title: Comprehensive evaluation of the association between prostate cancer and genotypes/haplotypes in CYP17A1, CYP3A4, and SRD5A2.
abstract: Genes involved in the testosterone biosynthetic pathway - such as CYP17A1, CYP3A4, and SRD5A2 - represent strong candidates for affecting prostate cancer. Previous work has detected associations between individual variants in these three genes and prostate cancer risk and aggressiveness. To more comprehensively evaluate CYP17A1, CYP3A4, and SRD5A2, we undertook a two-phase study of the relationship between their genotypes/haplotypes and prostate cancer. Phase I of the study first searched for single-nucleotide polymorphisms (SNPs) in these genes by resequencing 24 individuals from the Coriell Polymorphism Discovery Resource, 92-110 men from prostate cancer case-control sibships, and by leveraging public databases. In all, 87 SNPs were discovered and genotyped in 276 men from case-control sibships. Those SNPs exhibiting preliminary case-control allele frequency differences, or distinguishing (ie, 'tagging') common haplotypes across the genes, were identified for further study (24 SNPs in total). In Phase II of the study, the 24 SNPs were genotyped in an additional 841 men from case-control sibships. Finally, associations between genotypes/haplotypes in CYP17A1, CYP3A4, and SRD5A2 and prostate cancer were evaluated in the total case-control sample of 1117 brothers from 506 sibships. Family-based analyses detected associations between prostate cancer risk or aggressiveness and a number of CYP3A4 SNPs (P-values between 0.006 and 0.05), a CYP3A4 haplotype (P-values 0.05 and 0.009 in nonstratified and stratified analysis, respectively), and two SRD5A2 SNPs in strong linkage disequilibrium (P=0.02). Undertaking a two-phase study comprising SNP discovery, haplotype tagging, and association analyses allowed us to more fully decipher the relation between CYP17A1, CYP3A4, and SRD5A2 and prostate cancer.
authors.affiliation: Amersham Biosciences, Sunnyvale, CA 94085, USA.
authors.forename: Anu
authors.initials: A
authors.lastname: Loukola
authors.forename: Monica
authors.initials: M
authors.lastname: Chadha
authors.forename: Sharron G
authors.initials: SG
authors.lastname: Penn
authors.forename: David
authors.initials: D
authors.lastname: Rank
authors.forename: David V
authors.initials: DV
authors.lastname: Conti
authors.forename: Deborah
authors.initials: D
authors.lastname: Thompson
authors.forename: Mine
authors.initials: M
authors.lastname: Cicek
authors.forename: Brad
authors.initials: B
authors.lastname: Love
authors.forename: Vesna
authors.initials: V
authors.lastname: Bivolarevic
authors.forename: Qiner
authors.initials: Q
authors.lastname: Yang
authors.forename: Yalin
authors.initials: Y
authors.lastname: Jiang
authors.forename: David K
authors.initials: DK
authors.lastname: Hanzel
authors.forename: Katherine
authors.initials: K
authors.lastname: Dains
authors.forename: Pamela L
authors.initials: PL
authors.lastname: Paris
authors.forename: Graham
authors.initials: G
authors.lastname: Casey
authors.forename: John S
authors.initials: JS
authors.lastname: Witte
mesh_terms: D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000235:genetics*; D016022:Case-Control Studies; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide; D011471:Prostatic Neoplasms / Q000235:genetics*; D013254:Steroid 17-alpha-Hydroxylase / Q000235:genetics*
chemical_list: D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; D013254:Steroid 17-alpha-Hydroxylase; C510163:CYP3A4 protein, human; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase