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1 Department of Medicine and Vanderbilt-Ingram Cancer Center and 2 Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee; 3 Department of Epidemiology and Public Health, Yale Cancer Center, Yale University School of Medicine, New Haven, Connecticut; and 4 Department of Epidemiology, Shanghai Cancer Institute, Shanghai, China
Requests for reprints: Wei Zheng, Center for Health Services Research, Medical Center East, Suite 6000, Nashville, TN 37232-8300. Phone: 615-936-0682; Fax: 615-936-1269. E-mail: wei.zheng{at}vanderbilt.edu
Cumulative evidence suggests that insulin-like growth factors (IGF) play an important role in the etiology of breast cancer. The IGF binding proteins regulate the action of IGFs, and >90% of circulating IGFs are bound to IGFBP-3. We evaluated the associations of five (A–202C, G227C, C3804G, 5606InsA, and C5827T) genetic polymorphisms in the IGFBP3 gene with breast cancer risk and the blood IGFBP-3 protein level in a population-based, case-control study conducted among Chinese women in Shanghai. Genomic DNA samples from 1,193 incident breast cancer patients and 1,310 community controls were genotyped for IGFBP3 polymorphisms. Blood IGFBP-3 levels were determined for 390 controls. A 30% to 60% elevated risk of breast cancer was found to be associated with homozygosity for the variant allele in polymorphisms A–202C, G227C, 5606InsA, and C5827T. Carrying the variant allele in C3804G was also associated with an increased risk. About 13.5% of cases and 9.7% of controls had one or more of the above risk genotypes, resulting in odds ratio [OR; 95% confidence interval (95% CI)] of 1.4 (1.0-1.9). The ORs (95% CIs) were 1.3 (1.0-1.8) and 1.7 (1.1-2.5) for women with one to two and three to five risk genotypes, respectively (P for trend < 0.01). Four common haplotypes for the IGFBP3 gene were identified. Compared with the haplotype containing only the wild-type allele in the five loci, the haplotype with the variant allele in all sites was associated with an elevated risk of breast cancer (OR 1.4, 95% CI 1.0-1.9), particularly among younger women (OR 2.3, 95% CI 1.3-3.9). With the exception of C3804G, in which no homozygote was identified, the level of circulating IGFBP-3 was reduced in a dose-response manner with an increasing number of variant alleles in each of the other four polymorphic sites (P for trend < 0.05). These results indicated that IGFBP3 polymorphisms may be associated with the level of blood IGFBP-3 protein and an increased risk of breast cancer.
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