SNPs in the kallikrein gene region associated with prostate cancer risk: true cause or association by design?
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ABSTRACT:
SUBMITTER: Eeles R
PROVIDER: S-EPMC3882634 | biostudies-literature | 2008 Sep
REPOSITORIES: biostudies-literature
Publications
SNPs in the kallikrein gene region associated with prostate cancer risk: true cause or association by design?
Eeles R R Giles G G Neal D D Hamdy F F Donovan J J Muir K K Easton D D
Nature genetics 20080901 9
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Project description:Epidemiological studies have assessed the association between kallikrein 3 (KLK3) polymorphisms and prostate cancer (PCa) susceptibility. However, published data on this association are somewhat inconclusive. Articles investigating the association between three KLK3 (rs1058205, rs2735839, and rs266882) variants and PCa susceptibility were searched from online databases, which included 35,838 patients and 36,369 control participants. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to demonstrate the strength of the association. We also utilized ELISA to detect serum expression of KLK3. In addition, in silico tools were adopted to evaluate the relationship of KLK3 expression and PCa survival time. The overall results indicated that polymorphism T>C of rs1058205 was associated with decreased risk of PCa (allele contrast: OR = 0.75, 95% CI = 0.64-0.88, Pheterogeneity < 0.001; homozygote comparison: OR = 0.58, 95% CI = 0.42-0.81, Pheterogeneity < 0.001), particularly in Caucasian population (allele contrast: OR = 0.77, 95% CI = 0.65-0.91, Pheterogeneity < 0.001; homozygote comparison: OR = 0.58, 95% CI = 0.41-0.82, Pheterogeneity < 0.001). No association was observed between the polymorphism A>G of rs2735839 and risk of PCa. In addition, no association was observed between polymorphism A>G of rs266882 and risk of PCa. Serum KLK3 levels in PCa patients carrying CC/CT genotypes were statistically lower than those carrying TT genotypes. Conclusion: This meta-analysis suggests that rs1058205 polymorphism of KLK3 is a risk factor for PCa development, polymorphism T>C of rs1058205 is associated with decreased susceptibility to PCa particularly in Caucasian population.
| S-EPMC6265624 | biostudies-literature
Project description:We have conducted a three-stage, comprehensive single nucleotide polymorphism (SNP)-tagging association study of ESR1 gene variants (SNPs) in more than 55,000 breast cancer cases and controls from studies within the Breast Cancer Association Consortium (BCAC). No large risks or highly significant associations were revealed. SNP rs3020314, tagging a region of ESR1 intron 4, is associated with an increase in breast cancer susceptibility with a dominant mode of action in European populations. Carriers of the c-allele have an odds ratio (OR) of 1.05 [95% Confidence Intervals (CI) 1.02-1.09] relative to t-allele homozygotes, P = 0.004. There is significant heterogeneity between studies, P = 0.002. The increased risk appears largely confined to oestrogen receptor-positive tumour risk. The region tagged by SNP rs3020314 contains sequence that is more highly conserved across mammalian species than the rest of intron 4, and it may subtly alter the ratio of two mRNA splice forms.
| S-EPMC2722230 | biostudies-literature
Project description:We profiled androgen receptor (AR) genomic targets using high-throughput sequencing of chromatin-immunoprecipitated (ChIP) DNA from TMPRSS2-ERG fusion gene positive DUCaP prostate cancer cells. ChIp-seq and microarray gene expression profiling datasets were integrated with the NHGRI GWAS PCa risk SNPs catalog to identify disease susceptibility SNPs localized within functional androgen receptor binding sites (ARBSs). Eighty GWAS index or linked SNPs were found to be localized in ARBSs. Among these rs11891426:T>G in the 7th intron of the melanophilin gene was found located within a novel putative auxiliary AR binding motif, which we found enriched in the neighborhood of canonical androgen responsive elements. T→G exchange attenuated the transcriptional activity of the ARBS in an AR reporter gene assay of prostate cancer cell models. It went also in line with decreased melanophilin protein level in primary prostate tumors with G allele.These results unravel a hidden link between androgen receptor and a functional PCa risk SNP, whose allele alteration affects androgen regulation of its host gene melanophilin . Genomic profile of androgen receptor binding sites of androgen or vehicle treated DUCaP cells using ChIP-seq. IgG precipiated DNAs from both treatments served as controls.
2015-07-10 | E-GEOD-70679 | biostudies-arrayexpress
Project description:We profiled androgen receptor (AR) genomic targets using high-throughput sequencing of chromatin-immunoprecipitated (ChIP) DNA from TMPRSS2-ERG fusion gene positive DUCaP prostate cancer cells. ChIp-seq and microarray gene expression profiling datasets were integrated with the NHGRI GWAS PCa risk SNPs catalog to identify disease susceptibility SNPs localized within functional androgen receptor binding sites (ARBSs). Eighty GWAS index or linked SNPs were found to be localized in ARBSs. Among these rs11891426:T>G in the 7th intron of the melanophilin gene was found located within a novel putative auxiliary AR binding motif, which we found enriched in the neighborhood of canonical androgen responsive elements. T→G exchange attenuated the transcriptional activity of the ARBS in an AR reporter gene assay of prostate cancer cell models. It went also in line with decreased melanophilin protein level in primary prostate tumors with G allele.These results unravel a hidden link between androgen receptor and a functional PCa risk SNP, whose allele alteration affects androgen regulation of its host gene melanophilin .
