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Carcinogenesis Advance Access originally published online on February 2, 2007
Carcinogenesis 2007 28(6):1323-1328; doi:10.1093/carcin/bgm007
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

A population-based association study of SNPs of GSTP1, MnSOD, GPX2 and Barrett's esophagus and esophageal adenocarcinoma

Seamus J. Murphy1,2,*, Anne E. Hughes1, Chris C. Patterson3, Lesley A. Anderson2, R.G.Peter Watson4, Brian T. Johnston4, Harry Comber5, Jim McGuigan6, John V. Reynolds7 and Liam J. Murray2

1 Department of Medical Genetics, Queen's University Belfast, Royal Group of Hospitals, Grosvenor Road, Belfast BT12 6BA
2 Centre for Clinical and Population Sciences, Queen's University Belfast, Mulhouse Building, Grosvenor Road, Belfast BT12 6BJ
3 Department of Medical Statistics, Queen's University Belfast, Mulhouse Building, Grosvenor Road, Belfast, BT12 6BJ
4 Department of Gastroenterology, Royal Group of Hospitals, Grosvenor Road, Belfast, BT12 6BA
5 National Cancer Registry Ireland, Elm Court, Boreenmonna Road, Cork, Ireland
6 Department of Thoracic Surgery, Royal Group of Hospitals, Grosvenor Road, Belfast, BT12 6BA
7 Department of Thoracic Surgery, St James's Hospital, James's Street, Dublin 8, Ireland

* To whom correspondence should be addressed at Division of Gastroenterology, Box 1069, Mount Sinai Medical Center, One Gustave Levy Place, New York, NY 10029-6574, USA. Tel: +1 212 659 9393; Fax: +1 212 659 9853; Email: s.murphy{at}qub.ac.uk


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Oxidative stress appears to be important in the pathogenesis of Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC). Single-nucleotide polymorphisms (SNPs) of antioxidant enzyme genes may play a part in determining individual susceptibility to these diseases. The Factors Influencing the Barrett's Adenocarcinoma Relationship (FINBAR) study is a population-based, case–control study of BE and EAC in Ireland. DNA from EAC (n = 207), BE (≥3 cm BE at endoscopy with specialized intestinal metaplasia on biopsy, n = 189) and normal population controls (n = 223) were analyzed. Several SNPs spanning the genes for glutathione S-transferase P1 (GSTP1), manganese superoxide dismutase (MnSOD) and glutathione peroxidase 2 (GPX2) were genotyped using multiplex polymerase chain reaction and SNaPshotTM. The {chi}2 test was used to compare genotype and allele frequencies between case and control subjects. Linkage disequilibrium between SNPs was quantified using Lewontin's D' value and haplotype frequency estimates obtained using Haploview. Eleven SNPs were genotyped (six for GSTP1, three for MnSOD and two for GPX2); all were in Hardy–Weinberg equilibrium. None was significantly associated with EAC or BE even before Bonferroni correction. Odds ratios for EAC for individual SNPs ranged from 0.68 [95% confidence interval (CI) 0.43–1.08] to 1.25 (95% CI 0.73–2.16), and for BE from 0.84 (95% CI 0.52–1.30) to 1.30 (95% CI 0.85–1.97). SNPs in all three genes were in strong linkage disequilibrium (D' > 0.887) but haplotype analysis did not show any significant association with EAC or BE. SNPs involving the GSTP1, MnSOD and GPX2 genes were not associated with BE or EAC. Further studies aimed at identifying susceptibility genes should focus on different antioxidant genes or different pathways.

Abbreviations: BE, Barrett's esophagus; CI, confidence interval; EAC, esophageal adenocarcinoma; FINBAR, Factors Influencing the Barrett's Adenocarcinoma Relationship; GI, gastrointestinal; GPX2, glutathione peroxidase 2; GSTP1, glutathione S-transferase P1; MnSOD, manganese superoxide dismutase; OR, odds ratio; PCR, polymerase chain reaction; ROS, reactive oxygen species; SIM, specialized intestinal metaplasia; SNP, single-nucleotide polymorphism


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Barrett's esophagus (BE) is a condition in which the native squamous mucosa of the lower esophagus is replaced by columnar mucosa, defined histologically as specialized intestinal metaplasia (SIM). It is an important risk factor for the development of esophageal adenocarcinoma (EAC) (1). Most subjects with BE never develop EAC, and both environmental and genetic susceptibility factors are believed to be important in determining individual risk.

