title: Family-based association analysis of 42 hereditary prostate cancer families identifies the Apolipoprotein L3 region on chromosome 22q12 as a risk locus.
abstract: Multiple genome-wide scans for hereditary prostate cancer (HPC) have identified susceptibility loci on nearly every chromosome. However, few results have been replicated with statistical significance. One exception is chromosome 22q, for which five independent linkage studies yielded strong evidence for a susceptibility locus in HPC families. Previously, we refined this region to a 2.53 Mb interval, using recombination mapping in 42 linked pedigrees. We now refine this locus to a 15 kb interval, spanning Apolipoprotein L3 (APOL3), using family-based association analyses of 150 total prostate cancer (PC) cases from two independent family collections with 506 unrelated population controls. Analysis of the two independent sets of PC cases highlighted single nucleotide polymorphisms (SNPs) within the APOL3 locus showing the strongest associations with HPC risk, with the most robust results observed when all 150 cases were combined. Analysis of 15 tagSNPs across the 5' end of the locus identified six SNPs with P-values < or =2 × 10(-4). The two independent sets of HPC cases highlight the same 15 kb interval at the 5' end of the APOL3 gene and provide strong evidence that SNPs within this 15 kb interval, or in strong linkage disequilibrium with it, contribute to HPC risk. Further analyses of this locus in an independent population-based, case-control study revealed an association between an SNP within the APOL3 locus and PC risk, which was not confirmed in the Cancer Genetic Markers of Susceptibility data set. This study further characterizes the 22q locus in HPC risk and suggests that the role of this region in sporadic PC warrants additional studies.
authors.affiliation: National Human Genome Research Institute, National Institutes of Health, 50 South Drive, Building 50, Room 5351, Bethesda, MD 20892, USA.
authors.forename: Bo
authors.initials: B
authors.lastname: Johanneson
authors.forename: Shannon K
authors.initials: SK
authors.lastname: McDonnell
authors.forename: Danielle M
authors.initials: DM
authors.lastname: Karyadi
authors.forename: Pascale
authors.initials: P
authors.lastname: Quignon
authors.forename: Laura
authors.initials: L
authors.lastname: McIntosh
authors.forename: Shaun M
authors.initials: SM
authors.lastname: Riska
authors.forename: Liesel M
authors.initials: LM
authors.lastname: FitzGerald
authors.forename: Gregory
authors.initials: G
authors.lastname: Johnson
authors.forename: Kerry
authors.initials: K
authors.lastname: Deutsch
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Williams
authors.forename: Lori S
authors.initials: LS
authors.lastname: Tillmans
authors.forename: Janet L
authors.initials: JL
authors.lastname: Stanford
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Schaid
authors.forename: Stephen N
authors.initials: SN
authors.lastname: Thibodeau
authors.forename: Elaine A
authors.initials: EA
authors.lastname: Ostrander
mesh_terms: D000368:Aged; D001053:Apolipoproteins / Q000235:genetics*; D002892:Chromosomes, Human, Pair 22 / Q000235:genetics*; D024202:Electrophoretic Mobility Shift Assay; D005190:Family; D005260:Female; D056726:Genetic Association Studies; D056426:Genetic Loci / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011471:Prostatic Neoplasms / Q000235:genetics*; D012307:Risk Factors; D016385:TATA Box / Q000235:genetics; D044465:White People / Q000235:genetics
chemical_list: D001053:Apolipoproteins