Lozić Bernarda, Krželj Vjekoslav, Kuzmić-Prusac Ivana, Kuzmanić-Šamija Radenka, Čapkun Vesna, Lasan Ružica, Zemunik Tatijana
Department of Pediatrics, University Hospital Centre Split, Split, Croatia.
Department of Pathology, University Hospital Centre Split, Split, Croatia.
Med Sci Monit. 2014 Aug 28;20:1531-8. doi: 10.12659/MSM.890916.
Involvement of development-related gene polymorphisms in multifactorial/polygenic etiology of stillborn/neonatal deaths due to malformations has been insufficiently tested. Since these genes showed evolutional stability and their mutations are very rare, we can assume that their polymorphic variants may be a risk factor associated with the occurrence of developmental disorders of unknown etiology or can enhance the phenotypic variability of known genetic disorders.
To determine the association of 3 polymorphisms involved in the regulation of the early embryonic development of different organs, we conducted an association study of their relation to the particular malformation. We selected 140 samples of archived paraffin tissue samples from deceased patients in which fetal/neonatal autopsy examination had shown congenital abnormalities as the most likely cause of death. The polymorphisms of OSR1 rs12329305, rs9936833 near FOXF1, and HOXA1 rs10951154 were genotyped using the TaqMan allelic discrimination assay.
After Bonferroni correction for multiple testing, significant allelic association with stillborn/neonatal deaths was observed for rs12329305 (p=7×10-4). In addition, association analysis for the same polymorphism was shown in the subgroup with isolated anomalies (1.25×10^-5), particularly in the subgroup of cases with kidney and heart anomalies (p=4.18×10^-5, p=5.12×10^-8, respectively).
The findings of the present study showed, for the first time, the role of the OSR1 rs12329305 polymorphism in the development of congenital malformations in cases of stillborn/neonatal death, particularly in those with congenital kidney and heart developmental defects.
与发育相关的基因多态性在因畸形导致的死产/新生儿死亡的多因素/多基因病因中的作用尚未得到充分验证。由于这些基因具有进化稳定性且其突变非常罕见，我们可以假设它们的多态性变体可能是与不明病因发育障碍的发生相关的危险因素，或者可以增强已知遗传疾病的表型变异性。
为了确定参与不同器官早期胚胎发育调控的3种多态性之间的关联，我们对它们与特定畸形的关系进行了关联研究。我们从已故患者的存档石蜡组织样本中选取了140份样本，这些患者的胎儿/新生儿尸检显示先天性异常是最可能的死亡原因。使用TaqMan等位基因鉴别分析法对OSR1 rs12329305、FOXF1附近的rs9936833以及HOXA1 rs10951154的多态性进行基因分型。
在对多重检验进行Bonferroni校正后，观察到rs12329305与死产/新生儿死亡存在显著的等位基因关联（p = 7×10^-4）。此外，在孤立异常亚组中也显示出相同多态性的关联分析结果（1.25×10^-5），特别是在肾脏和心脏异常病例亚组中（分别为p = 4.18×10^-5，p = 5.12×10^-8）。
本研究结果首次表明，OSR1 rs12329305多态性在死产/新生儿死亡病例的先天性畸形发生中起作用，特别是在那些患有先天性肾脏和心脏发育缺陷的病例中。
