Association between polymorphisms in TGF(Beta)-3, IRF6, SKI and MTHFD1 and frontoethmoidal encephalomeningocele and oral cleft

Abstract

Oral cleft and frontoethmoidal encephalomeningocele (FEEM) are among the most severe congenital craniofacial malformations. Oral cleft consists of two major groups, cleft lip with or without cleft palate (CL/P) and cleft palate only (CPO). The variability incidence of cleft lip and/or palate is related to geographic origin, 1/500 or higher. In Thailand.CL/P incidence is 1/600. FEEM is an endemic neural tube defect (NTD), usually situated at the root of the nose, affecting children more commonly in Southern and Southeast Asia including Thailand with an incidence of approximately 1/6,000. We performed an association study between these diseases and genes in transforming growth factor β, transforming growth factor β-3 (TGFβ-3), Interferon regulatory factor 6 (IFR6), and SKI, and a gene in folate pathway, trifunctional enzyme methylenetetrahydrofolate dehydrogenes/methylenetetrahydrofolate cyclohydrolase/formyltetrahydrofolate synthese (MTHFD1), The results showed no TGFβ-3 179C→T, TGFβ-3 383A→G and SKI 1163C→T polymorphisms. Whereas IRF6 820G→A polymorphism showed a protective effect for CL/P (OR = 0.57 [0.37 <OR< 0.86]). On the other hand a susceptible risk for CPO was found in individuals with homozygous AA genotype for MTHFD1 1958G→A (OR = 4.42 [1.05 <OR< 16.52]), as seen in heterozygous GA mothers (OR = 2.25 [1.05 <OR< 4.86]). Homozygous GG of SKI 185C→G was found in 2/186 patient with CL/P but not found in 269 controls. No association between FEEM and our candidate genes was observed. In conclusion, we found an evidence that IRF6 820G→A in the patients may be a protective factor for CL/P, while AA at MTHFD1 1958G→A in children and heterozygous GA in mother may be a risk factor for CPO.