Genetic variation in folate metabolism is associated with the risk of conotruncal heart defects in a Chinese population

Abstract

BackgroundConotruncal heart defects (CTDs) are a subgroup of congenital heart defects that are considered to be the most common type of birth defect worldwide. Genetic disturbances in folate metabolism may increase the risk of CTDs.MethodsWe evaluated five single-nucleotide polymorphisms (SNPs) in genes related to folic acid metabolism: methylenetetrahydrofolate reductase (MTHFR C677T and A1298C), solute carrier family 19, member 1 (SLC19A1 G80A), methionine synthase (MTR A2576G), and methionine synthase reductase (MTRR A66G), as risk factors for CTDs including various types of malformation, in a total of 193 mothers with CTD-affected offspring and 234 healthy controls in a Chinese population.ResultsLogistic regression analyses revealed that subjects carrying the TT genotype of MTHFR C677T, the C allele of MTHFR A1298C, and the AA genotype of SLC19A1 G80A had significant 2.47-fold (TT vs. CC, OR [95% CI] = 2.47 [1.42–4.32], p = 0.009), 2.05–2.20-fold (AC vs. AA, 2.05 [1.28–3.21], p = 0.0023; CC vs AA, 2.20 [1.38–3.58], p = 0.0011), and 1.68-fold (AA vs. GG, 1.68 [1.02–2.70], p = 0.0371) increased risk of CTDs, respectively. Subjects carrying both variant genotypes of MTHFR A1298C and SLC19A1 G80A had a higher (3.23 [1.71–6.02], p = 0.0002) increased risk for CTDs. Moreover, the MTHFR C677T, MTHFR A1298C, and MTRR A66G polymorphisms were found to be significantly associated with the risk of certain subtypes of CTD.ConclusionsOur data suggest that maternal folate-related SNPs might be associated with the risk of CTDs in offspring.

The Roles of Reduced Folate Carrier-1 (RFC1) A80G (rs1051266) Polymorphism in Congenital Heart Disease: A Meta-Analysis

“…Among them, the data of Pei et al [ 25 ] were duplicated, and Christensen et al [ 26 ] could not submit the data. As a result, a total of 6 studies [ 18 , 19 , 22 , 28 , 29 ] that met the inclusion criteria was finally included in our meta-analysis ( Figure 1 ). After pooling the data, our meta-analysis contained 724 fetal cases, 760 fetal controls, 258 maternal cases, and 334 maternal controls.…”

“…Second, part of the control population included in the study came from hospitals, so the recruited subjects may not be representative of the general population. Third, in the maternal group, studies by Wang et al [ 18 ] lack information on the folic acid status of pregnant women, and it is impossible to determine whether the genetic polymorphism will affect the risk of CHD if the mother consumes enough folic acid early in the pregnancy. Fourth, our research only studied 1 gene polymorphism of RFC1, namely A80G (rs1051266).…”

“…A80G (rs1051266) is the most common single nucleotide polymorphism (SNP) in RFC1. It affects plasma folate and Hcy levels alone or together with the C677T polymorphism in the methylenetetrahydrofolate reductase gene [ 18 ]. Shaw et al [ 19 ] described the highly frequent A80G SNP, which results in the change of amino acid from histidine (encoded by CAG) to arginine (encoded by CGG) in the second exon, altering its metabolic pathways, and affecting the absorption rate of folic acid into the cell.…”

Maternal Risk Factors Triggering Congenital Heart Defects in Down Syndrome: A Case-Control Study

“…The association between maternal history of miscarriage and risk of having a DS fetus in the future is well documented. In addition, previous studies have shown a positive association between maternal history of miscarriages and increased risk of heart diseases in DS fetuses (OR = 1.45; 95% CI = 1.18 to 1.78), whereas some studies have reported inconclusive results due to limited availability of data [ 7 , 19 , 20 , 21 , 22 , 23 ]. In line with these findings, interestingly, our study showed the increased incidence of developing CHD in DS fetuses in women having a history of miscarriages.…”

Associations between the Level of Trace Elements and Minerals and Folate in Maternal Serum and Amniotic Fluid and Congenital Abnormalities

“…Another study suggests that elevated levels of cadmium in maternal circulation increases the risk of preeclampsia and contributes to the restriction of fetal growth in patients with preeclampsia [ 13 ]. The relationship between folate status and both neural tube and cardiac defects has been known for quite some time [ 14 , 15 , 16 ].…”