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No Association between GPX1 Pro¹⁹⁸Leu and Breast Cancer Risk

¹ Department of Epidemiology and ² Program in Molecular and Genetic Epidemiology, Harvard School of Public Health, and ³ Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts

Requests for reprints: David G. Cox, Epidemiology Department, Harvard School of Public Health, 677 Huntington Ave., Boston, MA 02115. Fax: 617-432-1722. E-mail: dcox{at}hsph.harvard.edu

	Introduction

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Polymorphisms in the antioxidant selenoprotein glutathione peroxidase (GPX1) have been proposed to be associated with lung cancer (1) and breast cancer (2). In particular, the Leu allele of the Pro¹⁹⁸Leu polymorphism has been shown to have lower activity in MCF-7 cell lysates stimulated with sodium selenite (2). This polymorphism was strongly associated with risk of lung cancer (1); a significant association [odds ratio (OR), 1.9; 95% confidence interval (95% CI), 1.02-3.58] in a study of 79 breast cancer cases and 517 controls also has been observed (2). We assessed the association between GPX1 polymorphisms and breast cancer risk in the prospective Nurses' Health Study.

	Materials and Methods

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Detailed information regarding the design of this nested case-control study (cases, n = 1,323; controls, n = 1,910) has been published previously (3). In brief, 32,826 women who were free of diagnosed breast cancer were followed for incident disease from time of blood sample collection in 1989 and 1990 up to May 31, 2000. The two single nucleotide polymorphisms studied [–1040 G/A (rs3448) and Pro¹⁹⁸Leu (rs1050450)] were chosen as haplotype-tagging single nucleotide polymorphisms from the four single nucleotide polymorphisms in the National Cancer Institute's SNP500 database (http://snp500cancer.nci.nih.gov/home.cfm). Briefly, haplotype frequencies from 31 Caucasian samples were generated using the Phase program and haplotype-tagging single nucleotide polymorphisms were chosen using the BEST program (4). GPX1 genotyping analysis was done by the Taqman Allelic Discrimination method (Applied Biosystems, Foster City, CA) using primers and probe sequences available from the SNP500 database. Genotype-specific ORs and 95% CIs were calculated using unconditional logistic regression and were adjusted for age, age at menopause, postmenopausal hormone use, body mass index at age 18 years, weight gain since age 18 years, benign breast disease, and family history of breast cancer. ORs in relation to tumor stage and size were calculated in cases only, with <4 nodes involved and tumor size 2 cm being the reference categories. In these analyses, we compared carriers of the rare allele with noncarriers. Haplotype frequencies in pooled cases and controls were estimated using PROC HAPLOTYPE and linkage disequilibrium was calculated using PROC ALLELE in the SAS System version 8.0 (SAS Institute, Cary, NC). Regression substitution (5) and unconditional logistic regression (adjusted as above) were used for haplotype association testing, with the G-Pro haplotype as the reference category. Power was calculated using STPLAN (http://calculators.stat.ucla.edu/powercalc/).

	Results

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Both polymorphisms were in Hardy-Weinberg equilibrium, and significant linkage disequilibrium existed between them (r = 0.4, D' = 1.00; P < 0.001). There was no difference in genotype frequency between our control group and that of Hu et al. (P = 0.26, Fisher's exact test). No association was observed between either GPX1 genotype or the associated haplotypes and breast cancer risk (Table 1). No association was seen between GPX1 alleles and advanced disease [4 involved nodes (n = 81) compared with <4 nodes (n = 967) involved: –1040A OR, 1.37; 95% CI, 0.87-2.16; Leu¹⁹⁸ OR, 0.75; 95% CI, 0.48-1.19]. Additionally, rare GPX1 alleles were not significantly overrepresented among larger tumors [>2 cm (n = 245) compared with 2 cm (n = 964): –1040A OR, 1.09; 95% CI, 0.83-1.44; Leu¹⁹⁸ OR, 1.09; 95% CI, 0.83-1.45]. Lastly, no association was seen with any haplotype and tumor size or progression.

	Conclusions

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	Footnotes

 
Grant support: NIH research grants CA87969 and CA65725 and training grant CA 09001-27 (D.G. Cox).

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 2/ 6/04; accepted 4/26/04.

	References

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1. 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]
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. De Vivo I, Hankinson SE, Colditz GA, Hunter DJ. A functional polymorphism in the progesterone receptor gene is associated with an increase in breast cancer risk. Cancer Res 2003;63:5236–8.[Abstract/Free Full Text]
4. Sebastiani P, Lazarus R, Weiss ST, Kunkel LM, Kohane IS, Ramoni MF. Minimal haplotype tagging. Proc Natl Acad Sci U S A 2003;100:9900–5.[Abstract/Free Full Text]
5. Stram DO, Leigh Pearce C, Bretsky P, et al. Modeling and E-M estimation of haplotype-specific relative risks from genotype data for a case-control study of unrelated individuals. Hum Hered 2003;55:179–90.[CrossRef][Medline]

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