Evidence of interaction between genes in the folate/homocysteine metabolic pathway in controlling risk of nonsyndromic oral cleft.

ObjectiveLittle consistent evidence is available for the association between the risk of non-syndromic cleft lip with or without cleft palate (NSCL/P) and any of the individual genes in the folate/homocysteine metabolic pathway. We investigated the genes in the folate pathway to further clarify its potential influence on the risk of NSCL/P considering gene-gene (GxG) interaction. Subjects and methodsWe selected markers in 18 genes from the pathway and applied Cordell's method to test for GxG interaction using 1,908 NSCL/P case-parent trios ascertained in an international consortium where a genomewide association study (GWAS) of oral clefts was conducted. ResultsWe found intriguing signals among Asian and European ancestry groups for GxG interaction between markers in betaine-homocysteine methyltransferase gene (BHMT/BHMT2) and dimethylglycine dehydrogenase gene (DMGDH) attaining genomewide significance. In the pooled data, the top significant interaction was found between rs13158309 (BHMT) and rs10514154 (DMGDH, p=1.45x10(-12)). ConclusionsOur study illustrated the importance of taking into account potential GxG interaction for genetic association analysis in NSCL/P, and this study suggested both BHMT/BHMT2 and DMGDH should be considered as candidate genes for NSCL/P in future studies.