore, undertaken to investigate the association of functional polymorphisms in VEGF (2578C>A, 1154A>G) and IL-18 (607C>A, 137G>C) genes with risk of allograft rejection in renal transplant recipients of North India. Two hundred renal transplant recipients, 150 matched recipients-donors, and 200 unrelated healthy individuals were genotyped by amplification refractory mutation specific polymerase chain reaction and by polymerase chain reaction-restriction fragment length polymorphism. Variant allele VEGF 1154A>G ( p = 0.56; odds ratio [OR] = 1.32) and variant allele ( p = 0.004, OR = 1.54) and variant genotype ( p = 0.007, OR = 3.26) of IL-18 607C>A, GC of IL-18 137G>C ( p = 0.043, OR = 0.63) were significantly different in healthy individuals as compared with the patients with renal transplant. When 114 nonrejectors were compared with 36 rejectors (150 recipients) for association with allograft rejection, significant association was observed in heterozygous genotype of VEGF 2578C>A ( p = 0.033), VEGF 1154A>G ( p = 0.024). In IL-18 137G>C, CC genotype, C allele showed protective association with allograft rejection. Kaplan-Meier analysis indicated a higher mean time for first rejection episode in CA genotype carriers (31 months) as compared with AA (29 months) for VEGF 2578C>A (log p = 0.035). In VEGF, the haplotypes A-A and A-G (2578-1154) were associated with reduced risk and in IL-18 607A-137G, they were associated with high risk for allograft rejection. This observation suggests these polymorphisms are an ideal marker for prediction of pretransplant allograft outcome. [ABSTRACT FROM AUTHOR]

Background and Aims: P53 gene variants BstUI RFLP at codon 72 in exon 4, 16-bp tandem repeat in intron 3 and Msp I RFLP in intron 6 and P73 gene variants of G4C14-to-A4T14 (GC/AT), exon 2 polymorphism, which respectively codes for four functionally different protein isoforms, have been shown to modulate susceptibility to different types of human neoplasms. We undertook this study to evaluate the role of P53 and P73 SNPs in prostate cancer in a Northern Indian population. Methods: P53 and P73 genotypes were assessed in a hospital-based case-control study comprised of 177 prostate cancer cases and 265 healthy controls. After the extraction of genomic DNA from blood, genotyping was done using PCR-RFLP and PCR-CTPP methods, respectively. Results: A significant association was found in P53 intron 6 G>A and P53 R72P G>C polymorphism with PCa risk. In P53 intron 6 G>A polymorphism the heterozygous genotype (GA) showed marginal risk with the disease (OR = 1.48, 95% CI = 0.999–2.220). Individuals with heterozygous genotype only (GC) of P53 R72P G>C polymorphism demonstrated PCa risk (OR = 1.5, 95% CI = 1–2.199). Haplotypes G-C-D and A-G-D (OR = 1.58, 95% CI = 1.125–2.241 and OR = 2.70, 95% CI = 1.767–4.143, respectively) were also found to be associated with an increased risk of PCa. Conclusions: Our study provided evidence that the P53 intron 6 G>A and R72P G>C polymorphisms were associated with a higher risk of prostate cancer in a Northern Indian population. [ABSTRACT FROM AUTHOR]

DNA repair gene alterations may cause a reduction in DNA repair capacity and influence an individual's 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. [ABSTRACT FROM AUTHOR]

