The Rare Variant rs35356162 in UHRF1BP1 Increases Bladder Cancer Risk in Han Chinese Population

Junlong Wu,Haitao Chen,Chengyuan Gu,Qingyi Wei,Meilin Wang,Guiming Zhang,Jianfeng Xu,Yao Zhu,Dingwei Ye,Qiang Ding

doi:10.3389/fonc.2020.00134

Abstract

Background: Seventeen loci have been found to be associated with bladder cancer risk by genome-wide association studies (GWAS) in European population. However, little is known about contribution of low-frequency and rare variants to bladder cancer susceptibility, especially in Eastern population.Methods: We performed a three-stage case-control study including 3,399 bladder cancer patients and 4,647 controls to identify low-frequency and rare variants associated with bladder cancer risk in Han Chinese. We examined exome-array data in 1,019 bladder cancer patients and 1,008 controls in discovery stage. Two replication stages were included to validate variants identified. Bonferroni adjustment was performed to define statistical significance. Logistic regression was conducted to evaluate single marker association with bladder cancer risk. We used SKAT-O method to perform gene level-based analysis. We also conduct additional experiments to explore the underlying mechanism of filtered gene(s).Results: We identified a novel rare coding variant (rs35356162 in UHRF1BP1: G > T, OR = 4.332, P = 3.62E-07 < 7.93E-07, Bonferroni cutoff) that increased bladder cancer risk in Han Chinese. Gene-level analysis showed a significant association of UHRF1BP1 (P = 4.47E-03) with bladder cancer risk. Experiments indicated down-regulation of UHRF1BP1 promoted migration and invasion through epithelial-mesenchymal transition in bladder cancer cell lines.Conclusion: The rare variant of UHRF1BP1, rs35356162, increases bladder cancer risk in Han Chinese and UHRF1BP1 might act as a tumor suppressor in bladder cancer development and progression.Summary: Little is known about potential contribution of low-frequency and rare variants to bladder cancer susceptibility. We performed a three-stage case-control study and identified a new rare variant, rs35356162 in UHRF1BP1, which increased bladder cancer risk in Han Chinese.

Highlights

Bladder cancer is the 7th most common cancer globally [1] and ranks 1st in urologic malignancies in China [2]
Genome-wide association studies (GWAS) have identified 17 independent loci and single nucleotide variants (SNVs) that contribute to bladder cancer susceptibility in European population [(8–14); Table S1]
SNVs identified by GWAS are common variants with a minor allele frequency (MAF) over 5%, which only had small individual effect sizes with an odds ratio (OR) ranging from 1.1 to 1.5 mostly

Summary

Introduction

Bladder cancer is the 7th most common cancer globally [1] and ranks 1st in urologic malignancies in China [2]. Genome-wide association studies (GWAS) have identified 17 independent loci and single nucleotide variants (SNVs) that contribute to bladder cancer susceptibility in European population [(8–14); Table S1]. Many loci have been replicated in additional studies, and additional new loci found to be, associated with bladder cancer risk in Chinese population [15,16,17,18,19,20,21]. SNVs identified by GWAS are common variants with a minor allele frequency (MAF) over 5%, which only had small individual effect sizes with an odds ratio (OR) ranging from 1.1 to 1.5 mostly. Seventeen loci have been found to be associated with bladder cancer risk by genome-wide association studies (GWAS) in European population. Little is known about contribution of low-frequency and rare variants to bladder cancer susceptibility, especially in Eastern population

Methods

Results

Conclusion