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Melatonin pathway genes and breast cancer risk among Chinese women

  • Epidemiology
  • Published:
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Abstract

Previous studies suggest that melatonin may act on cancer growth through a variety of mechanisms, most notably by direct anti-proliferative effects on breast cancer cells and via interactions with the estrogen pathway. Three genes are largely responsible for mediating the downstream effects of melatonin: melatonin receptors 1a and 1b (MTNR1a and MTNR1b), and arylalkylamine N-acetyltransferase (AANAT). It is hypothesized that genetic variation in these genes may lead to altered protein production or function. To address this question, we conducted a comprehensive evaluation of the association between common single nucleotide polymorphisms (SNPs) in the MTNR1a, MTNR1b, and AANAT genes and breast cancer risk among 2,073 cases and 2,083 controls, using a two-stage analysis of genome-wide association data among women of the Shanghai Breast Cancer Study. Results demonstrate two SNPs were consistently associated with breast cancer risk across both study stages. Compared with MTNR1b rs10765576 major allele carriers (GG or GA), a decreased risk of breast cancer was associated with the AA genotype (OR = 0.78, 95% CI = 0.62–0.97, P = 0.0281). Although no overall association was seen in the combined analysis, the effect of MTNR1a rs7665392 was found to vary by menopausal status (P-value for interaction = 0.001). Premenopausal women with the GG genotype were at increased risk for breast cancer compared with major allele carriers (TT or TG) (OR = 1.57, 95% CI = 1.07–2.31, P = 0.020), while postmenopausal women were at decreased risk (OR = 0.58, 95% 0.36–0.95, P = 0.030). No significant breast cancer associations were found for variants in the AANAT gene. These results suggest that common genetic variation in the MTNR1a and 1b genes may contribute to breast cancer susceptibility, and that associations may vary by menopausal status. Given that multiple variants in high linkage disequilibrium with MTNR1b rs76653292 have been associated with altered function or expression of insulin and glucose family members, further research may focus on clarifying this relationship.

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Acknowledgments

Dr. Deming was supported by grants from the National Cancer Institute 5K99CA126978-02 and 4R00CA126978-03. In addition, this research was supported by R01CA064277 and R01CA124558. The authors wish to thank the participants and research staff of the Shanghai Breast Cancer Study for the contributions and commitment to this project and Bethanie Rammer and Jacqueline Stern for assistance with the preparation of this manuscript. Sample preparation and genotyping assays, using Affymetrix arrays, were conducted at the Survey and Biospecimen Shared Resource and the Vanderbilt Microarray Shared Resource, respectively, which was supported in part by the Vanderbilt-Ingram Cancer Center (P30CA68485).

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Authors and Affiliations

  1. Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Institute for Medicine and Public Health, Vanderbilt University School of Medicine, Eighth Floor, Suite 800. 2525 West End Ave, Nashville, TN, 3720-1738, USA

    Sandra L. Deming, Alicia Beeghly-Fadiel, Qiuyin Cai, Jirong Long, Xiao Ou Shu & Wei Zheng

  2. Shanghai Center for Disease Control and Prevention, Shanghai, China

    Wei Lu & Ying Zheng

  3. Department of Epidemiology, Shanghai Cancer Institute, Shanghai, China

    Yu-Tang Gao

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  1. Sandra L. Deming
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  2. Wei Lu
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Correspondence to Sandra L. Deming.

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Deming, S.L., Lu, W., Beeghly-Fadiel, A. et al. Melatonin pathway genes and breast cancer risk among Chinese women. Breast Cancer Res Treat 132, 693–699 (2012). https://doi.org/10.1007/s10549-011-1884-5

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