Rama Mittal
Research interests
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InterestsCancer Genetics, Pharmacogenetics, Kidney Transplantation, Epidemiologic Studies
Publications
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Caspase 8 gene variants in healthy North Indian population and comparison with worldwide ethnic group variations
Indian Journal of Human Genetics. 01/2010;
Background: Many strategies are being used for the quest for the disease causing genes. Inter-individual variations in several genes exist. Thus, even if they share the same disease-associated allele, the genomic backgrounds - and hence potential interacting alleles at other loci - of people with di... [more] Background: Many strategies are being used for the quest for the disease causing genes. Inter-individual variations in several genes exist. Thus, even if they share the same disease-associated allele, the genomic backgrounds - and hence potential interacting alleles at other loci - of people with different regional ancestries may differ, with a consequent variation in the severity of their disease. Materials and Method : The present study was conducted to determine the distribution of Caspase 8 IVS12-19G/A, Caspase 8D302H, Caspase 8 -652del and Caspase 8 -678del polymorphisms (as frequency distribution of caspases in Indians generally is not yet known), which was then compared with different populations globally. Polymerase chain reaction (PCR)-based analysis was conducted in 205 normal healthy individuals of similar ethnicity. Results : The variant allele frequencies were 17.6% (A) in Caspase 8 IVS12-19G/A, 13.2% (H) in Caspase 8D302H, 23.2% (Del) in Caspase 8 -652del and 24.6% (Del) in Caspase 8 -678del. Further, comparison of frequency distribution of these genes was done with various published studies of different ethnic groups globally. Conclusion : It is anticipated from our results that the frequency of these caspase genes exhibits distinctive patterns in India, which could perhaps be attributed to ethnic variation. This study is important as it can form a baseline for screening individuals who are at high risk due to exposure to environmental carcinogens and cancer predisposition, and therefore, might help in investigating linked polymorphisms in a way that will not obscure potential associations between genotype and phenotype.
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2.26Impact points
XPC gene variants: a risk factor for recurrence of urothelial bladder carcinoma in patients on BCG immunotherapy.
Journal of cancer research and clinical oncology. 11/2009;
PURPOSE: To investigate the association between two Xeroderma pigmentosum group C polymorphism (XPC Lys939Gln and insertion/deletion PAT -/+ in intron 9) and bladder cancer (BC) susceptibility. MATERIALS AND METHODS: Genotyping was performed in 208 BC patients and 245 controls by PCR-RFLP method. RE... [more] PURPOSE: To investigate the association between two Xeroderma pigmentosum group C polymorphism (XPC Lys939Gln and insertion/deletion PAT -/+ in intron 9) and bladder cancer (BC) susceptibility. MATERIALS AND METHODS: Genotyping was performed in 208 BC patients and 245 controls by PCR-RFLP method. RESULTS: XPC PAT +/+ genotype was associated with elevated risk of BC (p = 0.021, OR = 2.49). XPC Lys939Gln AC + CC genotype was significantly associated with risk in invasive stage of BC (p = 0.041, OR = 2.52). Haplotype analysis revealed that variant genotypes C of XPC Lys939Gln and + of PAT, C+ were significantly associated with risk of BC (p = 0.004, OR = 1.70). The CC genotype of Lys939Gln was associated with high risk for recurrence in BCG-treated patients (HR = 3.21, p = 0.036) thus, showing reduced recurrence-free survival (AC + CC/AA = 36/60 months; log rank p = 0.045). CONCLUSION: Polymorphisms and haplotypes in XPC appear to influence susceptibility to BC risk. The variant C allele at Lys939Gln may be responsible for early recurrence in BCG-treated patients.
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Role of Xenobiotic-Metabolizing Enzyme Gene Polymorphisms and Interactions with Environmental Factors in Susceptibility to Gastric Cancer in Kashmir Valley.