Antioxidant status has emerged as an important determinant of risk. Reactive oxygen species (ROS), such as superoxide anion (O2–.), are produced continuously in all cells (2). However, excess levels of ROS are harmful to cells, causing damage to cellular lipids, proteins and DNA. Antioxidant enzymes [e.g. superoxide dismutase and glutathione S-transferase (GST)] protect against the adverse effects of ROS by preventing their formation, scavenging them or promoting their decomposition.

There is substantial evidence that ROS plays an important role in the pathogenesis of BE and EAC in both animal models (3–5) and human studies (6–8); there is a positive correlation between the severity of esophagitis and ROS levels, with high levels found in BE (6,7) and EAC (9).

Glutathione S-transferase P1 (GSTP1) is quantitatively the most important GST isoform in normal esophageal epithelium (10). GSTP1 expression, GSTP1 mRNA levels, glutathione content and GST enzyme activities are all reduced in BE compared with normal esophageal epithelium (10–14). Glutathione peroxidase 2 (GPX2) is detected mainly in gastrointestinal (GI) tissues and liver in humans (15). Messenger RNA levels of GPX2 are significantly increased in BE tissue as compared with normal squamous mucosa (16). Manganese superoxide dismutase (MnSOD, SOD2) is a major cellular defense mechanism against oxidative damage (17,18). In humans, tissue MnSOD levels are reduced in patients with reflux esophagitis and BE compared with normal esophagus (7). Whereas expression of MnSOD is increased in EAC (19), superoxide dismutase activity is decreased, possibly due to enzyme inactivation (20). Further, exogenous administration of superoxide dismutase reduces the risk of developing SIM and EAC in a rat model (20).

Previous studies have looked for an association between single-nucleotide polymorphisms (SNPs) of GSTP1 and risk of BE or EAC. One study found that a functional SNP that leads to an Ile/Val substitution and lower GST enzyme activity was associated with risk of BE and EAC (21); however, no association between this SNP and risk of EAC was found in another study (22). A number of factors, including inappropriate control groups, lack of population-based DNA collections and small study size most probably account for the discrepancies between published studies. No previous studies have examined the relationship between MnSOD or GPX2 and these diseases. We carried out an association study of SNPs involving the genes encoding the antioxidant enzymes GSTP1, MnSOD and GPX2 within a population-based case–control study of EAC and BE, the Factors Influencing the Barrett's Adenocarcinoma Relationship (FINBAR) study.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
Study subjects and recruitment
The FINBAR study is an Irish population-based case–control study of BE and EAC. The study methods have been described in detail elsewhere (23). Three groups of subjects were recruited: subjects with EAC, subjects with long-segment BE and normal population controls. All subjects were white Caucasians aged 35–85 years. Cases of EAC were subjects with a histological confirmation of adenocarcinoma within the esophagus. Cases from Northern Ireland were identified from electronic pathology records from all pathology laboratories within the province. Cases from the Republic of Ireland were identified from the main hospitals involved in the diagnosis and treatment of esophageal cancer and through the National Cancer Registry in Ireland, Cork. Subjects with BE were identified in the following manner: In Northern Ireland, they were identified from electronic pathology records from all pathology laboratories within the province. These reports were made available to the Northern Ireland Cancer Registry each month. Subjects with BE were eligible for inclusion if ≥3 cm of typical Barrett's mucosa was seen at endoscopy and the presence of SIM had been confirmed by histological examination of biopsy specimens. Subjects with dysplasia on histological examination were not included. Endoscopy note review was necessary in most patients to confirm the length of the segment of BE, as length was infrequently recorded on the pathology report. In the Republic of Ireland, clinicians from large teaching Hospitals in the Dublin and Cork areas sent details of BE patients who met the inclusion criteria to the research personnel. Eligible control subjects were adults without a history of esophageal or other GI cancer or a known diagnosis of BE. Controls in Northern Ireland were selected at random from the General Practice Master Index (a province-wide database of all persons registered with a General Practitioner). Controls in the Republic of Ireland were selected at random from four general practices (two urban and two rural) in the Dublin and Cork areas. Control subjects were not required to have an upper GI endoscopy performed to exclude BE prior to entry into the study. Both subjects with BE and controls were frequency matched (within 5 year age and sex strata) to the distribution of EAC subjects, with a maximum age of 85 years.

