Search

Background: Obesity is an increasingly important health problem worldwide as well as in developing countries like India. Recent genetic studies suggest that obesity associatedFTOandIRX3are functionally linked and many effects due to genetic variants inFTOgene act throughIRX3. Aim: To evaluate the association ofFTOandIRX3genetic variants towards obesity risk. Subjects and methods: North Indian individuals categorised as non-obese (BMI < 30 kg/m2) and obese (BMI ≥ 30 kg/m2) were selected.FTOrs8050136, rs1421085, rs9939609, rs17817449 andIRX3rs3751723 were genotyped by means of validated Taqman® allelic discrimination to evaluate their association with obesity by means of single locus logistic regression by SPSS ver. 19 and multi-locus linkage and haplotype analysis by SNPStats and gene–gene interaction with Generalised Multifactor Dimensionality Reduction (GMDR) ver.6. Results: In single locus analysis,FTOrs8050136 CA (p = 0.0001; OR (95% CI) = 2.4 (1.7–3.4) and AA (p = 0.0001; OR (95% CI) = 3.1 (1.9–5.2);FTOrs1421085 TA (p = 0.0001; OR (95% CI) = 2.1 (1.4–3.0) and AA (p = 0.0001; OR (95% CI) = 3.0 (1.8–5.0);FTOrs9939609 TC (p = 0.0001; OR (95% CI) = 2.1 (1.5–3.1) and CC (p = 0.0001; OR (95% CI) = 4.2 (2.5–7.3) along with TG (p = 0.001; OR (95% CI) = 2.1 (1.3–3.2) and GG (p = 0.021; OR (95% CI) = 3.8 (1.2–11.8) genotypes ofFTOrs17817449 with GT (p = 0.0001; OR (95% CI) = 2.1 (1.5–3.1) and TT (p = 0.012; OR (95% CI) = 3.3 (1.8–3.6) genotypes ofIRX3rs3751723 were significantly associated with obesity. In multi-locus analysis, SNPs ofFTOandIRX3were in strong linkage disequilibrium and in haplotype and GMDR analysis the SNPs were significantly associated with obesity risk (p < 0.05). Conclusion: This is the first study to reveal that genetic variants of bothFTOandIRX3genes are in high linkage disequilibrium (LD) and are associated with obesity risk in North Indians. [ABSTRACT FROM AUTHOR]

Gallbladder cancer (GBC) is the most common malignancy of the biliary tract with adverse prognosis and poor survival. Wnt signaling plays an important role in embryonic development and regeneration of tissues in all the species. Deregulation of expression and mutations in this pathway may lead to disease state such as cancer. In this study, we assessed the association of common germline variants of Wnt pathway genes (SFRP2, SFRP4, DKK2, DKK3, WISP3, APC, β-catenin, AXIN-2, GLI-1) to evaluate their contribution in predisposition to GBC and treatment outcomes. The study included 564 GBC patients and 250 controls. Out of 564, 200 patients were followed up for treatment response and survival. Tumor response (RECIST 1.1) was recorded in 116 patients undergoing non-adjuvant chemotherapy (NACT). Survival was assessed by Kaplan-Meier curve and Cox-proportional hazard regression. Single locus analysis showed significant association of SFRP4 rs1802073G > T [ p value = 0.0001], DKK2 rs17037102C > T [ p value = 0.0001], DKK3 rs3206824C > T [ p value = 0.012], APC rs4595552 A/T [ p value = 0.021], APC rs11954856G > T [ p value = 0.047], AXIN-2 rs4791171C > T [ p value = 0.001], β-catenin rs4135385A > G [ p value = 0.031], and GLI-1 rs222826C > G [ p value = 0.001] with increased risk of GBC. Gene-gene interaction using GMDR analysis predicted APC rs11954856 and AXIN2 rs4791171 as significant in conferring GBC susceptibility. Cox-proportional hazard model showed GLI-1 rs2228226 CG/GG and AXIN-2 rs4791171 TT genotype higher hazard ratio. In recursive partitioning, AXIN-2 rs4791171 TT genotype showed higher mortality and hazard. Most of studied genetic variants influence GBC susceptibility. APC rs11954856, GLI-1 rs2228226, and AXIN-2 rs4791171 were found to be associated with poor survival in advanced GBC patients. [ABSTRACT FROM AUTHOR]

Background: Obesity is a multi-factorial disorder influenced by genetic and environmental factors. The physiological pathways associated with obesity are complex and involve several genes. Aim: The aim of this survey is to evaluate the association of genetic variants of melanocortin-4-receptor (MC4R), pro-opiomelanocortin (POMC), apolipoprotein E (APOE) and agouti-related protein (AGRP) with obesity in the North Indian population. Methods: MC4R rs17782313, POMC rs1042571, APOE-Hha1and AGRP rs3412352 polymorphisms were investigated for their association in 396 obese individuals with BMI ≥ 30 kg/m2and 300 healthy non-obese individuals with BMI < 30 kg/m2. Genotyping was performed using Taqman probes and PCR-RFLP methods. Single locus logistic regression analysis was conducted using (SPSS), ver.19 and PLINK software Version 1.01 and high order genetic interactions associated with obesity risk were analysed using MDR software (version 2.3.0.2). Results: The genotypes of MC4R rs17782313, POMC rs1042571 and APOE-Hha1were significantly associated with obese individuals (BMI ≥ 30 kg/m2) when compared with non-obese individuals (BMI < 30 kg/m2). No association of AGRP rs34123523 was seen with obesity. Conclusions: The best interaction model for predicting obesity risk by MDR analysis was the three factor model including POMC (C > T), MC4R (T > C) and APOE (Hha1) polymorphisms. Genetic variants in MC4R, POMC and APOE genes might play significant roles in predisposing obesity (BMI ≥ 30 kg/m2) in the North Indian population. [ABSTRACT FROM PUBLISHER]