2015-07-10 | GSE70679 | GEO
Project description:Genome-wide association studies have identified more than 100 SNPs that increase the risk of prostate cancer (PrCa). We identify and compare expression quantitative trait loci (eQTLs) and CpG methylation quantitative trait loci (meQTLs) among 147 established PrCa risk SNPs in primary prostate tumors (n = 355 from a Seattle-based study and n = 495 from The Cancer Genome Atlas, TCGA) and tumor-adjacent, histologically benign samples (n = 471 from a Mayo Clinic study). The role of DNA methylation in eQTL regulation of gene expression was investigated by data triangulation using several causal inference approaches, including a proposed adaptation of the Causal Inference Test (CIT) for causal direction. Comparing eQTLs between tumors and benign samples, we show that 98 of the 147 risk SNPs were identified as eQTLs in the tumor-adjacent benign samples, and almost all 34 eQTL identified in tumor sets were also eQTLs in the benign samples. Three lines of results support the causal role of DNA methylation. First, nearly 100 of the 147 risk SNPs were identified as meQTLs in one tumor set, and almost all eQTLs in tumors were meQTLs. Second, the loss of eQTLs in tumors relative to benign samples was associated with altered DNA methylation. Third, among risk SNPs identified as both eQTLs and meQTLs, mediation analyses suggest that over two-thirds have evidence of a causal role for DNA methylation, mostly mediating genetic influence on gene expression. In summary, we provide a comprehensive catalog of eQTLs, meQTLs and putative cancer genes for known PrCa risk SNPs. We observe that a substantial portion of germline eQTL regulatory mechanisms are maintained in the tumor development, despite somatic alterations in tumor genome. Finally, our mediation analyses illuminate the likely intermediary role of CpG methylation in eQTL regulation of gene expression.
| S-EPMC7145271 | biostudies-literature
Project description:ObjectivesTo assess the association of polymorphism rs198977 in the human kallikrein-2 gene (KLK2) and risk of prostate cancer (PCa).MethodsTwo investigators independently searched the PubMed, Elsevier, EMBASE, Web of Science, Wiley Online Library and Chinese National Knowledge Infrastructure (CNKI). Pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) for rs198977 and PCa were calculated in a fixed-effects model (the Mantel-Haenszel method) and a random-effects model (the DerSimonian and Laird method) when appropriate.ResultsSix studies met the inclusion criteria in this meta-analysis, which included 5859 PCa cases and 4867 controls. Overall, rs198977 was associated with the PCa risk (TT+CT vs. CC, pooled OR = 1.163, 95% CI = 1.076-1.258, P-value <0.0001). When stratified by ethnicity, significant association was observed in Caucasian samples under both allele comparison (T vs. C, pooled OR = 1.152, 95% CI = 1.079-1.229, P-value <0.0001) and dominant model (TT+CT vs. CC, pooled OR = 1.197, 95% CI = 1.104-1.297, P-value <0.0001). In the overall analysis, a comparably significant increase in the frequency of allele T for rs198977 was detected between cases and controls in Caucasian.ConclusionThis meta-analysis suggests that rs198977 of KLK2 was associated with susceptibility of PCa in Caucasian and the allele T might increase the risk of PCa in Caucasian.
| S-EPMC3688805 | biostudies-literature
Project description:Genome-wide association studies (GWAS) have identified dozens of genomic loci, whose single nucleotide polymorphisms (SNPs) predispose to prostate cancer (PCa). However, the biological functions of these common genetic variants and the mechanisms to increase disease risk are largely unknown. We integrated chromatin-IP coupled sequencing (ChIP-seq) and microarray expression profiling in the TMPRSS2-ERG gene rearrangement positive DuCaP cell model with the NHGRI GWAS PCa risk SNPs catalog, in an attempt to identify disease susceptibility SNPs localized within functional androgen receptor binding sites (ARBSs). Among the 48 GWAS index SNPs and 2,702 linked SNPs defined by the 1000G project 104 were found to be localized in the AR ChIP-seq peaks. Of these risk SNPs, rs11891426 T/G in the 7th intron of its host gene melanophilin (MLPH) was found located within a putative auxiliary ARE motif, which we found enriched in the neighborhood of canonical ARE motifs. Exchange of T to G attenuated the transcriptional activity of the MLPH-ARBS in a reporter gene assay. The expression of MLPH protein in tissue samples from prostate cancer patients was significantly lower in those with the G compared to the T allele. Moreover, a significant positive correlation of AR and MLPH protein expression levels was also confirmed in tissue samples. These results unravel a hidden link between AR and a functional PCa risk SNP rs11891426, whose allele alteration affects androgen regulation of its host gene MLPH. This study shows the power of integrative studies to pin down functional risk SNPs and justifies further investigations.
2015-10-12 | GSE63693 | GEO
Project description:Functional Significance of Prostate Cancer risk-SNPs
| PRJNA294704 | ENA
Project description: Not available
| S-EPMC3782371 | biostudies-literature
Project description: Not available
| S-EPMC4961360 | biostudies-literature