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Haplotype Analysis of CYP11A1 Identifies Promoter Variants Associated with Breast Cancer Risk

Departments of ¹ Cancer Biology, ² Medicine, and ³ Biostatistics, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine; ⁴ Medical Research Service, VA Tennessee Valley Healthcare System, Nashville, Tennessee; and ⁵ Department of Epidemiology, Shanghai Cancer Institute, Shanghai, China

Requests for reprints: Jeffrey R. Smith, Department of Medicine, Vanderbilt University School of Medicine, 529 Light Hall, 2215 Garland Avenue, Nashville, TN 37232-0275. Phone: 615-936-2171; Fax: 615-936-2296; E-mail: jeffrey.smith{at}vanderbilt.edu and Wei Zheng, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN. Phone: 615-936-0682; Fax: 615-322-1754; E-mail: wei.zheng{at}vanderbilt.edu.

The CYP11A1 gene encodes the cholesterol side chain cleavage enzyme that catalyzes the initial and rate-limiting step of steroidogenesis. A large number of epidemiologic studies have implicated the duration and degree of endogenous estrogen exposure in the development of breast cancer in women. Here, we conduct a systematic investigation of the role of genetic variation of the CYP11A1 gene in breast cancer risk in a study of 1193 breast cancer cases and 1310 matched controls from the Shanghai Breast Cancer Study. We characterize the genetic architecture of the CYP11A1 gene in a Chinese study population. We then genotype tagging polymorphisms to capture common variation at the locus for tests of association. Variants designating a haplotype encompassing the gene promoter are significantly associated with both increased expression (P = 1.6e–6) and increased breast cancer risk: heterozygote age-adjusted odds ratio (OR), 1.51 [95% confidence interval (95% CI), 1.19–1.91]; homozygote age-adjusted OR, 2.94 (95% CI, 1.22–7.12), test for trend, P = 5.0e–5. Among genes controlling endogenous estrogen metabolism, CYP11A1 harbors common variants that may influence expression to significantly modify risk of breast cancer. [Cancer Res 2007;67(12):5673–82]

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