Journal of gastrointestinal cancer. 07/2009;
BACKGROUND: Kashmir Valley has elevated incidence rate of gastric cancer (GC) and several environmental, host genetic factors have been suspected for it. Xenobiotic carcinogen exposure and interindividual differences in its cellular metabolism may modulate susceptibility to GC. AIM OF THE STUDY: The... [more] BACKGROUND: Kashmir Valley has elevated incidence rate of gastric cancer (GC) and several environmental, host genetic factors have been suspected for it. Xenobiotic carcinogen exposure and interindividual differences in its cellular metabolism may modulate susceptibility to GC. AIM OF THE STUDY: The aim of this study is to investigate the role of genetic variants of xenobiotic-metabolizing genes with susceptibility to GC in Kashmir Valley. METHODS: A case-control study was performed in 303 subjects (108 GC and 195 healthy controls) to analyze the association of polymorphisms in GSTM1, GSTT1, GSTP1, GSTM3, CYP1A1, and CYP2E1 genes in susceptibility to GC in Kashmir Valley. All subjects were genotyped through polymerase chain reaction-restriction fragment length polymorphism. RESULTS: GSTM1null and CYP2E1c1c2 genotypes imparted risk for GC (odds ratio [OR] = 1.98, 95% confidence interval [95%CI] = 1.22-3.21, P = 0.006 and OR = 2.56, 95%CI = 1.25-5.25, P = 0.010, respectively). GSTM3AB genotype/B allele was found to be associated with low risk for GC. Smokers and high salted tea consumers themselves were at higher risk for GC (OR = 8.98, 95%CI = 5.16-15.62, P = 0.0001 and OR = 14.78, 95%CI = 8.02-27.23, P = 0.0001, respectively). Cancer risk was further enhanced in smokers with the GSTM1null genotype. CONCLUSION: The results suggest that GSTM1null, GSTM3AB, and CYP2E1c1c2 genotypes modulate the risk of GC whereas GSTM1null genotypes enhance the risk of GC for smokers in the Kashmir population.
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4.13Impact points
Caspase 9 and Caspase 8 Gene Polymorphisms and Susceptibility to Bladder Cancer in North Indian Population.
Annals of surgical oncology. 06/2009;
BACKGROUND: Dysregulation of apoptosis plays a crucial role in carcinogenesis. Our aim was to investigate the association of Caspase 9 and Caspase 8 gene polymorphism with bladder cancer (BC) susceptibility. METHODS: We undertook a case-control study of 212 (BC) cases and 250 controls to investigate... [more] BACKGROUND: Dysregulation of apoptosis plays a crucial role in carcinogenesis. Our aim was to investigate the association of Caspase 9 and Caspase 8 gene polymorphism with bladder cancer (BC) susceptibility. METHODS: We undertook a case-control study of 212 (BC) cases and 250 controls to investigate the association between Caspase 9-1263A > G, Caspase 9-293del, and Caspase 8-6 N ins/del polymorphism and BC susceptibility by polymerase chain reaction (PCR) restriction fragment length polymorphism (RFLP) method, and further to study the influence on recurrence in patients after Bacillus Calmette-Guerin (BCG) immunotherapy. RESULTS: Overall, no statistically significant association was observed in Caspase 9-293del and Caspase 8. Nevertheless, Caspase 9-1263GG genotype was at reduced risk of BC [p = 0.010; odds ratio (OR) = 0.487]. Caspase 9-1263AG genotype was also observed to be significantly associated with reduced risk with high-risk non-muscle-invasive bladder cancer (NMIBC) (TaG(2-3), T1G(1-3)) and invasive tumors (T2 +) of BC (P = 0.042, OR = 0.39 and P = 0.013, OR = 0.028 respectively). Caspase 9-293del, heterozygous (-/+) genotype, too, demonstrated protective effect in high-risk NMIBC (P = 0.017; OR = 0.205). Haplotype analysis revealed variant genotypes Caspase 9AG + GG/Caspase 8 DI + II to be at reduced risk of BC (= 0P.014, OR = 0.47). The GG genotype of Caspase 9-1263 was associated with reduced risk for recurrence in BCG-treated patients [hazard ratio (HR) = 0.217, P = 0.005], thus showing increased recurrence-free survival (log-rank P = 0.024). CONCLUSION: Polymorphism in Caspase 9-1263 was observed to play a protective role in susceptibility to BC risk. Caspase 9 gene variants were also associated with reduced risk of NMBIC stages. The variant G allele at Caspase 9-1263 may be responsible for increased recurrence-free survival in BCG-treated patients.
