Maternal Folate Status and the BHMT c.716G>A Polymorphism Affect the Betaine Dimethylglycine Pathway during Pregnancy

Jose M Colomina, Pere Cavallé-Busquets, Sílvia Fernàndez-Roig, Pol Solé-Navais, Joan D Fernandez-Ballart, Mónica Ballesteros, Per M Ueland, Klaus Meyer, Michelle M Murphy, Jose M Colomina, Pere Cavallé-Busquets, Sílvia Fernàndez-Roig, Pol Solé-Navais, Joan D Fernandez-Ballart, Mónica Ballesteros, Per M Ueland, Klaus Meyer, Michelle M Murphy

Abstract

The effect of the betaine: homocysteine methyltransferase BHMT c.716G>A (G: guanosine; A: adenosine) single nucleotide polymorphism (SNP) on the BHMT pathway is unknown during pregnancy. We hypothesised that it impairs betaine to dimethylglycine conversion and that folate status modifies its effect. We studied 612 women from the Reus Tarragona Birth Cohort from ≤12 gestational weeks (GW) throughout pregnancy. The frequency of the variant BHMT c.716A allele was 30.8% (95% confidence interval (CI): 28.3, 33.5). In participants with normal-high plasma folate status (>13.4 nmol/L), least square geometric mean [95% CI] plasma dimethylglycine (pDMG, µmol/L) was lower in the GA (2.35 [2.23, 2.47]) versus GG (2.58 [2.46, 2.70]) genotype at ≤12 GW (p < 0.05) and in the GA (2.08 [1.97, 2.19]) and AA (1.94 [1.75, 2.16]) versus GG (2.29 [2.18, 2.40]) genotypes at 15 GW (p < 0.05). No differences in pDMG between genotypes were observed in participants with possible folate deficiency (≤13.4 nmol/L) (p for interactions at ≤12 GW: 0.023 and 15 GW: 0.038). PDMG was lower in participants with the AA versus GG genotype at 34 GW (2.01 [1.79, 2.25] versus 2.44 [2.16, 2.76] and at labour, 2.51 [2.39, 2.64] versus 3.00 [2.84, 3.18], (p < 0.01)). Possible deficiency compared to normal-high folate status was associated with higher pDMG in multiple linear regression analysis (β coefficients [SEM] ranging from 0.07 [0.04], p < 0.05 to 0.20 [0.04], p < 0.001 in models from early and mid-late pregnancy) and the AA compared to GG genotype was associated with lower pDMG (β coefficients [SEM] ranging from -0.11 [0.06], p = 0.055 to -0.23 [0.06], p < 0.001).

Conclusion: During pregnancy, the BHMT pathway is affected by folate status and by the variant BHMT c.716A allele.

Keywords: A; BHMT c.716G> betaine; betaine: homocysteine methyltransferase; dimethylglycine; folate; pregnancy.

Conflict of interest statement

The authors declare no conflicts of interests.

Figures

Figure 1
Figure 1
Flow chart of participation in the study.
Figure 2
Figure 2
Plasma dimethylglycine according to BHMT c.716G>A genotype and folate status in early pregnancy. G: guanosine; A: adenosine; GW: Gestational weeks. Low: possibly deficient (plasma folate ≤ 13.4 nmol/L). Normal: normal-high (plasma folate > 13.4 nmol/L). At ≤12 GW, Low: GG (n = 57), GA (n = 48), AA (n = 14); Normal: GG (n = 231), GA (n = 193), AA (n = 47). At 15 GW, Low: GG (n = 37), GA (n = 40), AA (n = 6); Normal: GG (n = 169), GA (n = 141), AA (n = 34). The triple screening blood sample at 15 GW is optional and blood samples were available from less participants. Values are least square geometric means. Error bars represent 95% confidence interval. Comparisons between genotypes were made using ANCOVA adjusting for plasma betaine and gestational age at time of blood draw with posthoc Bonferroni correction for multiple comparisons of p values: * p < 0.05.

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