Association of maternal MTHFD1 and MTHFD2 gene polymorphisms with congenital heart disease in offspring

CHEN Qian; HUANG Peng; SONG Xin-Li; LIU Yi-Ping; SUN Meng-Ting; WANG Ting-Ting; ZHANG Sen-Mao; QIN Jia-Bi

doi:10.7499/j.issn.1008-8830.2203002

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Chinese Journal of Contemporary Pediatrics ›› 2022, Vol. 24 ›› Issue (7) : 797-805. DOI: 10.7499/j.issn.1008-8830.2203002

CLINICAL RESEARCH

Association of maternal MTHFD1 and MTHFD2 gene polymorphisms with congenital heart disease in offspring

CHEN Qian, HUANG Peng, SONG Xin-Li, LIU Yi-Ping, SUN Meng-Ting, WANG Ting-Ting, ZHANG Sen-Mao, QIN Jia-Bi

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Abstract

Objective To study the association of maternal methylenetetrahydrofolate dehydrogenase 1 (MTHFD1) and methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) gene polymorphisms with congenital heart disease (CHD) in offspring. Methods A hospital-based case-control study was conducted. The mothers of 683 children with CHD alone who attended Hunan Children's Hospital, from November 2017 to March 2020 were enrolled as the case group, and the mothers of 740 healthy children who attended the same hospital during the same period and did not have any deformity were enrolled as the control group. A questionnaire survey was performed to collect related exposure data, and then venous blood samples (5 mL) were collected from the mothers to detect MTHFD1 and MTHFD2 gene polymorphisms. A multivariate logistic regression analysis was used to evaluate the association of MTHFD1 and MTHFD2 gene polymorphisms with CHD. The four-gamete test in Haploview 4.2 software was used to construct haplotypes and evaluate the association between haplotypes and CHD. The generalized multifactor dimensionality reduction method and logistic regression analysis were used to examine gene-gene interaction and its association with CHD. Results The multivariate logistic regression analysis showed that maternal MTHFD1 gene polymorphisms at rs11849530 (GA vs AA: OR=1.49; GG vs AA: OR=2.04) and at rs1256142 (GA vs GG: OR=2.34; AA vs GG: OR=3.25) significantly increased the risk of CHD in offspring (P<0.05), while maternal MTHFD1 gene polymorphisms at rs1950902 (AA vs GG: OR=0.57) and MTHFD2 gene polymorphisms at rs1095966 (CA vs CC: OR=0.68) significantly reduced the risk of CHD in offspring (P<0.05). The haplotypes of G-G-G (OR=1.86) and G-A-G (OR=1.35) in mothers significantly increased the risk of CHD in offspring (P<0.05). The gene-gene interaction analyses showed that the first-order interaction between MTHFD1 rs1950902 and MTHFD1 rs2236222 and the second-order interaction involving MTHFD1 rs1950902, MTHFD1 rs1256142, and MTHFD2 rs1095966 might be associated with risk of CHD (P<0.05). Conclusions Maternal MTHFD1 and MTHFD2 gene polymorphisms and their haplotypes, as well as the interaction between MTHFD1 rs1950902 and MTHFD1 rs2236222 and between MTHFD1 rs1950902, MTHFD1 rs1256142, and MTHFD2 rs1095966, are associated with the risk of CHD in offspring.

Key words

Congenital heart disease / Methylenetetrahydrofolate dehydrogenase / Case-control study / Haplotype / Gene-gene interaction / Offspring

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CHEN Qian, HUANG Peng, SONG Xin-Li, LIU Yi-Ping, SUN Meng-Ting, WANG Ting-Ting, ZHANG Sen-Mao, QIN Jia-Bi. Association of maternal MTHFD1 and MTHFD2 gene polymorphisms with congenital heart disease in offspring[J]. Chinese Journal of Contemporary Pediatrics. 2022, 24(7): 797-805 https://doi.org/10.7499/j.issn.1008-8830.2203002

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