Dagle John M, Lepp Nathan T, Cooper Margaret E, Schaa Kendra L, Kelsey Keegan J P, Orr Kristin L, Caprau Diana, Zimmerman Cara R, Steffen Katherine M, Johnson Karen J, Marazita Mary L, Murray Jeffrey C
Department of Pediatrics, University of Iowa, Iowa City, IA 52242, USA.
Pediatrics. 2009 Apr;123(4):1116-23. doi: 10.1542/peds.2008-0313.
Patent ductus arteriosus is a common morbidity associated with preterm birth. The incidence of patent ductus arteriosus increases with decreasing gestational age to approximately 70% in infants born at 25 weeks' gestation. Our major goal was to determine if genetic risk factors play a role in patent ductus arteriosus seen in preterm infants.
We investigated whether single-nucleotide polymorphisms in genes that regulate smooth muscle contraction, xenobiotic detoxification, inflammation, and other processes are markers for persistent patency of ductus arteriosus. Initially, 377 single-nucleotide polymorphisms from 130 genes of interest were evaluated in DNA samples collected from 204 infants with a gestational age of <32 weeks. A family-based association test was performed on genotyping data to evaluate overtransmission of alleles.
P values of <.01 were detected for genetic variations found in 7 genes. This prompted additional analysis with an additional set of 162 infants, focusing on the 7 markers with initial P values of <.01, and 1 genetic variant in the angiotensin II type I receptor previously shown to be related to patent ductus arteriosus. Of the initial positive signals, single-nucleotide polymorphisms in the transcription factor AP-2 beta and tumor necrosis factor receptor-associated factor 1 genes remained significant. Additional haplotype analysis revealed genetic variations in prostacyclin synthase to be associated with patent ductus arteriosus. An angiotensin II type I receptor polymorphism previously reported to be associated with patent ductus arteriosus after prophylactic indomethacin administration was not associated with the presence of a patent ductus arteriosus in our population.
Overall, our data support a role for genetic variations in transcription factor AP-2 beta, tumor necrosis factor receptor-associated factor 1, and prostacyclin synthase in the persistent patency of the ductus arteriosus seen in preterm infants.
动脉导管未闭是一种与早产相关的常见病症。动脉导管未闭的发病率随着孕周的降低而增加，在孕25周出生的婴儿中发生率约为70%。我们的主要目标是确定遗传风险因素在早产儿动脉导管未闭中是否起作用。
我们研究了调节平滑肌收缩、外源性物质解毒、炎症及其他过程的基因中的单核苷酸多态性是否为动脉导管持续开放的标志物。最初，在从204名孕周<32周的婴儿采集的DNA样本中评估了来自130个感兴趣基因的377个单核苷酸多态性。对基因分型数据进行基于家系的关联测试，以评估等位基因的过度传递。
在7个基因中发现的遗传变异检测到的P值<.01。这促使对另外162名婴儿进行进一步分析，重点关注初始P值<.01的7个标志物，以及先前已证明与动脉导管未闭相关的血管紧张素II 1型受体中的1个基因变异。在最初的阳性信号中，转录因子AP-2β和肿瘤坏死因子受体相关因子1基因中的单核苷酸多态性仍然显著。额外的单倍型分析显示前列环素合酶的遗传变异与动脉导管未闭相关。先前报道在预防性使用吲哚美辛后与动脉导管未闭相关的血管紧张素II 1型受体多态性在我们的人群中与动脉导管未闭的存在无关。
总体而言，我们的数据支持转录因子AP-2β、肿瘤坏死因子受体相关因子1和前列环素合酶的遗传变异在早产儿动脉导管持续开放中起作用。
