title: HSD3B and gene-gene interactions in a pathway-based analysis of genetic susceptibility to bladder cancer.
abstract: Bladder cancer is the 4(th) most common cancer among men in the U.S. We analyzed variant genotypes hypothesized to modify major biological processes involved in bladder carcinogenesis, including hormone regulation, apoptosis, DNA repair, immune surveillance, metabolism, proliferation, and telomere maintenance. Logistic regression was used to assess the relationship between genetic variation affecting these processes and susceptibility in 563 genotyped urothelial cell carcinoma cases and 863 controls enrolled in a case-control study of incident bladder cancer conducted in New Hampshire, U.S. We evaluated gene-gene interactions using Multifactor Dimensionality Reduction (MDR) and Statistical Epistasis Network analysis. The 3'UTR flanking variant form of the hormone regulation gene HSD3B2 was associated with increased bladder cancer risk in the New Hampshire population (adjusted OR 1.85 95%CI 1.31-2.62). This finding was successfully replicated in the Texas Bladder Cancer Study with 957 controls, 497 cases (adjusted OR 3.66 95%CI 1.06-12.63). The effect of this prevalent SNP was stronger among males (OR 2.13 95%CI 1.40-3.25) than females (OR 1.56 95%CI 0.83-2.95), (SNP-gender interaction P = 0.048). We also identified a SNP-SNP interaction between T-cell activation related genes GATA3 and CD81 (interaction P = 0.0003). The fact that bladder cancer incidence is 3-4 times higher in males suggests the involvement of hormone levels. This biologic process-based analysis suggests candidate susceptibility markers and supports the theory that disrupted hormone regulation plays a role in bladder carcinogenesis.
authors.affiliation: Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire, United States of America.
authors.forename: Angeline S
authors.initials: AS
authors.lastname: Andrew
authors.forename: Ting
authors.initials: T
authors.lastname: Hu
authors.forename: Jian
authors.initials: J
authors.lastname: Gu
authors.forename: Jiang
authors.initials: J
authors.lastname: Gui
authors.forename: Yuanqing
authors.initials: Y
authors.lastname: Ye
authors.forename: Carmen J
authors.initials: CJ
authors.lastname: Marsit
authors.forename: Karl T
authors.initials: KT
authors.lastname: Kelsey
authors.forename: Alan R
authors.initials: AR
authors.lastname: Schned
authors.forename: Sam A
authors.initials: SA
authors.lastname: Tanyos
authors.forename: Eben M
authors.initials: EM
authors.lastname: Pendleton
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Mason
authors.forename: Elaine V
authors.initials: EV
authors.lastname: Morlock
authors.forename: Michael S
authors.initials: MS
authors.lastname: Zens
authors.forename: Zhongze
authors.initials: Z
authors.lastname: Li
authors.forename: Jason H
authors.initials: JH
authors.lastname: Moore
authors.forename: Xifeng
authors.initials: X
authors.lastname: Wu
authors.forename: Margaret R
authors.initials: MR
authors.lastname: Karagas
mesh_terms: D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D004843:Epistasis, Genetic; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009097:Multienzyme Complexes / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011375:Progesterone Reductase / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics*; D013251:Steroid Isomerases / Q000235:genetics*; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000473:pathology*
chemical_list: C021425:3 beta-hydroxysteroid oxidoreductase-delta(5) 3-ketosteroid isomerase; D009097:Multienzyme Complexes; D011375:Progesterone Reductase; D013251:Steroid Isomerases