There are more than 30 CaP risk-associated SNPs identified in genome-wide association studies (GWAS) that have been verified as risk-associated germ-line genetic markers. Yet most of the SNPs were located in non-coding regions of the genome, making functional mechanisms unclear. This research group had previously used a bioinformatics approach to map the CaP risk-associated SNPs to functional databases and they found the risk-associated SNPs were enriched in genomic regions containing androgen receptor (AR) binding sites. In the present report they evaluated sequence variants in regions containing AR binding sites captured by chromatin immunoprecipitation with tiled oligonucleotides microarrays (ChIP-on-chip) for association with CaP risk in two CaP GWAS databases.
GWAS of CaP patients and controls was performed and a search for all known SNPS in the AR binding sites was conducted. The allele frequency differences between cases and controls were tested for each SNP in regions of AR binding sites. The linkage disequilibrium (LD) block was the unit of association used to identify SNPs that are independently associated with CaP risk. There were 18,401 SNPs identified in the 22,447 ChIP-on-chip detected AR binding sites. 12,724 were further investigated for association of CaP risk using an allelic test. Among 9,500 independent LD blocks, there were 4 blocks where at least one SNP was associated with CaP risk at P<10-5. The 4 blocks were 8p21 at 3’ of NKX3.1, 10q11 at 5’ of MSMB, and regions 1 and 2 of 8q24, all of which were known CaP risk-associated SNPs. They validated that the excess of observed CaP risk-associated LD blocks was statistically significant. In a second independent study population, among the 12,369 independent LD blocks containing AR binding sites, they found 2 blocks where at least one SNP was associated with CaP risk at P<10-5. They were at 15qp21 and the region 1 of 8q24. The researchers found the blocks that are significantly associated with CaP risk often overlapped with the LD blocks of known CaP risk-associated SNPs identified from GWAS; the proportion of overlap was significantly higher than that of the remaining LD blocks in the genome. In other words, the higher proportions of observed CaP risk-associated SNPs in the regions containing AR binding sites represent true association.
Lu Y, Sun J, Kader AK, Kim ST, Kim JW, Liu W, Sun J, Lu D, Feng J, Zhu Y, Jin T, Zhang Z, Dimitrov L, Lowey J, Campbell K, Suh E, Duggan D, Carpten J, Trent JM, Gronberg H, Zheng SL, Isaacs WB, Xu J
Prostate. 2011 Jun 10. Epub ahead of print.
10.1002/pros.21439
PubMed Abstract
PMID: 21671247
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