Polymorphisms in genes involved in the estrogen pathway and mammographic density.

backgroundSingle nucleotide polymorphisms (SNPs) in genes involved in the estrogen pathway appear to be associated with breast cancer risk and possibly with mammographic density (MD), but little is known of these associations among premenopausal women. This study examines the association of 11 polymorphisms in five estrogen-related genes (estrogen receptors alpha and beta (ERα, ERβ), 17β-hydroxysteroid dehydrogenase 1 (HSD17B1), catechol-O-methyltransferase (COMT), cytochrome P450 1B1 (CYP1B1)) with premenopausal MD. Effect modification of four estrogen-related factors (parity, age at menarche, hormonal derivatives use and body mass index (BMI)) on this relation is also assessed.

methodsPolymorphisms were genotyped in 741 premenopausal Caucasian women whose MD was measured in absolute density (AD, cm²) and percent density using a computer-assisted method. Multivariate linear models were used to examine the associations (P(trend)) and interactions (Pi).

resultsNone of the SNPs showed a statistically significant association with AD. However, each additional rare allele of rs1056836 CYP1B1 was associated with a reduction in AD among nulliparous women (P(trend) = 0.004), while no association was observed among parous women (P(trend) = 0.62; Pi = 0.02). An increase in the number of rare alleles of the HSD17B1 SNP (rs598126 and rs2010750) was associated with an increase in AD among women who never used hormonal derivatives (P(trend) = 0.06 and P(trend) = 0.04, respectively), but with a decrease in AD among past hormonal derivatives users (P(trend) = 0.04; Pi = 0.02 and P(trend) = 0.08; Pi = 0.01, respectively). Moreover, a negative association of rs598126 HSD17B1 SNP with AD was observed among women with higher BMI (>median) (P(trend) = 0.01; Pi = 0.02). A negative association between an increased number of rare alleles of COMT rs4680 SNP and AD was limited to women who never used hormonal derivatives (P(trend) = 0.02; Pi = 0.03) or with late age at menarche (>median) (P(trend) = 0.03; Pi = 0.02). No significant association was observed between polymorphisms in the ERα or ERβ genes and AD. Similar results, although less significant, were observed when MD was assessed in percent density.

conclusionSNPs located in CYP1B1, COMT or HSD17B1 genes seem to be associated with MD in some strata of estrogen-related factors. Our findings suggest that modifying effects of estrogen-related factors should be considered when evaluating associations of polymorphisms in estrogen-related genes with premenopausal mammographic density.