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

Abstract

Objective

Little consistent evidence is available for the association between the risk of nonsyndromic 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 (G×G) interaction.

Subjects and Methods

We selected markers in 18 genes from the pathway and applied the Cordell's method to test for G×G interaction using 1,908 NSCL/P case-parent trios ascertained in an international consortium where a genome-wide association study (GWAS) of oral clefts was conducted.

Results

We found intriguing signals among Asian and European ancestry groups for G×G interaction between markers in betaine-homocysteine methyltransferase gene (BHMT/BHMT2) and dimethylglycine dehydrogenase gene (DMGDH) attaining genome-wide significance. In the pooled data, the top significant interaction was found between rs13158309 (BHMT) and rs10514154 (DMGDH, P=1.45×10^-12).

Conclusions

Our study illustrated the importance of taking into account potential G×G 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.

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