All subjects underwent a structured computerized interview with trained interviewers. Information was collected on medication use, symptoms of gastroesophageal reflux, relevant medical history, weight, height, smoking history, education, occupational type (manual/non-manual) and alcohol consumption. Anthropometric measures (height, weight and waist and hip circumferences) were taken at the time of interview. Finally, 30 ml of blood was drawn and placed immediately on ice. This was centrifuged and separated within 4 h and buffy coats were stored at –80°C.

Genetic analysis
DNA was extracted from buffy coat using PUREGENE® DNA purification kit (Gentra Systems, Minneapolis, MI). All reactions were carried out with 96-well plates (ABgene Ltd, Epsom, Surrey, UK). Polymerase chain reaction (PCR) amplification was conducted in 7.5 µl reaction volumes using a multiplex reaction and the primers are listed in Table I. Genomic DNA (40 µg/ml) was used in a volume of 0.8 µl with 0.8 µl of PCR primers (2 µM), 2.15 µl of deionized water and 3.75 µl of Multiplex PCR kit (HotStarTaq DNA polymerase, MgCl2, deoxynucleoside triphosphates and PCR buffer; Qiagen Ltd, Crawley, West Sussex, UK). The SNaPshotTM Multiplex Kit (Applied Biosystems Inc. Foster City, California, USA) was used for genotyping all polymorphisms. Reactions were carried out in 5 µl volumes using 1.4 µl PCR template (after a cleaning step of 2 h incubation with ExoSAP-IT®, USB Corporation, Cleveland, OH), 0.5 µl SNaPshot primers (0.2 µM), 2.0 µl SNaPshotTM Multiplex Ready reaction mix, 0.1 µl buffer 10x and 1.0 µl deionized H2O. The chemistry of this reaction is based on the dideoxy single-base extension of an unlabeled oligonucleotide primer. Primers for the SNaPshot reaction were designed to anneal to the sequence just 5' of the SNP, Table II. A final clean-up step with shrimp alkaline phosphatase (USB Corporation) was carried out prior to denaturation of product in formamide. All analyses were carried out with a 3100 Genetic Analyser and Genescan software (Applied Biosystems). Cycle sequencing of PCR products was performed to confirm the accuracy of this method of SNP identification. SNPs were selected using online databases (dbSNP, EnSembl) with priority given to functional SNPs that were validated in several populations.


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  		Table I. Multiplex PCR conditions for genotyping GSTP1, MnSOD and GPX2 SNPs

 


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  		Table II. Primers for SNaPshot reaction

 
Statistical analysis
Deviation from Hardy–Weinberg equilibrium was assessed using a {chi}2 goodness of fit test. The {chi}2 test for association was used to compare genotype and allele frequencies between case and control subjects and logistic regression analysis was used to adjust the genotype comparisons for the potential confounding variables age, sex, smoking and alcohol intake. The extent of linkage disequilibrium between pairs of SNPs was quantified using Lewontin's D' value (24). Haplotype frequency estimates were obtained in Haploview (25). The permutation test in Haploview was used to compare cases of BE and cases of EAC with controls. In this method, tests of allele frequency in single SNPs and tests of frequencies of individual haplotypes were assessed jointly for significance. The method then takes account of multiple testing by comparing the maximum {chi}2 statistic obtained from the individual tests with its permutation distribution obtained by 10 000 random relabelings of cases and controls. A significant result was obtained if the observed maximum {chi}2 statistic fell in the top 5% of its permutation distribution. Where possible, we selected SNPs with a minor allele frequency of at least 20% because these would provide >90% power to detect a susceptibility allele with an odds ratio (OR) of 2.0 at the 0.5% level of significance (P < 0.005), with our sample size (26). The level of significance incorporated a Bonferroni correction for up to 10 comparisons.

