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Background: Cell surface biomarker CD44 plays an important role in breast cancer cell growth, differentiation, invasion, angiogenesis and tumour metastasis. Therefore, we aimed to investigate the role of CD44 gene polymorphisms in breast cancer risk and prognosis in North Indian population. Materials & Methods: A total of 258 breast cancer patients and 241 healthy controls were included in the case-control study for risk prediction. According to RECIST, 114 patients who received neo-adjuvant chemotherapy were recruited for the evaluation of breast cancer prognosis. We examined the association of tagging SNP (rs353639) of Hapmap Gujrati Indians in Houston (GIH population) in CD44 gene along with a significant reported SNP (rs13347) in Chinese population by genotyping using Taqman allelic discrimination assays. Statistical analysis was done using SPSS software, version 17. In-silico analysis for prediction of functional effects was done using F-SNP and FAST-SNP. Results: No significant association of both the genetic variants of the CD44 gene polymorphisms was found with breast cancer risk. On performing univariate analysis with clinicopathological characteristics and treatment response, we found significant association of genotype (CT+TT) of rs13347 polymorphism with earlier age of onset (P = 0.029, OR = 0.037). However, significance was lost in multivariate analysis. For rs353639 polymorphism, significant association was seen with clinical tumour size, both at the genotypic (AC+CC) (P = 0.039, OR = 3.02) as well as the allelic (C) (P = 0.042, OR = 2.87) levels. On performing multivariate analysis, increased significance of variant genotype (P = 0.017, OR = 4.29) and allele (P = 0.025, OR = 3.34) of rs353639 was found with clinical tumour size. In-silico analysis using F-SNP, showed altered transcriptional regulation for rs353639 polymorphism. Conclusions: These findings suggest that CD44 rs353639 genetic variants may have significant effect in breast cancer prognosis. However, both the polymorphisms- rs13347 and rs353639 had no effect on breast cancer susceptibility. [ABSTRACT FROM AUTHOR]

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]

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]

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]

Abstract: Objective(s): Targeting the Toll-like receptor (TLR) signaling pathway in elucidating the cellular and molecular mechanisms of human diseases, including cervical cancer, is gaining tremendous importance. The aim of our study was to identify the role of TLR 2(−196 to −174 del) and TLR 4(Asp299Gly and Thr399Ile) gene polymorphisms in cervical cancer susceptibility in North Indian women. Methods: For the study, blood samples were collected from histopathologically confirmed patients of cervical cancer (n =150) and unrelated, healthy female controls of similar ethnicity (n =150). Genomic DNA was extracted from peripheral blood leukocytes using salting-out method. TLR 2 and TLR 4 genotyping was done using Polymerase Chain Reaction and Restriction Fragment Length Polymorphism followed by 10% polyacrylamide gel electrophoresis. Results: TLR 2 del allele showed significant association (p =0.048, OR=1.6 [95%CI=1.00–2.51]) with cervical cancer susceptibility, while no significant association was found with TLR 4 (Asp299Gly and Thr399Ile). However, TLR 4 Thr/Ile genotype was found to be significantly associated with early stage (Stage II) of cervical cancer (p =0.044, OR=2.51 [95%CI=1.03–6.12]). Furthermore, TLR 2 ins/del genotype showed strong association (p =0.015, OR=1.95 [95%CI=1.14–3.33]) with tobacco usage in women with cervical cancer. Conclusion(s): Our study highlighted the involvement of TLR 2 (−196 to −174 del) and TLR 4 (Thr399Ile) gene polymorphisms in cervical cancer susceptibility. The TLR gene polymorphisms, upon further evaluation, may be helpful in elucidation of immunobiological mechanisms associated with cervical cancer susceptibility. [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]

Background & aim: The progression rate of chronic kidney disease (CKD) to its end-stage renal disease (ESRD), and the development and severity of various complications, are indirectly influenced by genetic and epigenetic factors. Chemokines are small inducible pro-inflammatory cytokines, which are implicated in many biological processes like migration of leukocytes, angiogenesis, tumor growth and metastasis. We tested association of four single nucleotide polymorphisms (SNPs) viz. CCL2I/D, CCL2A2518G, CXCL12G801A and CXCR2(+1208)C/T among individuals with ESRD (end stage renal disease) and normal healthy controls from North Indian population. Materials and method: CCL21/D, CCL2A2518G, CXCL12G801A and CXCR2(+1208)C/T were genotyped in blood samples of hospital-based case-control study comprising of 200 ESRD cases and 200 healthy controls using Restriction Fragment Length Polymorphism (RFLP) and ARMS (Amplification Refractory Mutation Specific) PCR methodology. Results: A significant association was found in CXCL12G801A with ESRD risk. In case of CXCL12G801A polymor-phism heterozygous (GA) genotype showed significant risk (p = 0.039; OR = 1.55) whereas A allele carrier (GA + AA) also exhibited risk with ESRD (p = 0.045, OR = 1.59). In CXCR2(+1208)C/T polymorphism, the heterozygous genotype (CT) showed significant risk for ESRD (p = 0.028; OR = 1.65) and combination of CT + TT demonstrated significant high risk for ESRD (p = 0.036; OR = 1.52). In case of CCL21/D, the variant genotype (D/D) showed reduced risk for ESRD patients. Upon analyzing the gene-gene interaction between CXCR2 and CXCL12, the combination (CT-GA) showed 2.65 fold risk for ESRD (p = 0.018). Conclusion: Our results indicated that polymorphism in CXCU2G801A and CXCR2( +1208)C/T showed high risk for ESRD in North Indian population. However, CCL2I/D showed reduced risk and CCL2A2518G exhibited no association. Study with large sample size and diverse ethnicity is required to validate these observations. [ABSTRACT FROM AUTHOR]

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]