Candidate gene association study implicates p63 in the etiology of nonsyndromic bladder-exstrophy-epispadias complex

Birth Defects Res A Clin Mol Teratol. 2013 Dec;97(12):759-63. doi: 10.1002/bdra.23161. Epub 2013 Aug 2.


Background: Bladder-exstrophy-epispadias complex (BEEC) is a severe congenital anomaly that represents a spectrum of urological abnormalities where parts or all of the distal urinary tract fail to close during development. Multiple lines of evidence strongly suggested p63 as a plausible candidate gene. We conducted a candidate gene association study to further investigate the role of p63 in human BEEC.

Methods: We conducted a family-based association study of p63 using 154 Caucasian patients with nonsyndromic BEEC and their unaffected parents. High throughput single nucleotide polymorphism (SNP) genotyping was carried out using Illumina's Golden Gate Assay for 109 selected tagging SNPs localized within p63 with a minor allele frequency > 0.01. Individual and haplotype SNP transmission disequilibrium tests were conducted using Plink and Haploview, respectively. We also examined parent-of-origin effects using paternal asymmetry tests implemented in FAMHAP (

Results: Nominally significant associations were identified between BEEC and six SNPs (rs17447782, rs1913720, rs6790167, rs9865857, rs1543969, rs4687100), and four haplotype blocks including or near these significant SNPs. Analysis of parent-of-origin effects showed significant results for seven SNPs (rs4118375, rs12696596, rs6779677, rs13091309, rs7642420, rs1913721, and rs1399774). None of these results remained significant after multiple testing correction.

Conclusion: The altered transmission of p63 variants in nonsyndromic BEEC patients may be suggestive of its involvement in the disease etiology. Further and large multi-institutional collaborative studies are required to elucidate the role of p63 in nonsyndromic BEEC.

Keywords: BEEC; association study; bladder exstrophy; candidate gene; case-parent trio; epispadias; p63.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Asymptomatic Diseases
  • Bladder Exstrophy / complications
  • Bladder Exstrophy / genetics*
  • Bladder Exstrophy / pathology
  • Epispadias / complications
  • Epispadias / genetics*
  • Epispadias / pathology
  • Female
  • Gene Frequency
  • Genetic Association Studies
  • Haplotypes
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Inheritance Patterns
  • Linkage Disequilibrium
  • Male
  • Membrane Proteins / genetics*
  • Polymorphism, Single Nucleotide*
  • Urinary Bladder / metabolism*
  • Urinary Bladder / pathology


  • CKAP4 protein, human
  • Membrane Proteins