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1.23Impact points
Impact of nucleotide excision repair ERCC2 and base excision repair APEX1 genes polymorphism and its association with recurrence after adjuvant BCG immunotherapy in bladder cancer patients of North India.
Medical oncology (Northwood, London, England). 03/2009;
Background Altered DNA repair capacity due to polymorphisms in DNA repair genes may modify response to Bacillus Calmette-Guerin (BCG) immunotherapy for high risk superficial bladder cancer (SBC).We evaluated the prospective outcome of exicision repair cross complementing group 2 (ERCC2) and apurinic... [more] Background Altered DNA repair capacity due to polymorphisms in DNA repair genes may modify response to Bacillus Calmette-Guerin (BCG) immunotherapy for high risk superficial bladder cancer (SBC).We evaluated the prospective outcome of exicision repair cross complementing group 2 (ERCC2) and apurinic/apyriminidic endonuclease (APEX1) gene in tumor recurrence after BCG immunotherapy in SBC patients. Materials and methods The study included 135 SBC patients, of which BCG immunotherapy was received by 74 patients. Genotyping was performed for ERCC2 Asp(312)Asn (G > A), Lys751Gln (A > C), and APEX1 Asp(148)Glu (T > G) polymorphisms by restriction fragment length polymorphism PCR and amplification refractory mutation system (ARMS) methods. Results Multiple Cox regression analysis demonstrated association of variant genotype of ERCC2 (312)AA polymorphism with high risk of recurrence in BCG treated patients (HR = 3.07, P = 0.016, P ( c ) = 0.048). Patients with the ERCC2 (312)AA polymorphic genotypes showed shorter recurrence free survival (log-rank, P = 0.005; AA/GA + AA = 14/44) who received BCG treatment. Overall, risk of recurrence in bladder cancer was observed with smokers and size of tumors (1-3 cm) (HR = 1.86, P = 0.023 and HR = 3.19, P = 0.031, respectively). Smokers were identified to be at elevated risk in BCG treated patients (HR = 2.84, P = 0.005). No association was observed with the (ERCC2 Lys(751)Gln and APEX1 Asp(148)Glu) polymorphisms and risk of recurrence. Conclusion Our data suggested variant (AA) of ERCC2 312 AA genotype to be associated with high risk of tumor recurrence and reduced recurrence free survival in superficial bladder cancer patients.
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2.63Impact points
IL-10 -1082 G>A: a risk for prostate cancer but may be protective against progression of prostate cancer in North Indian cohort.
World journal of urology. 02/2009;
BACKGROUND: Chronic intraprostatic inflammation is suspected to play a major role in the pathogenesis of prostate cancer (PCa). Polymorphisms in interleukin-10 (IL-10), a key anti-inflammatory cytokine gene can influence immune response and immune evasion of tumor cells. Its role as an anti-metastat... [more] BACKGROUND: Chronic intraprostatic inflammation is suspected to play a major role in the pathogenesis of prostate cancer (PCa). Polymorphisms in interleukin-10 (IL-10), a key anti-inflammatory cytokine gene can influence immune response and immune evasion of tumor cells. Its role as an anti-metastatic molecule is also well documented. METHODS: Gene promoter polymorphisms in IL-10 (-1082 G>A and -819 C>T) was analyzed in 159 PCa patients and 259 healthy controls to investigate their potential association with susceptibility for PCa. RESULTS: Our results indicated that the heterozygous (GA) and homozygous mutant (AA) genotypes of IL-10 -1082 to be more prevalent among PCa patients in comparison to controls (GA: OR - 2.8, p = 0.011; AA: OR - 2.3, p = 0.037). More patients (92.5%) than controls (82.7%) were positive for the A allele (GA + AA: OR - 2.6, p = 0.015). We observed lower frequency of T(-819)-G(-1082) haplotype in patients without bone metastasis (4.4%, OR - 0.30, p = 0.019) in comparison to PCa patients with bone metastasis (12.6%). CONCLUSION: Our results support the emerging hypothesis that genetically determined immune activity may play a role in the pathophysiology of PCa. Our findings of high producer of IL-10 -1082 variants suggest initiation of PCa. Future studies in large cohort of different ethnicity PCa groups are warranted to establish definite associations with other cytokine gene polymorphisms.
