Polymorphisms in genes involved in the estrogen pathway and mammographic density

Abstract

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 (Ptrend) 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 (Ptrend = 0.004), while no association was observed among parous women (Ptrend = 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 (Ptrend = 0.06 and Ptrend = 0.04, respectively), but with a decrease in AD among past hormonal derivatives users (Ptrend = 0.04; Pi = 0.02 and Ptrend = 0.08; Pi = 0.01, respectively). Moreover, a negative association of rs598126 HSD17B1 SNP with AD was observed among women with higher BMI (>median) (Ptrend = 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 (Ptrend = 0.02; Pi = 0.03) or with late age at menarche (>median) (Ptrend = 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.

Polymorphisms in Estrogen Synthesis Genes and Symptom Clusters During the Menopausal Transition and Early Postmenopause: Observations From the Seattle Midlife Women’s Health Study

“…For example, the 17HSDB1 gene polymorphisms examined in the SMWHS and SWAN studies have been associated with higher endogenous estrogen levels, thus presenting a challenge for health-care providers to prescribe safe levels of estrogen therapies for women with these polymorphisms. In addition, 17HSDB1 polymorphisms have been associated with diabetes mellitus (Lo, Zhao, Scuteri, Brockwell, & Sowers, 2006), mammographic density (Dumas & Diorio, 2010), reproductive diseases, including endometriosis (Hu et al, 2012; Tschuiya et al, 2005), and potentially to reproductive system cancers such as breast and endometrial cancer (Gaudet et al, 2008; Setiawan, Hankinson, Colditz, Hunter, & De Vivo, 2004). In order to address these issues, further research about the functional effects of these polymorphisms and symptoms and symptom clusters is needed, including the likely influence of multiple polymorphisms in the estrogen synthesis, metabolism, and receptor genes on symptoms and symptom clusters and additional health outcomes that women experience during the MT and early postmenopause.…”

Is There an Association Between Bone Mineral Density and Mammographic Density? A Systematic Review

“…5,6 Although the underlying mechanisms are still poorly understood, hormonal exposure is thought to play an important role in driving the association of mammographic density with breast cancer risk. [7][8][9][10] In the Women's Health Initiative (WHI) trial, 1 year of estrogen plus progestin use was associated with a 6% increase in mammographic density. 11 Hormonal exposure also plays an important role in BMD.…”

Polymorphisms in the estrogen receptor alpha gene (ESR1), daily cycling estrogen and mammographic density phenotypes.

“…The possible associations between SNPs in the ER genes and mammographic density are still under debate [ 25 , 26 , 29 – 31 ]. Some in vitro studies have shown that the expression of ERα in breast cancer cells may be down regulated by estradiol [ 59 ].…”

“…Our results suggest that having the minor homozygous allele is associated with decreased percent mammographic density, and the associations are stronger in lean women. However, no association has been observed within strata of estrogen-related factors (parity, hormonal derivatives used, age at menarche, BMI) among premenopausal women [ 26 ], nor in populations of premenopausal and postmenopausal women ([ 26 , 30 , 31 ]. Other investigated SNPs ( rs2228480 , rs728524 , rs3798577 and rs2077647 ) have shown no association with mammographic density in premenopausal and/or postmenopausal populations [ 25 , 26 ].…”

“…Specific polymorphisms (SNPs) in ESR1 may directly or indirectly lead to variations in its activity, and may have an effect on breast cancer risk. Although a number of studies have examined SNPs located in estrogen related genes and possible associations with mammographic density [ 25 – 36 ], few have focused on premenopausal women [ 25 , 27 , 28 , 33 , 36 ], and only a handful have considered SNPs in the ESR1 ( rs2234693 and rs9340799 ) [ 25 , 26 , 29 – 31 ]. Further, none have chacterized participants by menstrual cycle hormonal milieu.…”