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No Association Between Glutathione Peroxidase Pro198Leu Polymorphism and Breast Cancer Risk

¹ Department of Epidemiology, Roswell Park Cancer Institute, Buffalo, New York; ² Department of Epidemiology, School of Public Health, University of North Carolina, Chapel Hill, North Carolina; Departments of ³ Environmental Health Sciences and ⁴ Epidemiology, Mailman School of Public Health; ⁵ Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York; and ⁶ Departments of Community and Preventive Medicine, Mount Sinai School of Medicine, New York, New York

Requests for reprints: Jiyoung Ahn, Department of Epidemiology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263. Phone: 716-845-1220; Fax: 716-845-8125. E-mail: Jiyoung.Ahn{at}roswellpark.org

	Introduction

Top Introduction Materials and Methods Results Conclusions References

 
Selenium-dependent glutathione peroxidase (GPX1) is a cytosolic antioxidant enzyme that neutralizes H₂O₂ to water and oxygen (1). A GPX1 ProLeu polymorphism exists at codon 198, with the variant Leu allele being less responsive than the common Pro allele to the stimulation of enzyme activity during selenium supplementation (2). The Leu allele has been associated with increased risk of lung (3), bladder (4), and breast (2) cancer, although two other studies found a null association with breast cancer risk (5, 6). Because oxidative stress may play a role in breast carcinogenesis (7) and the GPX1 polymorphism may confer interindividual variability in the response to reactive oxygen species, we evaluated the association between the 198 GPX1 polymorphism (RS#1050450) and risk of breast cancer, and assessed potential modifying influences of diet and lifestyle factors, which may affect reactive oxygen species, and tumor characteristics on risk relationships in the Long Island Breast Cancer Study Project.

	Materials and Methods

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The Long Island Breast Cancer Study Project, a population-based case-control study of breast cancer, was described previously (8). In brief, the cases were English-speaking women >20 years of age with newly diagnosed breast cancer who resided in Nassau and Suffolk Counties in Long Island, NY. Population-based controls were identified from the same geographic area, and frequency-matched to the expected age distribution of cases by 5-year age groups.

Known and suspected risk factors for breast cancer were ascertained by an in-person interview (8). Usual dietary intake was assessed by a self-administered modified National Cancer Institute–Block food frequency questionnaire (9). Genotyping was done by BioServe Biotechnologies (Laurel, MD) using Sequenom's high-throughput matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, as previously described (10), using PCR primers (5'-ACGTTGGATGATCGAGCCTGACATCGAAGC-3' and 5'-ACGTTGGATGATCCCGAGACAGCAGCA-3').

There was excellent observer agreement in the 8% of randomly selected duplicates of genotyping results that were included for quality control purposes ( statistic: 0.95), with <1% assay failure rate. Among those with DNA available (1,038 cases and 1,088 controls), 94% of cases and 93% of controls were Caucasian.

Unconditional logistic regression (11) was used to calculate odds ratios (OR) and corresponding 95% confidence intervals (CI) for breast cancer, in relation to genotype. The final multivariate models shown include matching factor (age) as well as those factors that changed the estimated effect by 10% or more (11). Factors found not to confound the associations of interest included: race, body mass index, age at first birth, smoking status, age at menarche, hormone replacement therapy use, menopausal status, benign breast disease, and lifetime alcohol intake. We examined potential interactions between GPX1 genotypes and diet (fruit and vegetable consumption, and vitamin supplement; ref. 9), lifestyle factors (cigarette smoking, parity status, age at first birth, and lactation; refs. 8, 12), and tumor characteristics [in situ versus invasive, and estrogen receptor (ER)/progesterone receptor (PR) status; ref. 12]. Gene-environment interactions were evaluated by joint categories of GPX1 genotype and diet and lifestyle factors. To test interactions on a multiplicative scale, a cross-product term of the ordinal score for each genotype and the specific risk factors was included in multivariate models. To test for potential heterogeneity by tumor characteristics, stratified analysis was done.

	Results

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Genotype distribution of GPX1 followed Hardy-Weinberg equilibrium (P = 0.34) among controls. Genotype distribution and allele frequencies (Pro, 69%; Leu, 31%) were comparable with those observed in other published studies (2, 3, 5, 6). As shown in Table 1, having at least one leu allele (Pro/Leu and Leu/Leu genotypes) was not associated with breast cancer risk.

	Conclusions

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There are several possible explanations for the null association between GPX1 genotypes and breast cancer. One possibility is that the effects of GPX1 on risk may only be observed in individuals with very high intake of selenium or fruits and vegetables, due to the observation that in vitro GPX1 enzyme activity differed between Pro and Leu alleles at high selenium supplementation (2). This is unlikely, however, because in our study, associations between GPX1 genotype and breast cancer risk were null even among vitamin supplement users or higher fruit and vegetable consumers. Furthermore, mean consumption of total fruits and vegetables in Long Island Breast Cancer Study Project participants was higher than that of average women in the U.S. (26 svg/wk among National Health and Nutrition Examination Survey women versus 30 svg/wk among the Long Island Breast Cancer Study Project participants, excluding juice). Finally, our findings are based on a large population-based study, and we have adequate power (0.80) to be able to detect an OR of 1.28 or greater, with the sample size available.

