Fine mapping association study and functional analysis implicate a SNP in MSMB at 10q11 as a causal variant for prostate cancer risk
Fine mapping association study and functional analysis implicate a SNP in MSMB at 10q11 as a causal variant for prostate cancer risk
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DOI：
10.1093/hmg/ddp035
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发表时间：
2009-04-01
影响因子：
3.5
通讯作者：
Xu, Jianfeng
中科院分区：
文献类型：
--
作者：
Chang, Bao-Li;Cramer, Scott D.;Xu, Jianfeng
最近，在两项全基因组关联研究中，MSMB基因5'区10q11（rs10993994）处的单核苷酸多态性（SNP）与前列腺癌风险有关。为了确定该区域可能的致病变异，我们在一项基于瑞典人群的病例对照研究（瑞典前列腺癌）中，对16个标签SNP进行了基因分型，并在10q11的65 kb基因组区域内估算了29个额外的SNP，包括2899例病例和1722例对照。我们发现了两个独立的基因座与前列腺癌风险相关的证据，这两个基因座被重组热点分开。在位点1的多个显著SNP中，起始SNP rs10993994最显著。重要的是，使用MSMB启动子报告基因测定，我们发现该SNP的风险等位基因在前列腺癌模型LNCaP细胞中的启动子活性仅为野生型等位基因的13%。奇怪的是，第二个新的基因座（基因座2）位于NCOA 4（也称为ARA 70）内，已知NCOA 4可增强前列腺癌细胞中雄激素受体的转录活性。然而，在三个额外的研究人群中，只有一个弱证实了其相关性。rs10993994是该区域最强的相关变异，其风险等位基因对MSMB（一种具有先前描述的前列腺癌抑制功能的基因）的转录活性具有主要影响，这一观察结果共同表明rs10993994的T等位基因是10q11处的潜在因果变异，可增加前列腺癌的风险。
A single nucleotide polymorphism (SNP) at 10q11 (rs10993994) in the 5' region of the MSMB gene was recently implicated in prostate cancer risk in two genome-wide association studies. To identify possible causal variants in the region, we genotyped 16 tagging SNPs and imputed 29 additional SNPs in similar to 65 kb genomic region at 10q11 in a Swedish population-based case-control study (CAncer of the Prostate in Sweden), including 2899 cases and 1722 controls. We found evidence for two independent loci, separated by a recombination hotspot, associated with prostate cancer risk. Among multiple significant SNPs at locus 1, the initial SNP rs10993994 was most significant. Importantly, using an MSMB promoter reporter assay, we showed that the risk allele of this SNP had only 13% of the promoter activity of the wild-type allele in a prostate cancer model, LNCaP cells. Curiously, the second, novel locus (locus 2) was within NCOA4 (also known as ARA70), which is known to enhance androgen receptor transcriptional activity in prostate cancer cells. However, its association was only weakly confirmed in one of the three additional study populations. The observations that rs10993994 is the strongest associated variant in the region and its risk allele has a major effect on the transcriptional activity of MSMB, a gene with previously described prostate cancer suppressor function, together suggest the T allele of rs10993994 as a potential causal variant at 10q11 that confers increased risk of prostate cancer.