Population-based case–control study of AhR (aryl... : Pharmacogenetics and Genomics (original) (raw)

ORIGINAL ARTICLES

Population-based case–control study of AhR (aryl hydrocarbon receptor) and CYP1A2 polymorphisms and breast cancer risk

Long, Ji-Ronga; Egan, Kathleen M.a; Dunning, Lisac; Shu, Xiao-Oua; Cai, Qiuyina; Cai, Huia; Dai, Qia; Holtzman, Jordanc; Gao, Yu-Tangb; Zheng, Weia

aDepartment of Medicine and Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee, USA

bDepartment of Epidemiology, Shanghai Cancer Institute, Shanghai, China

cVeterans Affairs Medical Center, Minneapolis, Minnesota, USA

Correspondence and requests for reprints to Wei Zheng, Department of Medicine and Vanderbilt-Ingram Cancer Center, Vanderbilt University, 1161 21st Avenue South, S-1121 Medical Center North, Nashville, TN 37232-2587, USA

Tel: +1 615 936 0682; fax: +1 615 322 1754;

e-mail: [email protected]

Sponsorship: This study was supported by National Cancer Institute USPHS RO1CA64277 and RO1CA90899.

Received 22 August 2005 Accepted 1 November 2005

Abstract

The aryl hydrocarbon receptor (AhR) is a key regulator of the transcriptional expression for the cytochrome P450 1 (CYP1) genes. CYP1A2 is one of the major CYP1 enzymes that catalyse 2-hydroxylation of estrogen, a hormone that plays a critical role in the etiology of breast cancer. In this study, we investigated whether two common polymorphisms in these two genes, CYP1A2*1F and AhR Lys554Arg, were associated with breast cancer risk in 1090 cases and 1183 controls, a subset of the population-based case–control study, the Shanghai Breast Cancer Study. Caffeine tests were performed in vivo in a subset of 236 study subjects to investigate the relationship of these two polymorphisms with CYP1A2 activity. For the AhR gene, the A (Lys) allele was associated with a decreased risk of breast cancer. Using the genotype GG as reference, odds ratios of 0.82 [95% confidence interval (CI)=0.69–0.99] for the AG genotype and 0.76 (95% CI=0.58–1.01) for the AA genotype (P for trend=0.018) were obtained. However, no association was observed between CYP1A2 genotypes and breast cancer risk, although the CYP1A2*1F polymorphism was found to be related to CYP1A2 activity. The geometric mean values for the caffeine metabolites ratio were 2.90, 2.30, and 1.95 for CC, AC, and AA genotypes, respectively (P for trend=0.024). In conclusion, the results from our study suggest that the AhR Lys554Arg polymorphism may be a genetic susceptibility factor for breast cancer, whereas CYP1A2*1F, which is a potentially functional single nucleotide polymorphism, may not be related to breast cancer risk.