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Objective: Cholesterol gallstone disease (CGD) is a multifactorial and multistep disease. Apart from female gender and increasing age being the documented non-modifiable risk factor for gallstones the pathobiological mechanisms underlying the phenotypic expression of CGD appear to be rather complex, and one or more variations in genes could play critical roles in the diverse pathways further progressing to cholesterol crystal formation. In the present study we performed genotyping score, Multifactor dimensionality reduction (MDR) and Classification and Regression Tree analysis (CART) to identify combinations of alleles among the hormonal, hepatocanalicular transporter and adipogenesis differentiation pathway genes in modifying the risk for CGD. Design: The present case-control study recruited total of 450 subjects, including 230 CGD patients and 220 controls. We analyzed common ESR1, ESR2, PGR, ADRB3, ADRA2A, ABCG8, SLCO1B1, PPARγ2, and SREBP2 gene polymorphisms to find out combinations of genetic variants contributing to CGD risk, using multi-analytical approaches (G-score, MDR, and CART). Results: Single locus analysis by logistic regression showed association of ESR1 IVS1-397C>T (rs2234693), IVS1-351A>G (rs9340799) PGR ins/del (rs1042838) ADRB3-190 T>C (rs4994) ABCG8 D19H (rs11887534), SLCO1B1 Exon4 C>A (rs11045819) and SREBP2 1784G>C (rs2228314) with CGD risk. However, the MDR and CART analysis revealed ESR1 IVS1-397C>T (rs2234693) ADRB3-190 T>C (rs4994) and ABCG8 D19H (rs11887534) polymorphisms as the best polymorphic signature for discriminating between cases and controls. The overall odds ratio for the applied multi-analytical approaches ranged from 4.33 to 10.05 showing an incremental risk for cholesterol crystal formation. In conclusion, our muti-analytical approach suggests that, ESR1, ADRB3, in addition to ABCG8 genetic variants confer significant risk for cholesterol gallstone disease. [ABSTRACT FROM AUTHOR]

Gallstone disease is an important cause of abdominal morbidity Organic anion transport protein 1B1 (OATP1B1) (encoded by SLCO1B1) is a major transporter protein for bile salt uptake in enterohepatic circulation of bile salts. Disturbance in this pathway can decrease relative concentration of bile salts in gallbladder and may lead to formation of gallstones. We investigated role of SLCO1B1 polymorphisms [(Exon4 C > A (Pro155Thr; rs11045819) and Ex6 + 40T > C (Val174Ala; rs4149056)] in conferring interindividual susceptibility to gallstone disease. A total of 173 healthy controls and 226 gallstone patients (USG positive) were recruited. Genotyping was done by using standard polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) method. The observed control frequencies of both polymorphisms of SLCO1B1 gene [(Exon4 C > A (Pro155Thr; rs11045819) and Ex6 + 40T > C (Val174Ala; rs4149056)] were in agreement with Hardy-Weinberg equilibrium. The frequency CA genotype and A allele of Exon4 C > A polymorphism was higher in gallstones patients (12.4% and 6.2%) as compared to controls (5.2% and 2.6%) which was statistically significant [( P = 0.029; OR = 2.31; 95% CI = 1.1-5.0); ( P = 0.034; OR = 2.22; 95% CI = 1.1-4.8)], respectively). However, distribution of genotypes and alleles of Ex6 + 40T > C polymorphism was almost similar between gallstone patients and controls. Haplotype analysis showed frequency of A,T haplotype consisting of was significantly higher in gallstone patients as compared to controls and was imposing risk for the disease ( P = 0.036; OR = 2.34; 95% CI = 1.0-5.1). These results suggest that SLCO1B1 Exon4 C > A polymorphism confers increased risk for gallstone disease in North Indian population. [ABSTRACT FROM AUTHOR]

