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

Abstract

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 (E 1 ) and estradiol (E 2 ) and with the urinary ratio of 2-hydroxyestrone (2-OHE 1 )/ 16A-hydroxyestrone (16A-OHE 1 ). 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 E 1 , E 2 , 2-OHE 1 , and 16A-OHE 1 were measured by enzyme immunoassays. The DNA samples were analyzed by PCR/RFLP for the COMT Val 158 Met, CYP1A1*2A, CYP1A1*2B, CYP1A2*1F, CYP1B1Val 432 Leu, 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 E 2 levels; in CC genotype carriers, serum E 2 levels were 26.3% lower than in homo-and heterozygous common allele carriers combined (P = 0.01). CYP1A2*1F also affected the urinary 2-OHE 1 /16A-OHE 1 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 E 2 , and that it may be a susceptibility locus for breast cancer.

Genetic polymorphisms, hormone levels, and hot flashes in midlife women

“…Current data regarding the effects of genotype on hormone levels, however, are limited. Consistent with previous reports, we showed no difference in estradiol levels with a polymorphism in CYPc17α [12] and no difference in estradiol or estrone levels with a polymorphism in COMT [16,40], CYP19 [40], or CYP1B1 [40]. Other studies, however, have shown lower estradiol [10,11] and estrone [10] levels with a polymorphism in CYP19.…”

Associations between the CYP17, CYPIB1, COMT and SHBG polymorphisms and serum sex hormones in post-menopausal breast cancer survivors

“…Our results for CYP17 add to the growing number of studies reporting little or no association for genetic control by this particular SNP and hormone levels [18,19,[30][31][32][33][34][35][36]. Similarly, there is little evidence that circulating hormone levels vary substantially by the CYP1B1 or COMT genotypes [18,19,35,36]; however, the relationship with urinary metabolites of estrogen has been more consistent with higher concentrations observed for the variant genotypes [19,37].…”

“…Similarly, there is little evidence that circulating hormone levels vary substantially by the CYP1B1 or COMT genotypes [18,19,35,36]; however, the relationship with urinary metabolites of estrogen has been more consistent with higher concentrations observed for the variant genotypes [19,37]. One reason for the lack of an observed effect may be due to the limited ability of most previous studies to look at polymorphisms for several genes or SNPs jointly.…”

“…For the present analysis, we excluded women who did not complete the 24-month interview (240); developed recurrent or new cancer following baseline (84); were pre-menopausal (163),; were taking hormone therapy (other than tamoxifen) at the time of blood draw (35); were missing stage (1), genotyping (93) or hormone (41) data; or were of a race other than white, Hispanic, or African-American (12). An additional 45 women were excluded for unknown menopausal status or hormone levels inconsistent with being post-menopausal.…”

Pharmacogenetics and Regulation of Human CytochromeP450 1B1: Implications in Hormone-Mediated Tumor Metabolism and a Novel Target for Therapeutic Intervention

“…121). A large multiethnic study has indicated that CYP1B1 genotype is not associated with serum estrogen levels in premenopausal women (122). Another study investigating circulating estrogens in postmenopausal women has indicated that CYP1B1 genotype is not correlated with circulating estrogen levels (123), whereas another large study indicated that serum levels of estrogen are increased with the CYP1B1*1 genotype, whereas the CYP1B1*3 genotype correlates with an increased percentage of ER-positive tumors (124), thus confirming a previous observation (106).…”