University of Oulu

Zhang, N., Huang, D., Jiang, G., Chen, S., Ruan, X., Chen, H., Huang, J., Liu, A., Zhang, W., Lin, X., Wu, Y., Zhang, Q., Li, J., Tsu, J. H., Wei, G., & Na, R. (2022). Genome‐wide 3′‐utr single nucleotide polymorphism association study identifies significant prostate cancer risk‐associated functional loci at 8p21. 2 in chinese population. Advanced Science, 9(23), 2201420.

Genome-wide 3′-UTR single nucleotide polymorphism association study identifies significant prostate cancer risk-associated functional loci at 8p21.2 in Chinese population

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Author: Zhang, Ning1; Huang, Da1; Jiang, Guangliang1;
Organizations: 1Department of Urology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025 China
2Department of Urology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080 China
3School of Public Health Shenzhen, Sun Yat-sen University, Guangzhou, 510006 China
4Department of Urology, Changhai Hospital, Second Military Medical University, Shanghai, 200433 China
5Department of Urology, Huashan Hospital, Fudan University, Shanghai, 200040 China
6Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, 90014 Finland
7Department of Bioinformatics, Center for Translational Medicine, Second Military Medical University, Shanghai, 200433 China
8MOE Key Laboratory of Metabolism and Molecular Medicine & Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, and Fudan University Shanghai Cancer Center, Shanghai Medical College of Fudan University, Shanghai, 200032 China
9Division of Urology, Department of Surgery, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 2.5 MB)
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Language: English
Published: John Wiley & Sons, 2022
Publish Date: 2023-03-08


MicroRNAs (miRNAs) are involved in the regulation of gene expression via incomplete base pairing to sequence motifs at the three prime untranslated regions (3′-UTRs) of mRNAs and play critical roles in the etiology of cancers. Single nucleotide polymorphisms (SNPs) in the 3′-UTR miRNA-binding regions may influence the miRNA affinity. However, this biological mechanism in prostate cancer (PCa) remains unclear. Here, a three-stage genome-wide association study of 3′-UTR SNPs (n=33 117) is performed in 5515 Chinese men. Three genome-wide significant variants are discovered at 8p21.2 (rs1567669, rs4872176, and rs4872177), which are all located in a linkage disequilibrium region of the NKX3–1 gene. Phenome-wide association analysis using the FinnGen data reveals a specific association of rs1567669 with PCa over 2,264 disease endpoints. Expression quantitative trait locus analyses based on both Chinese PCa cohort and the GTEx database show that risk alleles of these SNPs are significantly associated with low expression of NKX3–1. Based on the MirSNP database, dual-luciferase reporter assays show that risk alleles of these SNPs downregulate the expression of NKX3–1 via increased miRNA binding. These results indicate that the SNPs at the 3′-UTR of NKX3–1 significantly downregulate NKX3–1 expression by influencing the affinity of miRNA and increase the PCa risk.

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Series: Advanced science
ISSN: 2198-3844
ISSN-E: 2198-3844
ISSN-L: 2198-3844
Volume: 9
Issue: 23
Article number: 2201420
DOI: 10.1002/advs.202201420
Type of Publication: A1 Journal article – refereed
Field of Science: 3111 Biomedicine
Funding: N.Z., D.H., G.J., S.C., X.R., and H.C. contributed equally to this work. The authors thank all the subjects included in this study (ChinaPCa Consortium). The authors also want to acknowledge the participants and investigators of the FinnGen study ( and the TCGA Research Network ( This work was supported by grants from National Natural Science Foundation of China (81772741 and 81972645), Shanghai Rising-Star Program (18QA1402800), Shanghai Youth Talent Support Program, the Sigrid Juselius Foundation grant, Fudan University recruit funding, and the Shanghai Sailing Program (22YF1440500).
Copyright information: © 2022 The Authors. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.