Background. Matrix metalloproteinases (MMPs), especially basement membrane-degrading MMP-9 and MMP-2, play an important role in immune-mediated tissue destruction of the allograft by allowing influx of leucocytes and mononuclear cells into the graft. The present study was, therefore, undertaken to investigate the association of functional polymorphisms in MMP-9 (836A>G, 1721G>C and 2003G>A) and MMP-2 (−735C>T) genes with risk of allograft rejection in renal transplant recipients of North India.Methods. Three hundred and six renal transplant recipients categorized into 228 non-rejecters and 78 rejecters were genotyped for MMP-9 and MMP-2 polymorphisms by polymerase chain reaction–restriction fragment length polymorphism methodology.Results. A significant difference in genotype/allele frequencies was observed between healthy individuals in comparison to non-rejecters/rejecters for MMP-9 836A>G, MMP-9 2003G>A and MMP-2 −735C>T. Mutant allele carriers for MMP-9 2003G>A [GA+AA−; odds ratio (OR) = 0.45, 95% confidence intervals (95% CI) = 0.24–0.85, P = 0.014] and MMP-2 −735C>T (CT+TT−; OR = 0.40, 95% CI = 0.18–0.91, P = 0.029) demonstrated significantly reduced risk for allograft rejection. The mean time to first rejection episode was significantly higher in GA/AA and CT/TT genotype recipients for MMP-9 2003G>A (log P = 0.026) and MMP-2 −735C>T (log P = 0.003), respectively. Haplotypes with mutant alleles for MMP-9 1721C>G-2003G>A and mutant allele genotype combinations for both MMP-9 2003G>A and MMP-2 −735C>T conferred significantly reduced risk for allograft rejection.Conclusion. Mutant alleles for MMP-9 2003G>A and MMP-2 −735C>T are associated with reduced risk for allograft rejection and improved allograft survival in North Indian transplant recipients and could serve as an ideal marker to predict pre-transplant allograft outcome. [ABSTRACT FROM AUTHOR]

Perturbations in the cell cycle and apoptotic genes have been implicated in human malignancies. Cell cycle ( MDM2 and Cyclin D1) and apoptotic ( Fas) genes that are differentially expressed in urinary bladder cancer (UBC) were investigated with the susceptibility to UBC in northern India. A total of 212 UBC patients and age- and sex-matched 250 controls were investigated for MDM2 G309T, Cyclin D1 G870A, and Fas A670G polymorphisms by polymerase chain reaction and restriction fragment length polymorphism. MDM2 309GG was at reduced risk for developing UBC when compared with TT genotype ( p = 0.027; odds ratio, 0.55). GG genotype was also associated with reduced risk in nonmuscle invasive bladder cancer (NMIBC) and muscle invasive BC ( p = 0.006 and p = 0.049). Cyclin D1 AA genotype was associated with high risk in NMIBC (intermediate risk) stage ( p = 0.015; odds ratio, 4.55). MDM2–Cyclin D1 interaction revealed overall protective effect. The GG genotype of MDM2 also showed a protective effect and high recurrence-free survival in Bacillus Calmette–Guerin-treated NMIBC patients (log rank p = 0.008). MDM2 GG genotype had protective effect and MDM2T309G polymorphism had profound influence in Bacillus Calmette–Guerin-treated UBC patients in the North Indian population. [ABSTRACT FROM AUTHOR]

Introduction: Bladder cancer is a disease characterized by multiple recurrences. Some investigators assume urokinase to be involved in the causation of bladder cancer, although there is lack of genetic evidence. Our aim was to evaluate whether polymorphism of the urokinase gene is associated with transitional cell carcinoma (TCC) of the urinary bladder. Materials and Methods: The study included 100 patients (mean age 62.5 ± 10.2 years) with TCC of urinary bladder and 150 healthy controls (mean age 60 ± 11.5 years) living in the same area. Polymerase chain reaction (PCR)-based restriction analysis was used to identify the C/T polymorphism of the urokinase gene. Genotyping distribution and allelic frequencies between patients and controls were compared. Results and Conclusion: There was a significant difference in the frequency distribution of the urokinase gene 3′-UTR C/T polymorphism in bladder cancer patients as compared to the normal control group (p < 0.05), but no significant difference in allelic frequencies or in carriage rates between bladder cancer patients and normal controls were observed. Our study suggests that urokinase gene polymorphism may be associated with bladder cancer and can thus serve as a potential genetic marker in screening for the possible causes of bladder cancer. Perhaps analysis of patients with superficial bladder TCC and mutated urokinase might help clarify this aspect in large cohort studies in different populations. Copyright © 2006 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Introduction: Vitamin D plays an important role in the proliferation and differentiation of normal and malignant cells. In several studies polymorphism in the vitamin D receptor (VDR) gene has been reported to be associated with prostate cancer (CaP). The rationale of this study was to determine the association between the VDR (Fok-I) polymorphism and the risk of developing CaP. Materials and Methods: Polymorphism was detected by the polymerase chain reaction (PCR)-restriction fragment length polymorphism method in 128 CaP patients (age range 43–89 years) and 147 age-matched controls (age range 42–91 years). PCR products were designated as F or f allele according to the absence or presence of a restriction site. Results and Conclusions: The frequencies of the FF, Ff and ff genotypes were 60.9, 35.2 and 3.9% in CaP patients and 42.2, 46.9 and 10.9% in healthy controls, respectively. The genotype frequency distribution between CaP and the control group was statistically significant (p = 0.003). However, the distribution of genotypes was not significantly associated with the Gleason score. The present study thus demonstrates that the FF genotype (or F allele) of the VDR gene plays an important role in determining the risk of CaP and could be postulated as a good candidate genetic marker. Copyright © 2005 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

