Candidate gene association study implicates p63 in the etiology of nonsyndromic bladder-exstrophy-epispadias complex.
Candidate gene association study implicates p63 in the etiology of nonsyndromic bladder-exstrophy-epispadias complex.
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DOI：
10.1002/bdra.23161
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发表时间：
2013-12
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通讯作者：
L. Qi;mei Wang;Garima Yagnik;M. Mattheisen;J. Gearhart;Y. Lakshmanan;A. Ebert;W. Rösch;M. Ludwig;Markus Draaken;H. Reutter;S. Boyadjiev
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作者：
L. Qi;mei Wang;Garima Yagnik;M. Mattheisen;J. Gearhart;Y. Lakshmanan;A. Ebert;W. Rösch;M. Ludwig;Markus Draaken;H. Reutter;S. Boyadjiev
背景膀胱外翻外翻复合体(BEEC)是一种严重的先天性异常，表现为发育过程中远端尿路部分或全部未能闭合的一系列泌尿系统异常。多条证据有力地表明p63是一个可能的候选基因。我们进行了候选基因关联研究，以进一步研究p63在人BEEC中的作用。方法我们对154名患有非综合征BEEC的高加索患者及其未患BEEC的父母进行了基于家庭的P63关联研究。应用Illumina的金门试验对109个标记SNP进行高通量单核苷酸多态(SNP)基因分型，这些SNP位于p63内，等位基因频率较低。分别用Plink和Haploview进行个体和单倍型SNP传递不平衡检验。我们还使用FAMHAP(http://famhap.meb.uni-bonn.de/index.html).)中实施的父系不对称测试来检验父母的原籍效应结果BEEC与6个SNPs(rs17447782、rs1913720、rs6790167、rs9865857、rs1543969、rs4687100)和包括或靠近这些SNPs的4个单倍型区块存在显著关联。对7个SNP(rs4118375、rs12696596、rs6779677、rs13091309、rs7642420、rs1913721和rs1399774)进行了亲本效应分析。在多次测试校正后，这些结果都没有显著意义。结论p63基因在非综合征性BEEC患者中的传递改变可能提示其参与了BEEC的发病机制。需要进一步的大型多机构合作研究来阐明p63在非综合征性BEEC中的作用。
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 (http://famhap.meb.uni-bonn.de/index.html). 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.