Maternal MTR genotype contributes to the risk of non‐syndromic cleft lip and palate in the Polish population

Abstract

The aetiology of non-syndromic cleft lip with or without cleft palate (CL/P) is very complex. It has been shown that polymorphic variants of genes encoding key proteins of folate and methionine metabolism might be important maternal risk factors of having a child with this craniofacial anomaly. Therefore, in our study, mothers with CL/P children as well as control mothers were examined for prevalence of polymorphisms of genes that encode methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTR), 5,10-methylenetetrahydrofolate dehydrogenase, 5,10-methenyltetrahydrofolate cyclohydrolase and 10-formyltetrahydrofolate synthetase (MTHFD1) and reduced folate carrier 1 (RFC1). We observed that there were no statistical differences in allele and genotype frequencies of MTHFR c.677C>T, MTHFD1 c.1958G>A and RFC1 c.80G>A between mothers who had children with CL/P and control mothers. However, mothers with MTR c.2756AG or GG genotype displayed a 2.195-fold increased risk of having a child with CL/P (95% CI 1.189-4.050, p = 0.011). The mechanism by which polymorphic transition of MTR gene might increase the maternal risk of having CL/P progeny is unknown. Our observations are consistent with a significant role of the methyl cycle in the development of craniofacial structures in humans.

Molecular Genetics of Non-Syndromic Clefts Revisited

“…In this regard, using the case-control design, Tolarova et al [88] first observed that homozygotes for the 677 T allele were three times more frequent in CL/P Argentinean patients than in controls. However, these findings were not confirmed by most of the subsequent studies using California [89], Brazil [90], Polish [91] and Irish [92] population samples. However, in an, homozygosity for the C677T allele was associated with an increased risk for isolated cleft palate (OR =3.2; 95 percent CI: 1.3, 7.9) and possibly for cleft lip with or without cleft palate (OR =1.6; 95 percent CI: 0.8, 3.4) [92].…”

Genome-wide Association Scan for Childhood Caries Implicates Novel Genes

“…Genes affecting tooth enamel, such as ACTN2, may play a role in caries susceptibility. MTR (methionine synthase), the gene responsible for methionine and homocysteine production, has not been previously implicated in dental caries, although maternal MTR may be associated with non-syndromic cleft lip and palate (Mostowska et al, 2006), which in turn is associated with dental caries (Al-Dajani, 2009;Parapanisiou et al, 2009;Britton and Welbury, 2010). Genes involved in the structure and development of orofacial features may provide the basis for the link between clefting and dental caries.…”

Registries of cleft lip/palate cases between 2004 and 2010 in Denizli, Turkey

“…WNT3 rs3809857 variant and some haplotypes are associated with a decrease in the risk of nonsyndromic CL/P in Poland, in which the prevalence of CL/P is as high as 15.6 in 10,000 births (Mostowska et al, 2012). Significant epistatic interaction has been observed between MTHFR (rs1801133), MTR (rs1805087), and PEMT (rs4646406) in nonsyndromic CL/P susceptibility in Poland (Mostowska et al, 2006).…”