To examine the association of glutathione-S-transferase (GST) gene polymorphisms in patients with sporadic prostate cancer, in a North Indian population, as GSTs are active in detoxifying a wide variety of endogenous or exogenous carcinogens, and genetic polymorphisms of GSTM1, GSTT1 and GSTP1 have been assessed to evaluate the relative risk of various cancers.We assessed 127 patients with prostate cancer and 144 age-matched controls, all from North India. The GSTT1 and GSTM1 null genotypes were identified by multiplex polymerase chain reaction (PCR) in peripheral blood DNA samples, and GSTP1-313 A/G polymorphism was determined by PCR/restriction fragment length polymorphism.There was a significant association in null alleles of the GSTM1 (odds ratio 2.239, 95% confidence interval 1.37–3.65,P = 0.001) and GSTT1 (1.891, 1.089–3.282,P = 0.026) with prostate cancer risk, and in the -313 G alleles (Val) of the GSTP1 gene (2.48, 1.51–4.08,P < 0.001). The combined analysis of these three genotypes showed a further increase in the risks of prostate cancer (7.23, 2.42–22.6,P < 0.001).The GSTP1-313 G polymorphism, and null alleles of GSTM1 and GSTT1, are strong predisposing risk factors for sporadic prostate cancer in North India. [ABSTRACT FROM AUTHOR]

Azoospermia factor locus (AZF) is assumed to contain the genes responsible for spermatogenesis. Deletions in these genes are thought to be pathologically involved in some cases of male infertility associated with azoospermia or oligozoospermia. An attempt was made to establish the prevalence of micro-deletions on the Y chromosome in 79 infertile North Indians with azoospermia and oligozoospermia. Detail clinical examinations as well as endocrinological parameters were also done. Polymerase chain reaction (PCR) micro-deletion analysis was done in 79 infertile men. For this, genomic DNA was extracted from the peripheral blood. Seven sets of primers were used encompassing AZFa, AZFb and AZFc regions. Micro-deletions in five of the 79 cases (6.3%) showed deletions of at least one of the STS markers. Deletions were detected with known and unknown aetiology and at least in one of the infertile male with varicocele. AZF micro-deletions seen in idiopathic infertile males suggest the need for molecular screening in non-idiopathic cases. [Copyright &y& Elsevier]

