Genetic and functional analyses implicate the NUDT11, HNF1B, and SLC22A3 genes in prostate cancer pathogenesis
Genetic and functional analyses implicate the NUDT11, HNF1B, and SLC22A3 genes in prostate cancer pathogenesis
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DOI：
10.1073/pnas.1200853109
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发表时间：
2012-07-10
影响因子：
11.1
通讯作者：
Freedman, Matthew L.
中科院分区：
文献类型：
--
作者：
Grisanzio, Chiara;Werner, Lillian;Freedman, Matthew L.
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定位于非蛋白质编码区。由于我们对这部分基因组的了解相对较少，性状相关变异的功能后果构成了相当大的挑战。为了确定风险基因座通过哪些基因起作用，我们假设风险变异是调控元件。对于12个已知的风险多态性，我们评估了风险等位基因状态和1 Mb间隔内所有注释的蛋白质编码转录本的转录丰度之间的相关性。在来自483个个体[欧洲裔美国人（n = 233）、日本人（n = 127）和非洲裔美国人（n = 123）]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个转录物。在汇总分析中，12种风险变异中的4种与组织学正常组织中的5种转录本（NUDT 11、MSMB、NCOA 4、SLC 22 A3和HNF 1B）密切相关（P
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