title: Polymorphisms located in the region containing BHMT and BHMT2 genes as maternal protective factors for orofacial clefts.
abstract: Nonsyndromic cleft lip with or without cleft palate (NCL/P) is one of the most common craniofacial malformations; however, its aetiology is still unclear. Because the effects of maternal nutrition on fetal development are well known, we decided to pursue the question of whether polymorphic variants of genes encoding enzymes involved in choline metabolism might be associated with the maternal risk of having a baby with NCL/P. Analysis of 18 single nucleotide polymorphisms (SNPs) of betaine-homocysteine methyltransferase (BHMT), betaine-homocysteine methyltransferase-2 (BHMT2), choline dehydrogenase (CHDH), choline kinase (CHKA), dimethylglycine dehydrogenase (DMGDH), choline-phosphate cytidylyltransferase A (PCYT1A), and phosphatidylethanolamine N-methyltransferase (PEMT) provided evidence that polymorphisms located in the region containing BHMT and BHMT2 were protective factors against NCL/P affected pregnancies in our population. The strongest signal was found for the SNP located in the intronic sequence of BHMT2. Women carrying two copies of the rs625879 T allele had a significantly decreased risk of having offspring with orofacial clefts. These results were significant, even after correction for multiple comparisons. Moreover, the gene-gene interaction analysis revealed a significant epistatic interaction of BHMT2 (rs673752), PEMT (rs12325817), and PCYT1A (rs712012) with maternal NCL/P susceptibility. Altogether, our study identified a novel gene, the nucleotide variants of which were be associated with a decreased risk of having a baby with NCL/P.
authors.affiliation: Department of Biochemistry and Molecular Biology, Poznan University of Medical Sciences, Poznan, Poland. amostowska@wp.pl
authors.forename: Adrianna
authors.initials: A
authors.lastname: Mostowska
authors.forename: Kamil K
authors.initials: KK
authors.lastname: Hozyasz
authors.forename: Barbara
authors.initials: B
authors.lastname: Biedziak
authors.forename: Jan
authors.initials: J
authors.lastname: Misiak
authors.forename: Pawel P
authors.initials: PP
authors.lastname: Jagodzinski
mesh_terms: D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase / Q000235:genetics; D000483:Alleles; D050940:Betaine-Homocysteine S-Methyltransferase / Q000235:genetics*; D050545:Choline Dehydrogenase / Q000235:genetics; D002797:Choline Kinase / Q000235:genetics; D019916:Choline-Phosphate Cytidylyltransferase / Q000235:genetics; D002895:Chromosomes, Human, Pair 5 / Q000235:genetics; D002971:Cleft Lip / Q000235:genetics*; D002972:Cleft Palate / Q000235:genetics*; D050893:Dimethylglycine Dehydrogenase / Q000235:genetics; D004843:Epistasis, Genetic / Q000235:genetics; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006720:Homozygote; D006801:Humans; D007438:Introns / Q000235:genetics; D015810:Linkage Disequilibrium / Q000235:genetics; D024101:Mitochondrial Proteins / Q000235:genetics; D050918:Phosphatidylethanolamine N-Methyltransferase / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D018570:Risk Assessment; D013941:Thymine
chemical_list: C494551:BHMT2 protein, human; D024101:Mitochondrial Proteins; D050545:Choline Dehydrogenase; C494398:DMGDH protein, human; D050893:Dimethylglycine Dehydrogenase; D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase; C494489:PEMT protein, human; D050918:Phosphatidylethanolamine N-Methyltransferase; C494548:BHMT protein, human; D050940:Betaine-Homocysteine S-Methyltransferase; D002797:Choline Kinase; D019916:Choline-Phosphate Cytidylyltransferase; D013941:Thymine