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2.09Impact points
Implications of XRCC1, XPD and APE1 gene polymorphism in North Indian population: a comparative approach in different ethnic groups worldwide.
Genetica. 11/2008;
Identifying risk factors for human cancers should consider combinations of genetic variations and environmental exposures. Several polymorphisms in DNA repair genes have impact on repair and cancer susceptibility. We focused on X-ray repair cross-complementing group 1 (XRCC1), Xeroderma pigmentosum ... [more] Identifying risk factors for human cancers should consider combinations of genetic variations and environmental exposures. Several polymorphisms in DNA repair genes have impact on repair and cancer susceptibility. We focused on X-ray repair cross-complementing group 1 (XRCC1), Xeroderma pigmentosum D (XPD) and apurinic/apyrimidinic endonuclease (APE1) as these are most extensively studied in cancer. Present study was conducted to determine distribution of XRCC1 C26304T, G27466A, G23591A, APE1 T2197G and XPD A35931C gene polymorphisms in North Indian population and compare with different populations globally. PCR-based analysis was conducted in 209 normal healthy individuals of similar ethnicity. Allelic frequencies in wild type of XRCC1 C26304T were 91.1% C(Arg); G27466A 62.9% G(Arg); G23591A 60.3% G(Arg); APE1 T2197G 75.1% T(Asp) and XPD A35931C 71.8% A(Lys). The variant allele frequency were 8.9% T(Trp) in XRCC1 C26304T; 37.1% A(His) in G27466A; 39.7% A(Gln) in G23591A; 24.9% G(Glu) in APE1 and 28.2% C(Gln) in XPD respectively. We further compared frequency distribution for these genes with various published studies in different ethnicity. Our results suggest that frequency in these DNA repair genes exhibit distinctive pattern in India that could be attributed to ethnicity variation. This could assist in high-risk screening of humans exposed to environmental carcinogens and cancer predisposition in different ethnic groups.
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3.31Impact points
Association of GSTM3 intron 6 variant with cigarette smoking, tobacco chewing and alcohol as modifier factors for prostate cancer risk.
Archives of toxicology. 08/2008;
Variations in glutathione-S-transferases (GSTs) genes may alter the catalytic efficiency of GST isoenzymes leading to potential increase in susceptibility to carcinogens present in cigarette smoke and tobacco. The present study aimed to explore the association of GSTM3 intron 6 polymorphism with sus... [more] Variations in glutathione-S-transferases (GSTs) genes may alter the catalytic efficiency of GST isoenzymes leading to potential increase in susceptibility to carcinogens present in cigarette smoke and tobacco. The present study aimed to explore the association of GSTM3 intron 6 polymorphism with susceptibility to prostate cancer (PCa), and to assess risks associated with cigarette smoking, tobacco chewing and alcohol consumption in PCa patients of North India. The study included 135 PCa patients and 169 controls. All subjects were genotyped for 3-bp deletion in intron 6 of GSTM3. Risk of developing prostate cancer associated with GSTM3 AB + BB was 2.5-fold (OR = 2.51, P = 0.028) as compared to AA genotype. Patients who were either smokers and/or had alcohol habits demonstrated a strong association with GSTM3 (AB + BB) genotype (OR = 4.11, P = 0.046; OR = 4.38, P = 0.027, respectively). Our results suggested GSTM3 (AB + BB) genotype to be significantly associated with PCa risk. The risk was even more apparent in case of cigarette smokers and alcohol consumers.
