Association of Maternal Betaine-Homocysteine Methyltransferase (BHMT) and BHMT2 Genes Polymorphisms with Congenital Heart Disease in Offspring.

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.