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Implications of Gene-Environment Interaction in Studies of Gene Variants in Breast Cancer: An Example of Dietary Isoflavones and the D356N Polymorphism in the Sex Hormone-Binding Globulin Gene

¹ Medical Research Council Dunn Human Nutrition Unit, ² Strangeways Research Laboratory, Department of Oncology, Cancer Research-UK, and ³ European Prospective Investigation of Cancer and Nutrition-Norfolk, Strangeways Research Laboratory, Cambridge, United Kingdom and ⁴ Institute of Cancer Research, London, United Kingdom

Requests for reprints: Sheila A. Bingham, Medical Research Council Dunn Human Nutrition Unit, Wellcome Trust/Medical Research Council Building, Hills Road, Cambridge, CB2 2XY, United Kingdom. Phone: 44-1223-252760; Fax: 44-1223-252765; E-mail: sab{at}mrc.cam.ac.uk.

Studies to identify common genetic variants contributing to breast cancer risk often yield inconsistent results. Breast cancer is a complex disease involving both genetic and environmental determinants. Dietary isoflavones are thought to reduce breast cancer risk by stimulating circulating sex hormone-binding globulin (SHBG) levels. The SHBG gene contains a D356N polymorphism and the N variant is associated with reduced SHBG clearance compared with the D variant. In this study, we show a significant gene-environment interaction between SHBG D356N polymorphism and dietary isoflavone exposure on circulating SHBG levels in 1,988 postmenopausal women. SHBG levels were positively associated with isoflavones in women carrying the N variant (_p² = 1.9%; P = 0.006) but not in women carrying only the D variant (_p² = 0.0%; P = 0.999; P_interaction = 0.019). This finding shows that the subtle effects of some genetic variants may be magnified and only become detectable in the presence of certain exposures. This gene-environment interaction might explain heterogeneity in studies associating SHBG gene variants and soy consumption with breast cancer risk in Far East population exposed to high isoflavone levels compared with populations with lower levels. (Cancer Res 2006; 66(18): 8980-3)

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