title: Polymorphisms in genes involved in the estrogen pathway and mammographic density.
abstract: BACKGROUND
  Single 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.
  
  
  METHODS
  Polymorphisms 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).
  
  
  RESULTS
  None 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.
  
  
  CONCLUSIONS
  SNPs 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.
authors.affiliation: Université Laval, Département de médecine sociale et préventive, Quebec City, QC, Canada.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Dumas
authors.forename: Caroline
authors.initials: C
authors.lastname: Diorio
mesh_terms: D000328:Adult; D000367:Age Factors; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism; D015992:Body Mass Index; D001941:Breast Diseases / Q000000981:diagnostic imaging* / Q000208:ethnology / Q000235:genetics* / Q000378:metabolism; D001943:Breast Neoplasms / Q000000981:diagnostic imaging* / Q000208:ethnology / Q000235:genetics* / Q000378:metabolism; D002394:Catechol O-Methyltransferase / Q000235:genetics / Q000378:metabolism; D016009:Chi-Square Distribution; D065633:Cytochrome P-450 CYP1B1; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D004960:Estradiol Dehydrogenases / Q000235:genetics / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006801:Humans; D016014:Linear Models; D015810:Linkage Disequilibrium; D008327:Mammography; D008875:Middle Aged; D010298:Parity; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011247:Pregnancy; D017697:Premenopause; D011792:Quebec; D018570:Risk Assessment; D012307:Risk Factors; D044465:White People / Q000235:genetics
chemical_list: D004967:Estrogens; D003577:Cytochrome P-450 Enzyme System; D004960:Estradiol Dehydrogenases; C513331:HSD17B1 protein, human; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; D065633:Cytochrome P-450 CYP1B1; D002394:Catechol O-Methyltransferase