Association between maternal MTHFR and MTRR gene polymorphisms and the risk of congenital heart disease in newborns

Background: Although numerous studies have explored the maternal genetic contributions to congenital heart disease (CHD), their findings remain inconsistent. This study aimed to investigate the association between maternal polymorphisms in MTHFR (rs1801133 and rs1801131) and MTRR (rs1801394) and the risk of neonatal CHD in the Chinese Han population from southern Fujian. Methods: We conducted a case–control study involving 155 mothers of neonates with CHD and 160 healthy controls. Three SNPs were genotyped using Sanger sequencing. Results: Our study showed that maternal polymorphisms of MTHFR at rs1801133 and MTRR at rs1801394 were significantly associated with risk of neonatal CHD in the homozygote comparisons (TT vs. CC at rs1801133: OR=2.346 [95% CI: 1.014–5.428]; GG vs. AA at 1801394: OR=3.127 [95% CI: 1.232–7.940]), as well as heterozygote comparison (CT vs. CC at rs1801133: OR=1.778 [95% CI: 1.107–2.856]) with mutant allele associated with a higher risk of CHDs (T vs. C at rs1801133: OR=1.665 [95% CI: 1.168-2.371]; G vs. A at 1801394: OR=1.588 [95% CI: 1.114-2.261]). Maternal polymorphisms were significantly associated with CHD subtypes: ASD risk was higher in TG vs. TT of MTHFR at rs1801131: OR=2.083 [95% CI: 1.185-3.662] and AG vs. AA of MTRR at rs1801394: OR=1.815 [95% CI: 1.043-3.156]; VSD risk was higher in GG vs. AA of MTRR at rs1801394 (OR = 3.837 [95% CI: 1.169–12.594])and CT vs. CC of MTHFR at 1801133: OR=2.094 [95% CI: 1.019-4.302]); PDA risk was higher in TT vs. CC of MTHFR at 1801133: OR=4.287 [95% CI: 1.426-12.893]. Mothers with the TT genotype at rs1801133 of the MTHFR gene had significantly higher serum Hcy levels than those with the CC or CT genotypes, and with the GG genotype at rs1801394 of MTRR higher than those with the AA genotype (all P < 0.05). Conclusion: Maternal polymorphisms in MTHFR rs1801133 and MTRR rs1801394 are significantly associated with elevated maternal serum Hcy levels and increased risk of neonatal CHD, including ASD, VSD, and PDA, in the Chinese Han population of southern Fujian. MTHFR rs1801131 polymorphism was significantly associated with neonatal ASD risk. Trial registration: Our study is an observational study. According to the International Committee of Medical Journal Editors (ICMJE), purely observational studies (in which the allocation of medical interventions is not under the investigator's discretion) do not require registration.