National Office for Maternal and Child Health Surveillance of China, West China Second University Hospital, Sichuan University, Chengdu, China.
Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China.
J Matern Fetal Neonatal Med. 2023 Dec;36(1):2183743. doi: 10.1080/14767058.2023.2183743.
Prenatal exposure to polycyclic aromatic hydrocarbons (PAHs) is a risk factor for the occurrence of congenital heart diseases (CHDs). Genetic susceptibility to PAHs metabolism may modify the exposure-risk relationship. The role of uridine diphosphoglucuronosyl transferase 1A1 () genetic polymorphisms for modulating the impacts of prenatal PAHs exposure on the risk of CHDs remains to be discovered.
The aim of this study was to investigate whether maternal genetic polymorphisms are associated with fetal susceptibility to CHDs and to assess whether the risk is modified by maternal PAHs exposure.
Maternal urinary biomarker of PAHs exposure was determined in 357 pregnant women with CHDs fetuses and 270 controls (pregnant women carrying fetuses without major congenital malformations). Urinary 1-hydroxypyrene-glucuronide (1-OHPG) concentration, a sensitive biomarker for PAHs exposure, was measured using ultra-high-performance liquid chromatography coupled with tandem mass spectrometry. Maternal single nucleotide polymorphisms (SNPs) in , including rs3755319, rs887829, rs4148323, rs6742078, and rs6717546, were genotyped using an improved multiplex ligation detection reaction (iMLDR) technique. Unconditional logistic regression was performed to determine the impacts of polymorphisms on the risks of CHDs and their subtypes. Generalized multifactor dimensionality reduction (GMDR) was used to analyze the gene-gene and gene-PAHs exposure interactions.
None of the selected polymorphisms was independently associated with the risk of CHDs. The interaction between SNP rs4148323 and PAHs exposure was observed to be associated with CHDs (< .05). Pregnant women with high-level PAHs exposure and rs4148323 had an increased risk of carrying CHDs fetuses (GA-AA vs. GG: aOR = 2.00, 95% CI = 1.06-3.79). Moreover, the joint effect of rs4148323 and PAHs exposure was found to be significantly associated with risks of septal defects, conotruncal heart defects, and right-sided obstructive malformations.
Maternal genetic variations of rs4148323 may modify the association between prenatal PAHs exposure and CHDs risk. This finding needs to be further confirmed in a larger-scale study.
多环芳烃（PAHs）的产前暴露是先天性心脏病（CHD）发生的一个危险因素。PAHs 代谢的遗传易感性可能会改变暴露-风险关系。尿苷二磷酸葡萄糖醛酸转移酶 1A1（UGT1A1）基因多态性在调节产前 PAHs 暴露对 CHD 风险的影响方面的作用仍有待发现。
本研究旨在探讨母体 UGT1A1 基因多态性是否与胎儿易患 CHD 相关，并评估母体 PAHs 暴露是否会改变这种风险。
在 357 名患有 CHD 胎儿的孕妇和 270 名对照孕妇（怀有无重大先天性畸形胎儿的孕妇）中，测定了其母体尿中 PAHs 暴露的生物标志物。采用超高效液相色谱-串联质谱法测定母体尿中 1-羟基芘-葡萄糖醛酸（1-OHPG）浓度，该浓度是 PAHs 暴露的敏感生物标志物。采用改良多重连接酶检测反应（iMLDR）技术，对 UGT1A1 中的母体单核苷酸多态性（SNP），包括 rs3755319、rs887829、rs4148323、rs6742078 和 rs6717546，进行基因分型。采用非条件逻辑回归法确定多态性对 CHD 及其亚型风险的影响。采用广义多因素维度缩减法（GMDR）分析基因-基因和基因-PAHs 暴露的相互作用。
在所选择的 SNP 中，没有一个与 CHD 的风险独立相关。观察到 SNP rs4148323 与 PAHs 暴露之间的相互作用与 CHD 相关（<0.05）。高水平 PAHs 暴露和 rs4148323 的孕妇发生 CHD 胎儿的风险增加（GA-AA 与 GG：aOR=2.00，95%CI=1.06-3.79）。此外，还发现 rs4148323 与 PAHs 暴露的联合效应与间隔缺损、圆锥动脉干畸形和右侧梗阻性畸形的风险显著相关。
母体 UGT1A1 rs4148323 的遗传变异可能会改变产前 PAHs 暴露与 CHD 风险之间的关联。这一发现需要在更大规模的研究中进一步证实。
