TY - JOUR
T1 - Family-based association analysis of 42 hereditary prostate cancer families identifies the Apolipoprotein L3 region on chromosome 22q12 as a risk locus
AU - Johanneson, Bo
AU - McDonnell, Shannon K.
AU - Karyadi, Danielle M.
AU - Quignon, Pascale
AU - McIntosh, Laura
AU - Riska, Shaun M.
AU - FitzGerald, Liesel M.
AU - Johnson, Gregory
AU - Deutsch, Kerry
AU - Williams, Gabrielle
AU - Tillmans, Lori S.
AU - Stanford, Janet L.
AU - Schaid, Daniel J.
AU - Thibodeau, Stephen N.
AU - Ostrander, Elaine A.
N1 - Funding Information:
This work was supported by the US Public Health Service, National Institutes of Health grants [RO1 CA080122, RO1 CA056678, RO1 CA092579 to J.L.S.], [P50 CA097186 supports L.M.F.] and [RO1 CA72818 to S.N.T. and D.J.S.]. PROGRESS investigators also acknowledge additional support from the Prostate Cancer Foundation and the Fred Hutchinson Cancer Research Center. Mayo Clinic investigators [S.N.T., S.K.M., S.M.R., D.J.S.] acknowledge additional support from the Ralph C. Wilson Medical Research Foundation. E.A.O., B.J., D.M.K., P.Q., G.J. and G.W. acknowledge support from the Intramural Program of the National Institutes of Health. Genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, Contract Number N01-HG-65403.
PY - 2010/7/14
Y1 - 2010/7/14
N2 - 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. Published by Oxford University Press 2010.
AB - 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. Published by Oxford University Press 2010.
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U2 - 10.1093/hmg/ddq283
DO - 10.1093/hmg/ddq283
M3 - Article
C2 - 20631155
AN - SCOPUS:77956547385
SN - 0964-6906
VL - 19
SP - 3852
EP - 3862
JO - Human molecular genetics
JF - Human molecular genetics
IS - 19
M1 - ddq283
ER -