We observed a somewhat suggestive interaction with parity status, although the exact mechanisms whereby GXP1 effects may be greatest for nulliparous women need to be further investigated. Although our findings could be due to chance, it is also possible that women whose breast cells have never fully differentiated during a full-term pregnancy may be more susceptible to reduced capabilities for removal of reactive oxygen species by low-activity GPX1 genotype, and thereby at increased risk of breast cancer.

In summary, we did not find evidence for associations between variant GPX1 genotypes and breast cancer risk, nor was the association modified by diet or tumor characteristics in the Long Island Breast Cancer Study Project. However, we did find that risk was somewhat elevated among nulliparous women with the variant GPX1 genotype, compared with parous women with the common GPX1 genotype.

	Acknowledgments

 
For their valuable contributions to the Long Island Breast Cancer Study Project, the authors thank: members of the Long Island Breast Cancer Network; the 31 participating institutions in Long Island and in New York City, NY; our NIH collaborators, Gwen Collman, PhD, National Institutes of Environmental Health Sciences; G. Iris Obrams, MD, PhD formerly of the National Cancer Institute; members of the External Advisory Committee to the population-based case-control study: Leslie Bernstein, PhD (Committee Chair); Gerald Akland, MS; Barbara Balaban, MSW; Blake Cady, MD; Dale Sandler, PhD; Roy Shore, PhD; and Gerald Wogan, PhD; as well as other collaborators who assisted with various aspects of our data collection efforts including Gail Garbowski, MPH; Mary S. Wolff, PhD; Steven D. Stellman, PhD; Maureen Hatch, PhD; Geoffrey Kabat, PhD; Jan Beyea, PhD; Bruce Levin, PhD; H. Leon Bradlow, PhD; David Camann, BS; Martin Trent, BS; Ruby Senie, PhD; Carla Maffeo, PhD; Pat Montalvan; Gertrud Berkowitz, PhD; Margaret Kemeny, MD; Mark Citron, MD; Freya Schnabel, MD; Allen Schuss, MD; Steven Hajdu, MD; and Vincent Vinceguerra, MD.

	Footnotes

 
Grant support: National Cancer Institute and the National Institutes of Environmental Health and Sciences, U.S. Army, the Babylon Breast Cancer Coalition (grant nos. CA/ES66572, CA58233, P30ES09089, BC990191, and P30ES10126). Dr. Ahn is the recipient of a Woodrow Wilson-Johnson and Johnson Fellowship.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 6/20/05; accepted 8/11/05.

	References

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1. de Haan JB, Bladier C, Griffiths P, et al. Mice with a homozygous null mutation for the most abundant glutathione peroxidase, Gpx1, show increased susceptibility to the oxidative stress-inducing agents paraquat and hydrogen peroxide. J Biol Chem 1998;273:22528–36.[Abstract/Free Full Text]
2. Hu YJ, Diamond AM. Role of glutathione peroxidase 1 in breast cancer: loss of heterozygosity and allelic differences in the response to selenium. Cancer Res 2003;63:3347–51.[Abstract/Free Full Text]
3. Ratnasinghe D, Tangrea JA, Andersen MR, et al. Glutathione peroxidase codon 198 polymorphism variant increases lung cancer risk. Cancer Res 2000;60:6381–3.[Abstract/Free Full Text]
4. Ichimura Y, Habuchi T, Tsuchiya N, et al. Increased risk of bladder cancer associated with a glutathione peroxidase 1 codon 198 variant. J Urol 2004;172:728–32.[CrossRef][Medline]
5. Cox DG, Hankinson SE, Kraft P, et al. No association between GPX1 Pro198Leu and breast cancer risk. Cancer Epidemiol Biomarkers Prev 2004;13:1821–2.[Free Full Text]
6. Knight JA, Onay UV, Wells S, et al. Genetic variants of GPX1 and SOD2 and breast cancer risk at the Ontario site of the Breast Cancer Family Registry. Cancer Epidemiol Biomarkers Prev 2004;13:146–9.[Abstract/Free Full Text]
7. Ambrosone CB. Oxidants and antioxidants in breast cancer. Antioxid Redox Signal 2000;2:903–17.[Medline]
8. Gammon MD, Neugut AI, Santella RM, et al. The Long Island Breast Cancer Study Project: description of a multi-institutional collaboration to identify environmental risk factors for breast cancer. Breast Cancer Res Treat 2002;74:235–54.[CrossRef][Medline]
9. Gaudet MM, Britton JA, Kabat GC, et al. Fruits, vegetables, and micronutrients in relation to breast cancer modified by menopause and hormone receptor status. Cancer Epidemiol Biomarkers Prev 2004;13:1485–94.[Abstract/Free Full Text]
10. Ahn J, Gammon MD, Santella RM, et al. Myeloperoxidase genotype, fruit and vegetable consumption, and breast cancer risk. Cancer Res 2004;64:7634–9.[Abstract/Free Full Text]
11. Hosmer DW, Lemeshow S. Applied logistic regression. New York (NY): John Wiley & Sons, Inc; 1989.
12. Gammon MD, Eng SM, Teitelbaum SL, et al. Environmental tobacco smoke and breast cancer incidence. Environ Res 2004;96:176–85.[Medline]

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