期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 109, 期 28, 页码 11252-11257出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1200853109
关键词
expression quantitative trait loci; prostate cancer risk SNPs; multi-ethnic
资金
- US National Institutes of Health [R01 CA129435, U19 CA148537 (GAME-ON)]
- Mayer Foundation
- H. L. Snyder Medical Foundation
- Dana-Farber/Harvard Cancer Center Prostate Cancer Specialized Program of Research Excellence (National Cancer Institute) [5P50CA90381]
- Kohlberg Foundation
- A. David Mazzone Awards Program
- Emerald Foundation
- Claudia Adams Barr award
- Howard Hughes Medical Institute
- MRC [G0900871] Funding Source: UKRI
- Medical Research Council [G0900871] Funding Source: researchfish
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.
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