title: Maternal Folate Status and the BHMT c.716G>A Polymorphism Affect the Betaine Dimethylglycine Pathway during Pregnancy.
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) (pfor 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).
  
  
  CONCLUSIONS
  During pregnancy, the BHMT pathway is affected by folate status and by the variant BHMT c.716A allele.
authors.affiliation: Area of Preventive Medicine and Public Health, Faculty of Medicine and Health Sciences, Universitat Rovira i Virgili, IISPV, C/Sant Llorenç 21, Reus 43201, Spain. josemaria.colomina@urv.cat.|Ciberobn Fisiopatología de la Obesidad y Nutrición (CB06/03), Instituto Carlos III, Madrid 28029, Spain. josemaria.colomina@urv.cat.
authors.forename: Jose M
authors.initials: JM
authors.lastname: Colomina
authors.affiliation: Ciberobn Fisiopatología de la Obesidad y Nutrición (CB06/03), Instituto Carlos III, Madrid 28029, Spain. pecavalle@grupsagessa.com.|Area of Obstetrics and Gynaecology, Hospital Universitari Sant Joan, Reus and Universitat Rovira i Virgili, Reus 43204, Spain. pecavalle@grupsagessa.com.
authors.forename: Pere
authors.initials: P
authors.lastname: Cavallé-Busquets
authors.affiliation: Area of Preventive Medicine and Public Health, Faculty of Medicine and Health Sciences, Universitat Rovira i Virgili, IISPV, C/Sant Llorenç 21, Reus 43201, Spain. silviafroig@gmail.com.|Ciberobn Fisiopatología de la Obesidad y Nutrición (CB06/03), Instituto Carlos III, Madrid 28029, Spain. silviafroig@gmail.com.
authors.forename: Sílvia
authors.initials: S
authors.lastname: Fernàndez-Roig
authors.affiliation: Area of Preventive Medicine and Public Health, Faculty of Medicine and Health Sciences, Universitat Rovira i Virgili, IISPV, C/Sant Llorenç 21, Reus 43201, Spain. pol.sole@urv.cat.|Ciberobn Fisiopatología de la Obesidad y Nutrición (CB06/03), Instituto Carlos III, Madrid 28029, Spain. pol.sole@urv.cat.
authors.forename: Pol
authors.initials: P
authors.lastname: Solé-Navais
authors.affiliation: Area of Preventive Medicine and Public Health, Faculty of Medicine and Health Sciences, Universitat Rovira i Virgili, IISPV, C/Sant Llorenç 21, Reus 43201, Spain. joan.fernandez-ballart@urv.cat.|Ciberobn Fisiopatología de la Obesidad y Nutrición (CB06/03), Instituto Carlos III, Madrid 28029, Spain. joan.fernandez-ballart@urv.cat.
authors.forename: Joan D
authors.initials: JD
authors.lastname: Fernandez-Ballart
authors.affiliation: Area of Obstetrics and Gynaecology, Hospital Universitari Joan XXIII, Tarragona and Universitat Rovira i Virgili, Tarragona 43005, Spain. mobape71@yahoo.es.
authors.forename: Mónica
authors.initials: M
authors.lastname: Ballesteros
authors.affiliation: Section for Pharmacology, Department of Internal Medicine, University of Bergen, Bergen N-5020, Norway. per.ueland@ikb.uib.no.
authors.forename: Per M
authors.initials: PM
authors.lastname: Ueland
authors.affiliation: Bevital A/S, Laboratory building, 9th floor, Bergen N-5021, Norway. klaus.meyer@bevital.no.
authors.forename: Klaus
authors.initials: K
authors.lastname: Meyer
authors.affiliation: Area of Preventive Medicine and Public Health, Faculty of Medicine and Health Sciences, Universitat Rovira i Virgili, IISPV, C/Sant Llorenç 21, Reus 43201, Spain. michelle.murphy@urv.cat.|Ciberobn Fisiopatología de la Obesidad y Nutrición (CB06/03), Instituto Carlos III, Madrid 28029, Spain. michelle.murphy@urv.cat.
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Murphy
mesh_terms: D001622:Betaine / Q000378:metabolism*; D050940:Betaine-Homocysteine S-Methyltransferase / Q000235:genetics*; D005260:Female; D005492:Folic Acid / Q000097:blood*; D005494:Folic Acid Deficiency / Q000378:metabolism*; D005786:Gene Expression Regulation; D005838:Genotype; D006801:Humans; D039382:Maternal Nutritional Physiological Phenomena; D011110:Polymorphism, Genetic; D011247:Pregnancy; D012521:Sarcosine / Q000031:analogs & derivatives* / Q000378:metabolism
chemical_list: D001622:Betaine; C025138:dimethylglycine; D005492:Folic Acid; C494548:BHMT protein, human; D050940:Betaine-Homocysteine S-Methyltransferase; D012521:Sarcosine
keywords: A; BHMT c.716G&gt; betaine; betaine: homocysteine methyltransferase; dimethylglycine; folate; pregnancy