Ethical committee approval for the FINBAR study was obtained from the Research Ethics Committee of the Queen's University Belfast, the Clinical Research Ethics Committee of the Cork Teaching Hospitals and the Research Ethics Committee Board of St James's Hospital, Dublin.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Participation rates
Overall 332 EAC patients were suitable for inclusion; of these, 49 patients died before contact was made, 42 patients were not contacted because their clinician, general practitioner or relative did not give permission and 37 patients themselves declined to participate. A total of 207 cases of EAC were recruited: the participation rate of eligible, alive patients was 73.1% and the overall response rate was 62.3%. The participation rates of BE and control subjects were 82.4 and 41.8%, respectively. In total, 207 EAC patients (118 esophageal, 86 junctional and 3 unclassified), 189 BE patients and 223 population controls were included in these analyses. The characteristics of each group of subjects are presented in Table III. There were significant differences in body mass index, years of education, manual/non-manual occupation, gastro-oesophageal reflux (GOR) symptoms and smoking between cases and controls, and significant differences in manual/non-manual occupation and GOR symptoms between BE and controls.


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  		Table III. Characteristics of controls, BE and EAC patients

 
SNP analysis results
There was no evidence of departures from Hardy–Weinberg. None of the 11 SNPs were associated with BE or EAC even before Bonferroni correction, Table IV. Adjustment of the genotype comparisons for the potential confounders age, sex, smoking, alcohol and body mass index produced similar findings (results not shown).


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  		Table IV. Allele and genotype frequencies for GSTP1, MnSOD and GPX2 SNPs

 
Haplotype results
Estimated haplotype frequencies in case and control groups are shown in Table V. The permutation P values for joint testing of the single-marker allele frequencies and the multi-marker haplotype frequencies in the comparison of EAC and controls were 0.16 for the six GSTP1 SNPs, 0.16 for the three MnSOD SNPs and 0.77 for the two GPX2 SNPs. The corresponding values for the comparison of BE and controls were 0.06, 0.58 and 0.91, respectively.


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  		Table V. Estimated haplotype frequencies for GSTP1, MnSOD and GPX2 SNPs

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
In this population-based study, no association was found between polymorphisms of antioxidant enzyme genes GSTP1, MnSOD, GPX2 and BE or EAC. Furthermore, haplotype analysis failed to show any association with risk. This is the first study to examine the frequency of SNPs involving the MnSOD and GPX2 genes in BE and EAC. Previous studies have reported the frequency of GSTP1 SNP variants in these diseases with different findings.

Van Lieshout et al. (21) studied the frequencies of polymorphic variants in GSTP1 among 247 blood donors, 98 subjects with BE and 21 subjects with EAC. They found an association between the GSTP1 polymorphic variant GSTP1b (equivalent to rs1695) and risk of both BE and EAC (P < 0.001 and P = 0.005, respectively). The use of blood donors as a control group may lead to unreliable findings since blood donors represent a highly selected proportion of the population. In support of this, the reported control GSTP1 genotype frequencies in their study were AA 59%, AG 36% and GG 5%, in contrast with the current estimates of these SNP frequencies in European populations: AA 33%, AG 55% and GG 12% (http://www.ncbi.nlm.nih.gov/projects/SNP/). Subjects with BE and EAC were recruited through a single center rather than using a population-based approach, increasing the risk of selection bias. Abbas et al. (22) carried out a case–control study of esophageal cancer in Northwest France. They studied the frequency of the same GSTP1 SNP variant but found no association between GSTP1 and risk of EAC in 27 subjects.

