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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. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNA) are a class of small noncoding RNA molecules that have been implicated in a wide variety of cellular functions through post-transcriptional regulations on target genes. Common genetic variants (single-nucleotide polymorphisms, SNPs) in pre-miRNA genes may alter their expression and/or maturation effecting thousands of target mRNAs, resulting in varied functional consequences. Three common SNPs ( hsa-mir-146a G>C rs2910164, hsa-mir-196a2 C>T rs11614913, and hsa-mir-499 T>C rs3746444) in pre-miRNAs were investigated to evaluate their association with urinary bladder cancer risk. The hospital-based case-control study comprised of 212 histologically confirmed patients with urinary bladder cancer and 250 healthy controls who were unrelated, of similar ethnicity, and age and gender matched. Genotyping was done using polymerase chain reaction-restriction fragment length polymorphism methodology. Our results showed that the heterozygous genotype of rs11614913 was higher in cases than controls but the results were marginally significant ( p = 0.055; odds ratio, 1.44). Smoking had no impact in modulating the effect of any of the three miRNA SNPs studied. No association was observed with either the tumor stage or grade in patients with bladder cancer. Even though there was no association between the individuals carrying the variant genotypes of the three miRNA studied and bladder cancer risk, marginal significance of heterozygousity in rs11614913 suggested further characterization of miRNA SNPs in a large cohort of varied ethnicity. This could further provide new prospects for understanding the underlying mechanisms between miRNAs and disease etiology. [ABSTRACT FROM AUTHOR]

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]

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]

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]

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. [ABSTRACT FROM AUTHOR]

End-stage renal disease (ESRD) is associated with the inflammatory state characterized by infiltrating macrophages/lymphocytes, a major source of cytokines and chemokines. This study examined the role of genetic polymorphisms in cytokine, IL-10, and chemokine receptors, CCR2 and CCR5, with susceptibility to ESRD. Polymorphisms in IL-10 (−1082 G/A, PCR-RFLP; −819 C/T, ARMS-PCR), CCR2 ( Val/Ile, PCR-RFLP), and CCR5Δ32 were detected in 184 ESRD patients and 180 controls. Our results demonstrated a significant difference in genotype frequencies of IL-10 −1082G/A ( p < 0.001), IL-10 −819C/T ( p = 0.007), and CCR2Val/Ile ( p = 0.033) between ESRD patients and controls. However, only low-producing genotype AA of IL-10 −1082G/A showed significantly threefold higher risk for all ESRD patients (odds ratio [OR] = 3.164, 95%CI = 1.74–5.72) as well as patients with only inflammatory causes of renal diseases (OR = 2.979, 95%CI = 1.61–5.52). No risk was seen in variant genotype of other genes. The genotypic frequencies of CCR5Δ32 were comparable in patients and controls ( p = 0.203). In haplotype analysis, A-T haplotype (low producer) of IL-10 showed 1.7-fold risk ( p > 0.05). No risk was seen for CCR2 and CCR5 haplotypes. The AA genotype of IL-10 −1082G/A polymorphism was associated with increased susceptibility to ESRD. This study implies the basis for defined antiinflammatory approaches to impede renal disease progression. [ABSTRACT FROM AUTHOR]

The cellular alterations that give rise to cancer initiate changes in cytokine expression. Though IL-6 is known to play a major role in proliferation of tumor cells, IL-4 upregulates androgen receptors and prostate-specific antigen (PSA). The present study was undertaken to evaluate the association of IL-4 and IL-6 gene polymorphisms for the susceptibility to prostate cancer (PCa) risk. Our study included 200 controls and 200 histologically confirmed cases of PCa. Polymorphisms in IL-4 (intron 3, by VNTR analysis) and IL-6 ( −174 G/C, by amplification refractory mutation system, i.e., ARMS-PCR) were genotyped in all the subjects. There was no significant association of IL-4 and IL-6 gene polymorphisms with the risk of PCa. Nevertheless, twofold risk with progression to bone metastasis (odds ratio = 2.09; 95% confidence interval = 1.16–3.75; p = 0.014) in PCa patients was observed. No association with other confounding factors such as PSA level, Gleason score, and lifestyle-associated risk factors like tobacco chewing and cigarette smoking was seen. Our study suggests that an IL-6 gene variant may be associated with prostate progression and bone metastasis. [ABSTRACT FROM AUTHOR]

End-stage renal disease has been associated with an inflammatory state. TGF- β plays a critical role in antiinflammation counteracting inflammatory cytokines, wound healing, and tissue repair. We, therefore, speculated the protective role of TGF- β in renal inflammation rather than inducing fibrosis. Three polymorphisms of TGF- β (713-8delC), i.e., C deletion in intron sequence 8 base prior to exon-5 by PCR-RFLP and codon-10, Leu/Pro, and codon-25, Arg/Pro by Amplification Refractory Mutation System (ARMS-PCR) techniques were genotyped in 228 end-stage renal disease (ESRD) patients and 180 controls. Linkage disequilibrium (LD) and haplotype analysis was performed by Arlequin software. Our data showed positive association between codon-10 polymorphism and ESRD risk ( P < 0.001; OR 4.845, 95% CI 2.57–9.11 for Pro/Pro). However, genotype frequencies were comparable in patients and controls for 713-8delC, while in the case of codon-25, a trend of higher frequency of Pro/Pro genotype (16.2% versus 10.0%) was observed but the P-value did not reach significant ( P = 0.187). Significant association of codon-10 Pro/Pro was observed in patients with glomerulonephritis ( P = 0.001; OR 4.138, 95%CI 2.1–8.13). LD was found significant between codon-10 and 25 ( P = 0.021). Haplotype “Pro-Pro” showed 1.8-fold higher risk for ESRD ( p = 0.003; OR = 1.867, 95%CI = 1.229–2.838). A combined analysis of the effect of TGF- β (codon-10) with C-deletion and codon-25 showed significant difference for TGF- β10-TGF- βC-del ( P = 0.010). In conclusion, the present study suggests that low-producing genotype (Pro/Pro) of TGF- β (codon-10) polymorphism is associated with ESRD. Haplotype analysis further suggested that “Pro-Pro” (low producer) is associated with higher risk for ESRD. Thus, high-producing genotype of TGF- β may be beneficial and may play a potential role in the resolution of renal inflammation. [ABSTRACT FROM AUTHOR]