National Center for Birth Defect Monitoring, West China Second University Hospital, Sichuan University, Sec.3 No.17, South RenMin Road, Chengdu, Sichuan, China.
Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, Sichuan, China.
BMC Pregnancy Childbirth. 2024 Feb 26;24(1):167. doi: 10.1186/s12884-024-06343-z.
The majority of congenital heart diseases (CHDs) are thought to result from the interactions of genetics and the environment factors. This study aimed to assess the association of maternal non-occupational phthalates exposure, metabolic gene polymorphisms and their interactions with risk of CHDs in offspring.
A multicenter case-control study of 245 mothers with CHDs infants and 268 control mothers of health infant was conducted from six hospitals. Maternal urinary concentrations of eight phthalate metabolites were measured by ultra-high performance liquid chromatography coupled with tandem mass spectrometry (UHPLC-MS/MS). Twenty single nucleotide polymorphisms (SNPs) in cytochrome P450 family 2 subfamily C member 9 (CYP2C9) and 19 (CYP2C19), uridine diphosphate (UDP) glucuronosyl transferase family 1 member A7 (UGT1A7), family 2 member B7 (UGT2B7) and B15(UGT2B15) genes were genotyped. The multivariate logistic regressions were used to estimate the association between maternal phthalates exposure or gene polymorphisms and risk of CHDs. Generalized multifactor dimensionality reduction (GMDR) was used to analyze the gene-gene and gene-phthalates exposure interactions.
There was no significant difference in phthalate metabolites concentrations between the cases and controls. No significant positive associations were observed between maternal exposure to phthalates and CHDs. The SNPs of UGT1A7 gene at rs4124874 (under three models, log-additive: aOR = 1.74, 95% CI:1.28-2.37; dominant: aOR = 1.86, 95% CI:1.25-2.78; recessive: aOR = 2.50, 95% CI: 1.26-4.94) and rs887829 (under the recessive model: aOR = 13.66, 95% CI: 1.54-121) were significantly associated with an increased risk of CHDs. Furthermore, the associations between rs4124874 (under log-additive and dominant models) of UGT1A7 were statistically significant after the false discovery rate correction. No significant gene-gene or gene-phthalate metabolites interactions were observed.
The polymorphisms of maternal UGT1A7 gene at rs4124874 and rs887829 were significantly associated with an increased risk of CHDs. More large-scale studies or prospective study designs are needed to confirm or refute our findings in the future.
大多数先天性心脏病（CHD）被认为是遗传和环境因素相互作用的结果。本研究旨在评估母体非职业邻苯二甲酸酯暴露、代谢基因多态性及其与后代 CHD 风险的相互作用。
本研究为多中心病例对照研究，纳入了来自六家医院的 245 名患有 CHD 的婴儿的母亲和 268 名健康婴儿的母亲。采用超高效液相色谱-串联质谱法（UHPLC-MS/MS）检测 8 种邻苯二甲酸酯代谢物在母体尿中的浓度。对细胞色素 P450 家族 2 亚家族 C 成员 9（CYP2C9）和 19（CYP2C19）、尿苷二磷酸葡萄糖醛酸转移酶家族 1 成员 A7（UGT1A7）、家族 2 成员 B7（UGT2B7）和 B15（UGT2B15）基因的 20 个单核苷酸多态性（SNP）进行基因分型。采用多变量 logistic 回归模型评估母体邻苯二甲酸酯暴露或基因多态性与 CHD 风险之间的关系。采用广义多因素降维分析（GMDR）分析基因-基因和基因-邻苯二甲酸酯暴露的相互作用。
病例组和对照组的邻苯二甲酸酯代谢物浓度无显著差异。母体邻苯二甲酸酯暴露与 CHD 之间无显著正相关。UGT1A7 基因 rs4124874 位点（三种模型下，加性模型：aOR=1.74，95%CI：1.28-2.37；显性模型：aOR=1.86，95%CI：1.25-2.78；隐性模型：aOR=2.50，95%CI：1.26-4.94）和 rs887829 位点（隐性模型：aOR=13.66，95%CI：1.54-121）与 CHD 风险增加显著相关。进一步校正假发现率后，UGT1A7 基因 rs4124874 位点（加性和显性模型）与 CHD 的相关性具有统计学意义。未观察到基因-基因或基因-邻苯二甲酸酯代谢物的相互作用。
母体 UGT1A7 基因 rs4124874 和 rs887829 多态性与 CHD 风险增加显著相关。未来需要更大规模的研究或前瞻性研究设计来证实或反驳我们的发现。
