Luo Manjun, Wang Tingting, Huang Peng, Zhang Senmao, Song Xinli, Sun Mengting, Liu Yiping, Wei Jianhui, Shu Jing, Zhong Taowei, Chen Qian, Zhu Ping, Qin Jiabi
Department of Epidemiology and Health Statistics, Xiangya School of Public Health, Central South University, Changsha, China.
NHC Key Laboratory of Birth Defect for Research and Prevention, Hunan Provincial Maternal and Child Health Care Hospital, Changsha, China.
Reprod Sci. 2023 Jan;30(1):309-325. doi: 10.1007/s43032-022-01029-3. Epub 2022 Jul 14.
To systematically explore the association of single nucleotide polymorphisms (SNPs) of maternal BHMT and BHMT2 genes with the risk of congenital heart disease (CHD) and its three subtypes including atrial septal defect (ASD), ventricular septal defect (VSD), and patent ductus arteriosus (PDA) in offspring. A hospital-based case-control study involving 683 mothers of CHD children and 740 controls was performed. Necessary exposure information was captured through epidemiological investigation. Totally twelve SNPs of maternal BHMT and BHMT2 genes were detected and analyzed systematically. The study showed that maternal BHMT gene polymorphisms at rs1316753 (CG vs. CC: OR = 1.96 [95% CI 1.41-2.71]; GG vs. CC: OR = 1.99 [95% CI 1.32-3.00]; dominant model: OR = 1.97 [95% CI 1.44-2.68]) and rs1915706 (TC vs. TT: OR = 1.93 [95% CI 1.44-2.59]; CC vs. TT: OR = 2.55 [95% CI 1.38-4.72]; additive model: OR = 1.77 [95% CI 1.40-2.24]) were significantly associated with increased risk of total CHD in offspring. And two haplotypes were observed to be significantly associated with risk of total CHD, including C-C haplotype involving rs1915706 and rs3829809 in BHMT gene (OR = 1.30 [95% CI 1.07-1.58]) and C-A-A-C haplotype involving rs642431, rs592052, rs626105, and rs682985 in BHMT2 gene (OR = 0.71 [95% CI 0.58-0.88]). Besides, a three-locus model involving rs1316753 (BHMT), rs1915706 (BHMT), and rs642431 (BHMT2) was identified through gene-gene interaction analyses (P < 0.01). As for three subtypes including ASD, VSD, and PDA, significant SNPs and haplotypes were also identified. The results indicated that maternal BHMT gene polymorphisms at rs1316753 and rs1915706 are significantly associated with increased risk of total CHD and its three subtypes in offspring. Besides, significant interactions between different SNPs do exist on risk of CHD. Nevertheless, studies with larger sample size in different ethnic populations and involving more SNPs in more genes are expected to further define the genetic contribution underlying CHD and its subtypes.
为系统探讨母亲甜菜碱同型半胱氨酸甲基转移酶（BHMT）和甜菜碱同型半胱氨酸甲基转移酶2（BHMT2）基因的单核苷酸多态性（SNP）与后代先天性心脏病（CHD）及其三种亚型（包括房间隔缺损（ASD）、室间隔缺损（VSD）和动脉导管未闭（PDA））风险之间的关联。开展了一项基于医院的病例对照研究，纳入了683名CHD患儿的母亲和740名对照。通过流行病学调查获取必要的暴露信息。对母亲BHMT和BHMT2基因的总共12个SNP进行了检测和系统分析。研究表明，母亲BHMT基因在rs1316753位点的多态性（CG与CC相比：比值比（OR）=1.96 [95%置信区间（CI）1.41 - 2.71]；GG与CC相比：OR = 1.99 [95% CI 1.32 - 3.00]；显性模型：OR = 1.97 [95% CI 1.44 - 2.68]）以及rs1915706位点的多态性（TC与TT相比：OR =
1.93 [95% CI 1.44 - 2.59]；CC与TT相比：OR = 2.55 [95% CI 1.38 - 4.72]；加性模型：OR = 1.77 [95% CI 1.40 - 2.24]）与后代患CHD的总体风险增加显著相关。并且观察到两种单倍型与CHD的总体风险显著相关，包括BHMT基因中涉及rs1915706和rs3829809的C - C单倍型（OR = 1.30 [95% CI 1.07 - 1.58]）以及BHMT2基因中涉及rs642431、rs592052、rs626105和rs682985的C - A - A - C单倍型（OR = 0.71 [95% CI 0.58 - 0.88]）。此外，通过基因 - 基因相互作用分析确定了一个包含rs1316753（BHMT）、rs1915706（BHMT）和rs642431（BHMT2）的三位点模型（P < 0.01）。对于ASD、VSD和PDA这三种亚型，也鉴定出了显著的SNP和单倍型。结果表明，母亲BHMT基因在rs1316753和rs1915706位点的多态性与后代患CHD的总体风险及其三种亚型的风险增加显著相关。此外，不同SNP之间在CHD风险上确实存在显著的相互作用。然而，期望在不同种族人群中进行更大样本量且涉及更多基因中更多SNP的研究，以进一步明确CHD及其亚型的遗传贡献。
