Research Paper Volume 13, Issue 10 pp 13898—13908

Increased hypospadias risk by GREM1 rs3743104[G] in the southern Han Chinese population

Fuming Deng1, *, , Jinglu Zhao2, *, , Wei Jia1, *, , Kai Fu1, , Xiaoyu Zuo2, , Lihua Huang2, , Ning Wang2, , Huiming Xia2, , Yan Zhang2, , Wen Fu1, &, , Guochang Liu1, &, ,

  • 1 Department of Pediatric Urology, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou 510623, Guangdong, China
  • 2 Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou 510623, Guangdong, China
* Equal contribution

Received: November 20, 2020       Accepted: March 23, 2021       Published: May 7, 2021
How to Cite

Copyright: © 2021 Deng et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Hypospadias is a common congenital genitourinary malformation characterized by ventral opening of the urethral meatus. As a member of the bone morphogenic protein antagonist family, GREM1 has been identified as associated with susceptibility to hypospadias in the European population. The present study was designed to elaborate on the mutual relationship between replicated single-nucleotide polymorphisms (SNPs) and hypospadias in Asia's largest case-control study in the Southern Han Chinese population involving 577 patients and 654 controls. Our results demonstrate that the GREM1 risk allele rs3743104[G] markedly increases the risk of mild/moderate and severe hypospadias (P<0.01, 0.28≤OR≤0.66). GTEx expression quantitative trait locus data revealed that the eQTL SNP rs3743104 has more associations of eQTL SNP rs3743104 and GREM1 targets in pituitary tissues. Additionally, Bioinformatics and Luciferase Assays show that miR-182 is identified as a suppressor for GREM1 expression, likely through regulation of its binding affinity to rs3743104 locus. In conclusion, the GREM1 risk allele rs3743104[G] increases hypospadias susceptibility in mild/moderate and severe cases among the southern Han population. rs3743104 regulates GREM1 expression by altering the binding affinity of miR-182 to their locus. Collectively, this study provides new evidence that GREM1 rs3743104 is associated with an increased risk of hypospadias. These findings provide a promising biomarker and merit further exploration.


eQTL: expression quantitative trait locus; SNP: single-nucleotide polymorphism; miRNAs: microRNAs; shRNA: short hairpin RNA; GWAS: genome-wide association study; EMT: epithelial-mesenchymal transition; GTEx: Genotype-Tissue Expression Project; HWE: Hardy–Weinberg equilibrium; CI: confidence interval; CRC: colorectal cancer; DBP: dibutyl phthalate.