The ABCB1 gene encodes a permeability glycoprotein, which is one of the most extensively studied human adenosine-triphosphate (ATP)-dependent efflux transporters. Permeability glycoprotein is expressed in the apical membranes of tissues such as intestine, liver, blood-brain barrier, kidney, placenta, and testis and contributes to intracellular drug disposition. It is also highly expressed in tumor cells conferring drug resistance, which is one of the major problems in the efficacy of cancer chemotherapy treatment. ABCB1 is highly polymorphic, and three well-known single-nucleotide polymorphisms such as 1236C.T, 2677G.T/A, and 3435C.T have been found to be associated with altered messenger RNA levels, protein folding, and drug pharmacokinetics. Many association studies and meta-analyses have demonstrated the clinical impact of ABCB1 polymorphisms in breast cancer treatment outcomes with respect to therapeutic response, chemotoxicity, and overall survival. Therefore, the aim of this review was to evaluate the effects of ABCB1 polymorphisms on the outcome of breast cancer treatment which, in future, would be important for tailoring individualized anticancer therapy. [ABSTRACT FROM AUTHOR]

Genes important to stem cell progression have been involved in the genetics and clinical outcome of cancers. We investigated germ line variants in cancer stem cell (CSC) genes to predict susceptibility and efficacy of chemoradiotherapy treatment in gallbladder cancer (GBC) patients. In this study, we assessed the effect of SNPs in CSC genes (surface markers CD44, ALCAM, EpCAM, CD133) and (molecular markers NANOG, SOX-2, LIN-28A, ALDH1A1, OCT-4) with GBC susceptibility and prognosis. Total 610 GBC patients and 250 controls were genotyped by using PCR-RFLP, ARMS-PCR, and TaqMan allelic discrimination assays. Chemotoxicity graded 2-4 in 200 patients and tumor response was recorded in 140 patients undergoing neoadjuvant chemotherapy (NACT). Differences in genotype and haplotype frequency distributions were calculated by binary logistic regression. Gene-gene interaction model was analyzed by generalized multifactor dimensionality reduction (GMDR). Overall survival was assessed by Kaplan-Meier survival curve and multivariate Cox-proportional methods. ALCAM AC ( P = 0.0035) haplotype was significantly associated with GBC susceptibility. In GMDR analysis, ALCAM rs1157G>A, EpCAM rs1126497T>C emerged as best significant interaction model with GBC susceptibility and ALDH1A1 rs13959T>G with increased risk of grade 3-4 hematological toxicity. SOX-2 rs11915160A>C, OCT-4 rs3130932T>G, and NANOG rs11055786T>C were found best gene-gene interaction model for predicting response to NACT. In both Cox-proportional and recursive partitioning ALCAM rs1157GA+AA genotype showed higher mortality and hazard ratio. ALCAM gene polymorphisms associated with GBC susceptibility and survival while OCT-4, SOX-2, and NANOG variants showed an interactive role with treatment response. [ABSTRACT FROM AUTHOR]

Multiple studies have investigated the association of gene variant of Deleted in colorectal carcinoma (DCC) and Prostate Stem cell antigen (PSCA) with various cancer susceptibility; however, the results are discrepant. Since SNPs are emerging as promising biomarker of cancer susceptibility, here, we aimed to execute a meta-analysis of DCC (rs714 A > G) and PSCA (rs2294008 C > T, rs2976392 G > A) polymorphism to demonstrate the more accurate strength of these associations. We followed a rigorous inclusion/exclusion criteria and calculated the pooled odds ratios (ORs) and 95% confidence intervals (CIs). Overall, the pooled analysis showed that the DCC rs714 conferred increased risk of cancer only in Asians (AA vs. GG: OR = 1.86, p ≤ 0.0001; AG vs. GG: OR = 1.43, p = 0.005; GA + AA vs. GG: OR = 1.66, p ≤ 0.0001; AA vs. GG + GA; OR = 1.52, p ≤ 0.004, A vs. G allele: OR = 1.41, p ≤ 0.0001). PSCA rs2294008 was associated with increased overall cancer risk (TT vs. CC: OR = 1.28, p = 0.002; CT vs. CC: OR = 1.21, p ≤ 0.0001; CT + TT vs. CC: OR = 1.24, P ≤ 0.0001; TT vs. CC + CT; OR = 1.17, p ≤ 0.005, T vs. C allele: OR = 1.16, p ≤ 0.0001); however, in stratified analysis this association was limited only to gastric and bladder cancer and the strength was more prominent in Asians. In contrast, the PSCA rs2976392 SNP did not modulate the cancer risk. Therefore, we concluded that rs714 and rs2294008 polymorphism may represent a potential genetic biomarker for cancer risk in Asians and gastric as well as bladder cancer, respectively. However, since our study is limited to Asians and cancer types, further larger studies involving other cancers and/or population, gene-environment interactions and the mechanism of DCC and PSCA gene deregulation are desired to define the role of genotype with overall cancer risk. [ABSTRACT FROM AUTHOR]