Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Proc Natl Acad Sci U S A. 2012 Jul 10;109(28):11252-7. doi: 10.1073/pnas.1200853109. Epub 2012 Jun 22.
One of the central goals of human genetics is to discover the genes and pathways driving human traits. To date, most of the common risk alleles discovered through genome-wide association studies (GWAS) map to nonprotein-coding regions. Because of our relatively poorer understanding of this part of the genome, the functional consequences of trait-associated variants pose a considerable challenge. To identify the genes through which risk loci act, we hypothesized that the risk variants are regulatory elements. For each of 12 known risk polymorphisms, we evaluated the correlation between risk allele status and transcript abundance for all annotated protein-coding transcripts within a 1-Mb interval. A total of 103 transcripts were evaluated in 662 prostate tissue samples [normal (n = 407) and tumor (n = 255)] from 483 individuals [European Americans (n = 233), Japanese (n = 127), and African Americans (n = 123)]. In a pooled analysis, 4 of the 12 risk variants were strongly associated with five transcripts (NUDT11, MSMB, NCOA4, SLC22A3, and HNF1B) in histologically normal tissue (P ≤ 0.001). Although associations were also observed in tumor tissue, they tended to be more attenuated. Previously, we showed that MSMB and NCOA4 participate in prostate cancer pathogenesis. Suppressing the expression of NUDT11, SLC22A3, and HNF1B influences cellular phenotypes associated with tumor-related properties in prostate cancer cells. Taken together, the data suggest that these transcripts contribute to prostate cancer pathogenesis.
人类遗传学的核心目标之一是发现驱动人类特征的基因和途径。迄今为止，通过全基因组关联研究 (GWAS) 发现的大多数常见风险等位基因都映射到非蛋白编码区域。由于我们对基因组这一部分的理解相对较差，因此与特征相关的变体的功能后果构成了相当大的挑战。为了确定风险基因座作用的基因，我们假设风险变体是调节元件。对于 12 个已知风险多态性中的每一个，我们评估了风险等位基因状态与 1 Mb 间隔内所有注释的蛋白编码转录本丰度之间的相关性。在来自 483 个人的 662 个前列腺组织样本[正常（n = 407）和肿瘤（n = 255）]中评估了总共 103 个转录本。在 pooled 分析中，12 个风险变体中的 4 个与组织学正常组织中的 5 个转录本（NUDT11、MSMB、NCOA4、SLC22A3 和 HNF1B）强烈相关（P ≤ 0.001）。尽管在肿瘤组织中也观察到了关联，但它们往往更为减弱。先前，我们表明 MSMB 和 NCOA4 参与了前列腺癌的发病机制。抑制 NUDT11、SLC22A3 和 HNF1B 的表达会影响与前列腺癌细胞中与肿瘤相关特性相关的细胞表型。总之，这些数据表明这些转录本参与了前列腺癌的发病机制。