The excretion of cholesterol from the liver is regulated by the ATP-binding cassette transporter ABCG8. A common genetic polymorphism D19H of ABCG8 might be related to the genetic predisposition of gallstone disease, which is causatively related to supersaturation of cholesterol in bile. We aimed to examine the role of the ABCG8 D19H (rs11887534) polymorphism in susceptibility to gallstone disease in the northern Indian population. The study included 220 confirmed gallstone patients and 230 controls. Genotyping for the ABCG8 D19H polymorphism was carried out using the PCR-RFLP method. We observed that the ABCG8 DH genotype frequency was significantly higher in gallstone patients ( P = 0.038; odds ratio [OR] = 2.20; 95% confidence interval [CI] = 1.1-4.6). At allele level also, the ABCG8 variant allele conferred an increased risk for gallstone susceptibility ( P = 0.043; OR = 2.12; 95% CI = 1.2-4.3). The risk as a result of ABCG8 D19H variation was more pronounced in female gallstone patients at genotype ( P = 0.026; OR = 3.01, 95% CI = 1.1-7.9) as well as allele level ( P = 0.030; OR = 2.85; 95% CI = 1.1-7.3). However, the molecular modeling results of the rs11887534 polymorphism showed that the overall configuration of both wild-type and polymorphic ABCG8 protein were similar, with negligible deviation at the site of polymorphism. Carriers of the DH genotype and H allele of the ABCG8 D19H polymorphism harbor a higher risk for gallstone susceptibility in the northern Indian population. [ABSTRACT FROM AUTHOR]

Gall bladder cancer (GBC) is a relatively rare but highly fatal disease, particularly in North India. The angiotensin I-converting enzyme ( ACE) insertion/deletion (I/D) gene polymorphism influences serum angiotensin II action, which has been associated with various malignancies. This population-based case–control study was undertaken to examine the potential association of ACE I/D variation with GBC in a North Indian population. Genotypes and allelic frequencies of the ACE I/D polymorphism (rs4646994) were determined for 233 GBC patients and 260 cancer-free controls randomly selected from the population using polymerase chain reaction. Odds ratio (OR) and 95% confidence interval were calculated in multivariate logistic regression analysis for the association of ACE polymorphism with GBC. The ACE I/D polymorphism was found to be nonsignificantly associated with an overall increased risk of GBC (OR = 1.04 and 1.38 for I/D and D/D genotypes, respectively; ptrend = 0.375). The increased risk was predominant significantly in female cohort and nonsignificantly in GBC patients with gallstone status (OR = 1.63; p = 0.039 and OR = 1.37; p = 0.187, respectively). In summary, ACE I/D polymorphism may alter the susceptibility to GBC, especially in women. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) are small, non-coding RNA molecules that function as negative regulators of gene expression. Common genetic variants (single nucleotide polymorphisms, SNPs) in miRNA genes may alter their expression or maturation resulting in varied functional consequences. Present case–control study evaluated the potential association of three SNPs (rs2910164, rs11614913 and rs3746444) in pre-miRNAs with gallbladder cancer (GBC) risk in 230 GBC cases and 230 controls in a North Indian population. Odds ratio (OR) and 95% confidence interval (95% CI) were calculated for the association of individual SNPs and their interactions with GBC. A non-significant increased risk was observed between carriers of variant genotypes of rs2910164, rs11614913 and rs3746444 (ORs=1.3, 1.3 and 1.1, respectively). This increased risk was more profound in GBC patients with gallstones (ORs=1.4, 1.6 and 1.1, respectively). To further evaluate the cumulative effects of the variant allele, we did a combined unfavorable genotype analysis, which showed a borderline statistical significance. In comparison with the low-risk group (0–2 variant alleles), the high-risk group (>2 variant alleles) had a 1.7-fold (95% CI=1.0–2.8) increased risk for GBC (Ptrend=0.056). These findings suggest, for the first time, that common miRNA variants may not contribute to GBC susceptibility in North Indian population. [ABSTRACT FROM AUTHOR]

The article offers information on the association of gene polymorphism with insulin resistance in a north Indian population. Topics discussed include genetic association of ENPP1/PC-1 K121Q polymorphism with obesity, homeostasis model assessment, and statistical analysis of alleles. Also present a table depicting clinical characteristics of study participants.

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]

