National Centre for Medical Genetics, Our Lady's Children's Hospital Crumlin, Dublin, 12, Ireland ; National Children's Research Centre, Our Lady's Children's Hospital Crumlin, Dublin, 12, Ireland.
Institute of Genetic Medicine, Newcastle University Newcastle upon Tyne, United Kingdom.
Mol Genet Genomic Med. 2014 Jan;2(1):7-29. doi: 10.1002/mgg3.22. Epub 2013 Jul 7.
Primary vesicoureteric reflux (VUR), the retrograde flow of urine from the bladder toward the kidneys, results from a developmental anomaly of the vesicoureteric valve mechanism, and is often associated with other urinary tract anomalies. It is the most common urological problem in children, with an estimated prevalence of 1-2%, and is a major cause of hypertension in childhood and of renal failure in childhood or adult life. We present the results of a genetic linkage and association scan using 900,000 markers. Our linkage results show a large number of suggestive linkage peaks, with different results in two groups of families, suggesting that VUR is even more genetically heterogeneous than previously imagined. The only marker achieving P < 0.02 for linkage in both groups of families is 270 kb from EMX2. In three sibships, we found recessive linkage to KHDRBS3, previously reported in a Somali family. In another family we discovered sex-reversal associated with VUR, implicating PRKX, for which there was weak support for dominant linkage in the overall data set. Several other candidate genes are suggested by our linkage or association results, and four of our linkage peaks are within copy-number variants recently found to be associated with renal hypodysplasia. Undoubtedly there are many genes related to VUR. Our study gives support to some loci suggested by earlier studies as well as suggesting new ones, and provides numerous indications for further investigations.
原发性膀胱输尿管反流(VUR)是尿液从膀胱向肾脏的逆行流动,是由于膀胱输尿管瓣膜机制的发育异常引起的,常与其他泌尿道异常有关。它是儿童中最常见的泌尿科问题,估计患病率为 1-2%,是儿童期高血压和儿童期或成年期肾衰竭的主要原因。我们报告了使用 90 万个标记物进行遗传连锁和关联扫描的结果。我们的连锁结果显示出大量提示性的连锁峰,在两组家庭中有不同的结果,表明 VUR 的遗传异质性甚至比以前想象的更为复杂。在两组家庭中,唯一达到连锁 P 值<0.02 的标记物是距离 EMX2 270kb 的位置。在三个同胞家庭中,我们发现与 KHDRBS3 的隐性连锁,先前在一个索马里家庭中报道过。在另一个家庭中,我们发现与 VUR 相关的性别反转,提示 PRKX 可能存在显性连锁,在整个数据集汇总存在微弱的支持。我们的连锁或关联结果提示了其他一些候选基因,并且我们的四个连锁峰都位于最近发现与肾发育不全相关的拷贝数变异内。毫无疑问,有许多与 VUR 相关的基因。我们的研究支持了一些先前研究提出的一些基因座,同时也提出了新的基因座,并为进一步的研究提供了许多线索。