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3.31Impact points
Genetic polymorphisms of cytochrome P450 CYP1A1 (*2A) and microsomal epoxide hydrolase gene, interactions with tobacco-users, and susceptibility to bladder cancer: a study from North India.
Archives of toxicology. 02/2008;
The role of low penetrance genes and environmental factors in the etiology of bladder cancer (CaB) is unclear, but may involve genetic and environmental factors. Most environmental pro-carcinogens require metabolic activation by phase I enzymes (CYP450s), However, phase II enzyme (i.e., microsomal e... [more] The role of low penetrance genes and environmental factors in the etiology of bladder cancer (CaB) is unclear, but may involve genetic and environmental factors. Most environmental pro-carcinogens require metabolic activation by phase I enzymes (CYP450s), However, phase II enzyme (i.e., microsomal epoxide hydrolase: mEH) is mainly involved in the detoxification of wide variety of endogenous or exogenous carcinogens. Genetic differences in CYP1A1 gene and the mEH gene polymorphisms have been reported to be associated with susceptibility to various cancers. In our case-control study, we assess whether Msp1 polymorphism of CYP1A1 (CYP1A1*2A), and His(113) in exon 3 and Arg(139) in exon 4 of the mEH susceptibility genotypes, tobacco-use and age factors contribute to bladder cancer risk among Indians. A case-control study was conducted in 106 bladder cancer (CaB) patients and 160 age matched controls from similar ethnic background. The CYP1A1*2A and mEH genotypes were determined by polymerase chain reaction/restriction fragment length polymorphism method from DNA extracted from peripheral blood samples. Binary logistic regression model was used for assessing differences in genotype prevalence between patients and the controls. The Arlequin software package was used to compute haplotype frequencies. We observed non-significant association in T/C polymorphism of the CYP1A1 gene (CYP1A1*2A); however, the exon 3 His genotype of the mEH gene polymorphism alone (odds ratio = 2.67, P = 0.001) or in combination with tobacco-users were significantly associated with the risk of bladder cancer. No associations were observed with stage or grade of bladder tumor with these genotypes. In conclusion, our study demonstrated that exon 3 His genotype of the mEH are more prone to the risk of sporadic bladder cancer in North India.
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2.71Impact points
XRCC1 Codon 399 Mutant Allele: A Risk Factor for Recurrence of Urothelial Bladder Carcinoma in Patients on BCG Immunotherapy.
Cancer biology & therapy. 02/2008; 7(5).
XRCC1 protein plays crucial role in base excision repair (BER) by acting as a scaffold for other BER enzymes. Variants in XRCC1 gene might alter protein structure/function or create alternatively spliced protein influencing BER efficiency and affect individual susceptibility/recurrence to urinary bl... [more] XRCC1 protein plays crucial role in base excision repair (BER) by acting as a scaffold for other BER enzymes. Variants in XRCC1 gene might alter protein structure/function or create alternatively spliced protein influencing BER efficiency and affect individual susceptibility/recurrence to urinary bladder cancer (BC). We tested whether polymorphisms in XRCC1 gene were associated with BC risk and further to substantiate risk of recurrence after Bacillus Calmette-Guerin (BCG) immunotherapy. Genotyping for three polymorphic sites of XRCC1 gene at codon Arg194Trp (PvuII), Arg280His (RsaI) and, Arg399Gln (MspI) in 140 BC cases and 190 controls by PCR-RFLP method was done. We observed significant association in heterozygous genotype (GA) of codon 280 and 399 with BC risk (OR=1.96, p=0.021 and OR = 1.81, p=0.021, respectively), however no association was seen for variant AA genotype. A trend of increased risk with high stage and grade in patients with codon 194 variant genotypes (CT+TT) was observed. Haplotype analysis showed that individuals with haplotype 194C-280G-399A were at >3-fold higher risk for BC (OR=3.48, p=0.01). The A/A genotype of codon 399 was associated with high risk for recurrence in BCG treated patients (HR=5.05, P=0.01) thus, showing reduced recurrence free survival (AA/GG=12/60months; log rank P=0.004). The study suggested no association of variant genotypes with the susceptibility to BC. Haplotype analysis however, revealed that XRCC1 399 A allele may have a major role as patients with haplotype 194C-280G-399A carrying variant allele of 399 were at higher risk.
