Family-based association analysis of 42 hereditary prostate cancer families identifies the Apolipoprotein L3 region on chromosome 22q12 as a risk locus
Open Access
- 14 July 2010
- journal article
- research article
- Published by Oxford University Press (OUP) in Human Molecular Genetics
- Vol. 19 (19), 3852-3862
- https://doi.org/10.1093/hmg/ddq283
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 ≤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.This publication has 43 references indexed in Scilit:
- Identification of seven new prostate cancer susceptibility loci through a genome-wide association studyNature Genetics, 2009
- Genotype ImputationAnnual Review of Genomics and Human Genetics, 2009
- The apolipoprotein L family of programmed cell death and immunity genes rapidly evolved in primates at discrete sites of host–pathogen interactionsGenome Research, 2009
- Statin Use and Risk of Prostate Cancer: Results from a Population-based Epidemiologic StudyAmerican Journal of Epidemiology, 2008
- Prostate Cancer Susceptibility Loci: Finding the GenesAdvances in Experimental Medicine and Biology, 2008
- A Genome-Wide Association Study of Type 2 Diabetes in Finns Detects Multiple Susceptibility VariantsScience, 2007
- Compelling evidence for a prostate cancer gene at 22q12.3 by the International Consortium for Prostate Cancer GeneticsHuman Molecular Genetics, 2007
- Efficient Study Designs for Test of Genetic Association Using Sibship Data and Unrelated Cases and ControlsAmerican Journal of Human Genetics, 2006
- Haploview: analysis and visualization of LD and haplotype mapsBioinformatics, 2004
- The International HapMap ProjectNature, 2003