Objective Genome-wide association studies have confirmed association of TP63C/T rs710521, TERTC/T rs2736098, and SLC14A1C/T rs17674580 gene variants with susceptibility to bladder cancer (BC) in European and White population. However, the risk conferred for BC for above gene variants in North Indians is unknown. We therefore, studied the association of TP63C/T , TERTC/T , and SLC14A1C/T single nucleotide polymorphisms (SNPs) with a risk of BC susceptibility in North Indian cohort. Material and methods In histologically confirmed 225 BC cases and 240 healthy controls, 3 SNPs were genotyped by real-time polymerase chain reaction. To evaluate the SNP effects on BC susceptibility, odds ratio (OR) and CI 95% were calculated. Results In case of TP63C/T , the variant genotype (TT) showed significant reduced risk for BC ( P = 0.045, OR = 0.53). Combining heterozygous and variant genotypes also demonstrated reduced risk for BC ( P < 0.001, OR = 0.54). In case of TERTC/T , heterozygous genotype (CT) as well as variant genotype (TT) showed significant risk for BC susceptibility ( P = 0.031, OR = 1.77 and P = 0.004, OR = 2.78, respectively) along with T allelic level ( P <0.001, OR = 4.19). Furthermore, in case of SLC14A1C/T gene polymorphism, the variant genotype (TT) showed significant high risk for BC susceptibility ( P = 0.006; OR = 3.01) along with variant T allelic level ( P = 0.003, OR = 1.52). Interestingly, smoking was also found to modulate risks for BC in case of TERT and SLC14A1 variant genotype (TT). Further clinical confounding factor, namely, tumor grade/stage level of cases, supports the genotypic data with TERT and SLC14A1 showing a risk for BC susceptibility. Conclusion Our results suggested that polymorphism in TERTC/T and SLC14A1C/T confirmed high risk for BC in North Indian population. However, TP63C/T showed reduced risk of BC susceptibility. More replicate studies with large sample size and diverse ethnicity are required to validate these observations. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: Matrix metalloproteinases (MMPs) have been implicated in progression and metastases of different tumors. The balance between the MMPs and their natural inhibitors (tissue inhibitors of matrix metalloproteinases; TIMP) seem to be an important factor related to its role. The purpose of this study was to evaluate polymorphisms in the MMP-3 and TIMP-3 genes for their associations with prostate cancer (PCa) risk in North Indians. Materials and methods: Genotypes were determined by PCR-RFLP (Polymerase Chain Reaction Restriction Fragment Length Polymorphism) method in 150 PCa patients and 200 age matched controls of similar ethnicity. Results: We found significant association in the MMP-3(1171)5A/6A and TIMP-3 (1298) C/T polymorphism with PCa risk. Variant genotype (5A/5A) of MMP-3(1171)5A/6A polymorphism had a high PCa risk (p =0.037, OR=3.52, 95%CI=1.08–11.5). Individuals with TIMP-3 (1298) CT genotype as well as T allele showed reduced risk of PCa (p <0.001; OR=0.31; 95%CI=0.18–0.52, and p =0.001; OR=0.49; 95%CI=0.32–0.75). This effect was even more evident in case of T allele carrier (CT+TT) (p <0.001; OR=0.36; 95%CI=0.22–0.59). Overall no significant association was observed statistically in MMP-3 and TIMP-3 with any of the grading stages and smoking habits in PCa. Haplotype analysis of MMP-3 showed that A-5A-A was associated with three folds (OR=3.06; 95%CI=1.71–5.47; p <0.001) increased risk in PCa patients. Conclusion: This is the first reported association between polymorphisms in the MMP-3 and TIMP-3 gene and PCa risk and supports the hypothesis that the protease/antiprotease balance has an important role. Due to the small sample size further investigations need to be done to prove a statistical significant correlation between the MMP/TIMP expression and clinicopathological parameters. [Copyright &y& Elsevier]