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Genetic polymorphism of the N-acetyltransferase 2 gene, and susceptibility to prostate cancer: a pilot study in north Indian population
BMC Urology. 01/2005;
Abstract Background N-acetyltransferase 2 is phase II metabolizing enzyme that participates in the bioconversion of heterocyclic arylamines into electrophilic nitrenium ions, which are important ultimate carcinogens that are directly implicated in tumor initiation process. This study was conducted... [more] Abstract Background N-acetyltransferase 2 is phase II metabolizing enzyme that participates in the bioconversion of heterocyclic arylamines into electrophilic nitrenium ions, which are important ultimate carcinogens that are directly implicated in tumor initiation process. This study was conducted to examine; (1) whether the N-acetyltransferase 2 (NAT2) genotype is a risk factor for prostate cancer, (2) to study effect of NAT2 genotype on modifying prostate cancer risk from tobacco use. Methods The case control study was undertaken over a period of 28 months and included 130 prostate cancer patients (CaP) and 140 controls. The NAT2 genotypes were identified by PCR-RFLP method in DNA extracted from peripheral blood. Genotype frequencies and the association of genotypes with patients and control groups were assessed by logistic regression model. Results We observed non-significant association of rapid acetylator genotype NAT2 (OR = 1.452, 95% CI: 0.54–1.87, P = 0.136) in prostate cancer patients. However significant association was observed between rapid acetylator genotype NAT2 and CaP tobacco users (OR = 3.43, 95% CI: 1.68–7.02, P -value < 0.001) when compared with controls. Conclusion The data suggests that the NAT2 rapid acetylator genotypes may play an important role in determining the risk of developing prostate cancer particularly in the tobacco users of north Indian population.
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Total PSA and free PSA in patients with severe liver dysfunction
Indian Journal of Urology. 01/2003;
Objectives: To evaluate the effect of liver diseases in patients, on serum free prostate specific antigen (JPSA) levels, total prostate specific antigen (tPSA) levels and fPSA/tPSA ratios. Methods: Serum concentrations of total and free as well as JPSA/tPSA were determined in 20 men with histologi-c... [more] Objectives: To evaluate the effect of liver diseases in patients, on serum free prostate specific antigen (JPSA) levels, total prostate specific antigen (tPSA) levels and fPSA/tPSA ratios. Methods: Serum concentrations of total and free as well as JPSA/tPSA were determined in 20 men with histologi-cally confirmed liver cirrhosis, 15 men with chronic hepa-titis and 20 healthy men. Results: The serum levels of total PSA in liver cirrhosis as well as in chronic hepatitis were significantly lower than those observed in control. Free PSA remained unchanged. Conclusions: Our study suggests that despite severe liver dysfunction the tPSA, fPSA as well as the ratio of fPSA/ tPSA were not elevated as it was hypothesized that liver impairment might affect the PSA levels, as liver is a site for PSA metabolism.
Following (10)
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Aditi Mittal
SMS MEDICAL COLLEGE ,JAIPUR -
Tanu Verma
Apollo Hospitals -
Malati Tangirala
Scientific Advisor, vasvi Hospital and Research Center, Hyderabad -
Gourdas Choudhuri
Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India -
Topics (2)