Gene polymorphism association studies are an active area of research in many human diseases. With regard to BE and EAC, the search for SNPs with associations with disease is driven by two main factors: first, because such a finding may shed light on the molecular biology of the diseases by highlighting important genes in biological pathways, and second, because there is an urgent need to identify biomarkers of risk in BE. This need for biomarkers arises because most patients with BE do not develop EAC, yet surveillance endoscopy with biopsy is recommended for the majority of patients diagnosed with the condition (27,28). This approach has many drawbacks, including cost, limited evidence of effectiveness and patient concerns about risk of cancer (29). Many potentially important biological pathways involved in the pathogenesis of BE and EAC have been examined using a gene polymorphism association approach. Casson et al. (30) have reported associations between DNA repair genes and these diseases, with a higher frequency of certain genetic abnormalities (XPC poly AT insertion/deletion) in EAC and a lower frequency of others (XPD and XRCC1 homozygous variants) in BE, as compared with normal controls. Gough et al. (31) examined several inflammatory cytokine polymorphisms and reported an association between functional SNPs in the interleukin-1 receptor antagonist gene and BE, and between the interleukin-10 gene and BE and EAC. Further studies are required to see if these findings can be replicated.

There are several strengths to the current study. Subject recruitment was population based and subject numbers are larger than in previous studies. Our population-based DNA collection avoids biases that may arise from single-center or multi-center collections. The phenotypes of subjects with EAC and BE were well characterized. Cases of EAC required biopsy confirmation of disease status, and, if available, pathology reports of resection specimens were obtained. BE controls required >3 cm Barrett's mucosa at endoscopy and SIM on biopsy specimens without dysplasia. Since it is impossible to know how long subjects with BE have had their condition prior to clinical diagnosis, both incident and prevalent cases were recruited. With regard to genetic analysis, several steps were undertaken to ensure high quality and repeatability of results. These included initial DNA sequencing of SNP regions to prove the reliability of SNaPshot as a rapid method of genotyping, blinding of the operator to the case–control status of samples to reduce observer bias, analysis of case and control samples simultaneously to avoid differential misclassification of exposure and inclusion of positive and negative controls in all reactions.

The participation rate among normal controls was low at 41.8% despite reminder letters being sent to non-responders, which could introduce selection bias into the study. Control subjects tended to have more years of education and were less likely to have a manual job compared with both BE and EAC, Table I. However, the allele frequencies reported among normal controls in this study are similar to those reported in previous studies among Caucasian populations (http://www.ncbi.nlm.nih.gov/projects/SNP/). Control subjects did not have upper GI endoscopy carried out to determine if they had BE present. A recent Swedish study found that the prevalence of BE in the general population was 1.6%, with a prevalence of long-segment BE of 0.5% (32). Applying this figure to our study would mean that one control subject with undiagnosed BE was misclassified and inadvertently included in the control group. This is unlikely to have an influence on our findings. The study was powered to detect an allele producing an OR for risk of disease of 2.0, but if any of these alleles were associated with smaller ORs for risk of disease, this effect would not be detected. Larger studies are required to detect disease-causing alleles with minor effects. To address this issue, a recently formed consortium has been formed through the National Cancer Institute in the USA: Barrett's Esophagus and Adenocarcinoma Consortium (http://dceg.cancer.gov/newsletter/Linkage1105.pdf).

In summary, this population-based study utilizing a large DNA collection failed to show any association between polymorphisms of antioxidant enzyme genes GSTP1, MnSOD, GPX2 and BE or EAC. Furthermore, haplotype analysis failed to show any association with risk. Further studies should focus on different genes potentially involved in these diseases.


   Acknowledgments
 
We appreciate the contributions made by the study participants and their families. We would like to thank the clinicians who were contacted throughout the study period and their secretaries for administrative support. Thanks also to the research team including Siobhan Reynolds, Majella Gallagher, Carol Anderson and Martin McAnaespie and to Dr Damian McManus with help in classifying the tumor sites. Thanks to the Northern Ireland Cancer Registry and the National Cancer Registry Cork for their support and involvement in the research.

Grant support: The FINBAR study was funded by an Ireland-Northern Ireland Co-operation Research Project grant sponsored by the Research and Development Office, Belfast, and the Health Research Board Dublin and by the Ulster Cancer Foundation, Northern Ireland.

Conflict of Interest Statement: None declared.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Received November 6, 2006; revised December 13, 2006; accepted January 9, 2007.


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