Background and Aims: Impairment of the immune system may contribute to the risk for having cancer as Toll-like receptors are important for innate immunity. We examined the association between candidate disease-susceptibility polymorphisms in the single nucleotide polymorphism (SNPs) like TLR2 (−196 to−174del), TLR3 (C1377T), TLR4 (Thr399Ile) and TLR9 (G2848A) genes in patients with bladder cancer in a North Indian population. Methods: SNPs were comprised of TLR2 (−196 to −174 Del), TLR3(C1377T), TLR4 (Thr399Ile) and TLR9 (G2848A) genes. Allelic and genotypic frequencies of these TLRs SNP from histopathologically confirmed patients of bladder cancer (n = 200) and unrelated healthy controls of similar ethnicity (n = 200) were genotyped by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) analysis. Results: In TLR2 I/D gene polymorphism, the combination of ID+DD showed a significant 3-fold increased risk (p = 0.001). TLR2 with heterozygous genotype ID showed a 3-fold risk and combination of heterozygous and variant genotype (ID+DD) also showed a 5-fold risk with tumor stage/grade of patients with bladder cancer. The other genotypes of TLR3, 4 and 9 did not exhibit any significant association with bladder cancer risk. Conclusions: Our results suggested the involvement of TLR2 (−196 to−174 del) in bladder cancer susceptibility; however, TLR3, 4 and 9 genes were not associated with risk of bladder cancer, implicating that polymorphisms in these tested TLRs genes are not likely to be associated with increased risk for developing bladder cancer. Functional studies in ethnically diverse populations may provide a more comprehensive involvement of innate immunity in identifying the disease-associated variants for the etiology of bladder cancer. [Copyright &y& Elsevier]

Background and Aims: The importance of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) in tumor progression is well documented. MMP2/TIMP2 system has a significant impact on the development and progression of cancer and genetic polymorphisms in the promoters of MMP2 (−1306C/T, 735C/T) and TIMP2 (−418G/A, −303C/T) are correlated with decreased enzyme activity. We sought to determine whether genetic polymorphisms in MMP2 and TIMP2 polymorphisms may be associated with varying risk of prostate cancer (PCa) in men in North India. Methods: Genotyping was done by PCR-restriction fragment length polymorphism method in 190 histologically confirmed PCa patients and 200 unrelated, healthy, age-matched individuals of similar ethnicity. Results: Patients with MMP2 (-1306) CT genotype as well as T allele were at higher risk of PCa (p = 0.018; OR = 1.68 and p = 0.015; OR = 1.52). This effect was even more evident in the case of the T allele carrier (CT + TT) (p = 0.011; OR = 1.71). MMP2 (735) C>T, TIMP2 (−418) G>C and TIMP2 (−303) C>T polymorphism demonstrated no association. However, TIMP2 (−418) GC was found to be involved in progression of PCa but not in initiation. Haplotype results demonstrated that MMP2 (1306T–735C) and TIMP2 (418G-303T) were associated with a 1.5- and 1.8-fold increased risk, respectively. Conclusions: Our data indicated that MMP2-1306C>T gene polymorphism contributes to PCa susceptibility. These findings suggested MMP2 variants as a predictor of PCa progression risk among North Indian men. We assume that analysis of these gene polymorphisms can help identify patient subgroups at high risk of poor disease outcome. [ABSTRACT FROM AUTHOR]

Abstract: Objective:: Glutathione-S-transferases (GSTs) are active in the detoxification of wide variety of endogenous or exogenous carcinogens. We examined the association of the GST gene polymorphism with sporadic bladder cancer patients in Northern India. Material and methods:: The study constituted of 106 bladder cancer cases and 370 age-matched controls. The GSTT1 and GSTM1 null genotypes were identified by multiplex PCR and GSTP1313 A/G by Polymerase Chain Reaction/Restriction Fragment Length Polymorphism method (PCR/RFLP). Results:: We observed non-significant association in null alleles of the GSTM1 (p =0.611, OR=1.12, 95% CI=0.72–1.74 and GSTT1 (p =0.135, OR=1.45, 95% CI=0.89–2.37) with risk of bladder cancer. However, the G/G genotype of the GSTP1 gene polymorphism was highly significant when compared to controls (p =0.000, OR=7.12, 95% CI=3.14–16.16). The combined analysis of the three risk genotypes demonstrated further increase in the risk of bladder cancer (p =0.000, OR=7.29 95% CI=2.81–18.93). Conclusion:: Our study demonstrated that GSTP1313 G/G polymorphism is a strong predisposing risk factor for bladder cancer. Combination of three GST genotypes association exhibiting gene-gene interaction further substantiates the increased risk of bladder cancer. [Copyright &y& Elsevier]