Melatonin pathway genes and breast cancer risk among Chinese women |
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Authors: | Sandra L Deming Wei Lu Alicia Beeghly-Fadiel Ying Zheng Qiuyin Cai Jirong Long Xiao Ou Shu Yu-Tang Gao Wei Zheng |
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Affiliation: | (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;(2) Shanghai Center for Disease Control and Prevention, Shanghai, China;(3) Department of Epidemiology, Shanghai Cancer Institute, Shanghai, China |
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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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