Open AccessGenome‐Wide 3′‐UTR Single Nucleotide Polymorphism Association Study Identifies Significant Prostate Cancer Risk‐Associated Functional Loci at 8p21.2 in Chinese Population
Author(s) -
Zhang Ning,
Huang Da,
Jiang Guangliang,
Chen Siteng,
Ruan Xiaohao,
Chen Haitao,
Huang Jingyi,
Liu Ao,
Zhang Wenhui,
Lin Xiaoling,
Wu Yishuo,
Zhang Qin,
Li Jing,
Tsu James HokLeung,
Wei GongHong,
Na Rong
Publication year - 2022
Publication title -
advanced science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.388
H-Index - 100
ISSN - 2198-3844
DOI - 10.1002/advs.202201420
Subject(s) - single nucleotide polymorphism , genetics , biology , linkage disequilibrium , three prime untranslated region , allele , expression quantitative trait loci , untranslated region , microrna , locus (genetics) , genetic association , genome wide association study , computational biology , gene , genotype , rna
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.