title: Association of genetic polymorphisms in ESR2, HSD17B1, ABCB1, and SHBG genes with colorectal cancer risk.
abstract: The incidence rates and relative risks for colorectal cancer (CRC) are higher in men than in women. Sex steroids may play a role in this gender-associated difference in CRC risk. This study was conducted to explore the relationship of single nucleotide polymorphisms (SNPs) in steroid hormone signaling (ESR1, ESR2, PGR, NR1I2, and SHBG), phase I- and II-metabolizing enzyme (COMT, HSD17B1, CYP1A1, CYP17A1, CYP1A2, CYP1B1, CYP2C9, CYP3A4, CYP2C19, and GSTP1), and hormone transporter (ABCB1) genes with the risk of CRC in German women and men, separately. From the population-based DACHS study (South Germany), 47 putatively functional SNPs were genotyped in 1798 CRC cases (746 women and 1052 men) and 1810 controls (732 women and 1078 men). Significant allele dose-response associations were observed with ESR2_rs1255998, ESR2_rs928554, HSD17B1_rs605059, and ABCB1_rs2229109 in women (P trend=0.004, 0.05, 0.03, and 0.05 respectively) and with ABCB1_rs1045642, ABCB1_rs9282564, and SHBG_rs6259 in men (P trend=0.01, 0.03, and 0.02 respectively). The ESR2_rs1255998_G allele showed the most significant association with risk for CRC in women, with a per-allele odds ratio (OR) of 0.68 (95% confidence interval (CI) 0.52-0.88). This finding was replicated in an independent study from North Germany including 1076 female CRC cases and 1151 controls (OR=0.84, 95% CI 0.71-1.04), yielding a per-allele OR of 0.80 (95% CI 0.69-0.93, P trend=0.003) in the pooled sample. These findings implicate a role of ESR2 in the risk for developing CRC in women and suggest that HSD17B1, ABCB1, and SHBG genes may contribute to sex steroid-mediated effects on CRC development.
authors.affiliation: Division of Molecular Genetic Epidemiology, German Cancer Research Center, Im Neuenheimer Feld 580, 69120 Heidelberg, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Sainz
authors.forename: A
authors.initials: A
authors.lastname: Rudolph
authors.forename: R
authors.initials: R
authors.lastname: Hein
authors.forename: M
authors.initials: M
authors.lastname: Hoffmeister
authors.forename: S
authors.initials: S
authors.lastname: Buch
authors.forename: W
authors.initials: W
authors.lastname: von Schönfels
authors.forename: J
authors.initials: J
authors.lastname: Hampe
authors.forename: C
authors.initials: C
authors.lastname: Schafmayer
authors.forename: H
authors.initials: H
authors.lastname: Völzke
authors.forename: B
authors.initials: B
authors.lastname: Frank
authors.forename: H
authors.initials: H
authors.lastname: Brenner
authors.forename: A
authors.initials: A
authors.lastname: Försti
authors.forename: K
authors.initials: K
authors.lastname: Hemminki
authors.forename: J
authors.initials: J
authors.lastname: Chang-Claude
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D002394:Catechol O-Methyltransferase / Q000235:genetics; D015179:Colorectal Neoplasms / Q000235:genetics*; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D004960:Estradiol Dehydrogenases / Q000235:genetics*; D047629:Estrogen Receptor beta / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011956:Receptors, Cell Surface / Q000235:genetics*; D012737:Sex Factors
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D047629:Estrogen Receptor beta; D011956:Receptors, Cell Surface; C063572:sex hormone-binding globulin receptor; D003577:Cytochrome P-450 Enzyme System; D004960:Estradiol Dehydrogenases; C513331:HSD17B1 protein, human; D002394:Catechol O-Methyltransferase