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Vitamin D Receptor Polymorphisms and Breast Cancer Risk: Results from the National Cancer Institute Breast and Prostate Cancer Cohort Consortium

¹ IARC, Lyon, France; ² Epidemiology and Surveillance Research, American Cancer Society, Atlanta, Georgia; Divisions of ³ Cancer Epidemiology and Genetics and ⁴ Cancer Prevention, National Cancer Institute, Bethesda, Maryland; ⁵ Program in Molecular and Genetic Epidemiology and ⁶ Department of Epidemiology, Harvard School of Public Health; ⁷ Division of Preventive Medicine, Department of Medicine, and ⁸ Departments of Nutrition and Epidemiology, Harvard School of Public Health and Department of Medicine, Channing Laboratory, Brigham & Women's Hospital, Harvard Medical School, Boston, Massachusetts; ⁹ Epidemiology Program, Cancer Research Center, University of Hawaii, Honolulu, Hawaii; ¹⁰ Department of Epidemiology and Public Health, Imperial College, London, United Kingdom; ¹¹ Public Health Institute of Navarra, CIBERESP, Pamplona, Spain; ¹² Departments of Laboratory Medicine and Clinical Sciences in Malmö, Lund University, University Hospital UMAS, Malmö, Sweden; ¹³ MRC Epidemiology Unit, Institute of Metabolic Science, Cambridge, United Kingdom; ¹⁴ Institute of Community Medicine, University of Tromsö, Tromsö, Norway; ¹⁵ National Institute for Public Health and the Environment, Bilhoven, The Netherlands; ¹⁶ Core Genotyping Facility, Science Applications International Corporation-Frederick, Inc., National Cancer Institute at Frederick, Gaithersburg, Maryland; ¹⁷ INSERM, Institut Gustave Roussy, Villejuif, France; ¹⁸ Division of Cancer Epidemiology, German Cancer Research Centre, Heidelberg, Germany; ¹⁹ University of Southern California, Los Angeles, California; ²⁰ Center for Human Genetics, Marshfield Clinical Research Foundation, Marshfield, Wisconsin; ²¹ Department of Clinical Epidemiology, Århus University Hospital, Åalborg, Denmark; and ²² Department of Clinical and Experimental Medicine, Federico II University, Naples, Italy

Requests for reprints: Marjorie L. McCullough, Epidemiology & Surveillance Research, 6D, American Cancer Society, 250 Williams Street, Atlanta, GA 30303-1002. Phone: 404-929-6816; Fax: 404-327-6450. E-mail: marji.mccullough{at}cancer.org

Background: Vitamin D is hypothesized to lower the risk of breast cancer by inhibiting cell proliferation via the nuclear vitamin D receptor (VDR). Two common single nucleotide polymorphisms (SNP) in the VDR gene (VDR), rs1544410 (BsmI), and rs2228570 (FokI), have been inconsistently associated with breast cancer risk. Increased risk has been reported for the FokI ff genotype, which encodes a less transcriptionally active isoform of VDR, and reduced risk has been reported for the BsmI BB genotype, a SNP in strong linkage disequilibrium with a 3'-untranslated region, which may influence VDR mRNA stability.

Methods: We pooled data from 6 prospective studies in the National Cancer Institute Breast and Prostate Cancer Cohort Consortium to examine associations between these SNPs and breast cancer among >6,300 cases and 8,100 controls for each SNP using conditional logistic regression.

Results: The odds ratio (OR) for the rs2228570 (FokI) ff versus FF genotype in the overall population was statistically significantly elevated [OR, 1.16; 95% confidence interval (95% CI), 1.04-1.28] but was weaker once data from the cohort with previously published positive findings were removed (OR, 1.10; 95% CI, 0.98-1.24). No association was noted between rs1544410 (BsmI) BB and breast cancer risk overall (OR, 0.98; 95% CI, 0.89-1.09), but the BB genotype was associated with a significantly lower risk of advanced breast cancer (OR, 0.74; 95% CI, 0.60-0.92).

Conclusions: Although the evidence for independent contributions of these variants to breast cancer susceptibility remains equivocal, future large studies should integrate genetic variation in VDR with biomarkers of vitamin D status. (Cancer Epidemiol Biomarkers Prev 2009;18(1):297–305)

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