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Association of Genetic Polymorphisms with Serum Estrogens Measured Multiple Times During a 2-Year Period in Premenopausal Women

¹ Cancer Research Center of Hawaii, University of Hawaii, Honolulu, Hawaii; ² IARC, Lyon, France; and ³ Department of Obstetrics and Gynecology and Preventive Medicine, University of Southern California, Keck School of Medicine, Los Angeles, California

Requests for reprints: Galina Lurie, Cancer Research Center of Hawaii, University of Hawaii, 1236 Lauhala Street, Honolulu, HI 96813. Phone: 808-586-5866; Fax: 808-586-2984. E-mail: glurie{at}CRCH.hawaii.edu

There is evidence that circulating estrogens are associated with breast cancer risk. In this study of premenopausal women, we explored the association of polymorphisms in genes in the estrogen synthesis and metabolism pathways with serum and urinary levels of estrone (E₁) and estradiol (E₂) and with the urinary ratio of 2-hydroxyestrone (2-OHE₁)/16-hydroxyestrone (16-OHE₁). This analysis included 220 women, who were participants in a 2-year randomized soy intervention. Blood specimens were collected in the luteal phase of the menstrual cycle an average of 4.4 times over 2 years. Overnight urinary specimens were collected on the same cycle day, only at baseline. Levels of E₁, E₂, 2-OHE₁, and 16-OHE₁ were measured by enzyme immunoassays. The DNA samples were analyzed by PCR/RFLP for the COMT Val¹⁵⁸Met, CYP1A1*2A, CYP1A1*2B, CYP1A2*1F, CYP1B1 Val⁴³²Leu, and CYP17 T27C polymorphisms. We applied mixed models to investigate the relations between genotypes and repeated serum hormone measurements and generalized linear models to assess associations between genotypes and urinary estrogen metabolites. The CYP1A2 C allele was significantly associated with lower serum E₂ levels; in CC genotype carriers, serum E₂ levels were 26.3% lower than in homo- and heterozygous common allele carriers combined (P = 0.01). CYP1A2*1F also affected the urinary 2-OHE₁/16-OHE₁ ratio; carriers of the variant C allele had a markedly lower ratio than individuals with the AA genotype (1.37 versus 1.76; P = 0.002). These data suggest that CYP1A2*1F is associated with lower circulating levels of E₂, and that it may be a susceptibility locus for breast cancer.

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