Objectives: The worldwide increasing prevalence of obesity is considered as a major health problem. Peroxisome proliferator-activated receptor gamma ( PPAR-γ) controls adipocyte differentiation and regulates a number of genes associated with energy homeostasis. In this study, we investigated the association of PPAR-γ gene Pro12Ala (rs1801282) and C1431T (rs3856806) polymorphisms with morbid obesity and related phenotypes, in north Indian population. Methods: A total of 6,42 subjects, 309, obese and 333 nonobese individuals were included in this case-control study. Insulin, adiponectin, glucose, and lipid levels were estimated using standard protocols. All subjects were genotyped by PCR restriction fragment length polymorphism (PCR-RFLP) method. Results: The ProAla+AlaAla genotypes of PPAR-γ Pro12Ala were significantly associated with higher risk of obesity while C1431T polymorphism did not show any significant association. None of the haplotypes showed association with morbid obesity. However, a strong association of variant genotypes was observed with higher levels of insulin, HOMA-IR, and lower serum adiponectin concentrations. Conclusion: PPAR-γ gene polymorphisms influence obesity and obesity phenotype in a complex manner, probably involving insulin resistance in north Indian population. Am. J. Hum. Biol., 2012. © 2012 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Srivastava P, Singh A, Kesarwani P, Jaiswal PK, Singh V, Mittal RD. Association studies of Toll-like receptor gene polymorphisms with allograft survival in renal transplant recipients of North India. Abstract: Organ transplantation itself inevitably activates the innate immune system by Toll-like receptors (TLRs), potentially leading to allograft rejection and graft failure. We evaluated the possible association of TLR2, TLR3, and TLR9 polymorphisms of donor-recipient pairs and acute rejection in renal transplant patients of North India. TLR2 (−196 to −174 del), TLR3 (c.1377C/T; rs 3775290), and TLR9 (+2848 G/A; rs 352140) were genotyped using DNA samples from 200 donor-recipient pairs of live donor kidney transplantation by applying Restriction Fragment Length Polymorphism (RFLP) methodology. The variant allele frequency of TLR2 (−196 to −174 del) was significantly different between recipients and donors (7.5% vs. 5.0%; p = 0.049; OR = 3.9; 95%CI = 1.01-15.32). However, no significant association for allograft rejection was observed in transplant recipients for TLR3 and TLR9. Interestingly, a low prevalence of AA genotype of TLR9 + 2848 G>A was observed in rejecters when compared with non-rejecters, demonstrating protective association with allograft rejection (OR = 0.30, 95% CI = 0.12-0.88, p = 0.028). An allele in patients was also observed to be associated with higher rejection-free survival (log-rank = 0.044). These TLR gene polymorphisms, upon further evaluation, may be helpful in elucidation of immunobiological mechanisms associated with renal graft rejection. [ABSTRACT FROM AUTHOR]

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]

There is a paucity of data on the prevalence of elevated homocysteine and its relation with plasma folate and the methylenetetrahydrofolate reductase ( MTHFR) gene in the population of North India. This study evaluates MTHFR gene polymorphism and its relationship with plasma homocysteine and folate levels in a healthy North Indian population. The age of the 200 subjects included in this study was in the range 18–73 (mean 39.4) years. The plasma homocysteine level was elevated in 56.5%, and the plasma folate level was low in 49.5% of the subjects. Heterozygous MTHFR gene polymorphism (CT) was present in 15.5%, and homozygous (TT) in 3.5% of the subjects. Age, diet, and MTHFR gene polymorphisms were related to homocysteine level. All the subjects with the TT and 79% with the CT genotype had a high level of plasma homocysteine, whereas 51% with the CC genotype had a high homocysteine level. After adjustment for the effect of covariates, however, homocysteine was not related to MTHFR gene polymorphism. [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]

Abstract: Background: Tumour necrosis factor alpha is a multifunctional proinflammatory cytokine involved in the pathogenesis of metabolic syndrome, insulin resistance, and obesity. Aim of this study is to investigate in a North Indian female population the impact of the G-308A TNF-α variant on various components of the metabolic syndrome, Insulin Resistance, serum TNF-α and Leptin levels. Methods: The G-308A TNF-α polymorphism has been studied in 269 females with metabolic syndrome (NCEP ATP III criteria) (age 31.91±6.05) and 272 healthy females without metabolic syndrome (age 30.96±7.01). The G-308A variant was detected by PCR amplification and Nco-1 digestion. Results: Homozygous mutant genotype (AA) (p=<0.001: OR=3.24: 95% CI=2.15–4.89) and mutant allele (A) (p=<0.001: OR=3.04: 95% CI=2.08–4.43) of TNF-α was significantly less frequently observed in the control population as compared to study group. Furthermore, on dividing the subjects into two groups according to the absence (TNF-1 allele) or presence of the mutant A (TNF-2) allele, significant results were obtained in most of the metabolic risk factors. Conclusions: Our results suggest that the G-308A polymorphism of the TNF-α gene may be independently associated with hypertension, leptin level and hypercholesterolemia leading to metabolic syndrome independent of Insulin resistance and hyperglycemia. [Copyright &y& Elsevier]