Rs1801133C>T polymorphism in MTHFR is a risk factor for nonsyndromic cleft lip with or without cleft palate in the Brazilian population.

Abstract

The MTHFR rs1801131A>C and rs1801133C>T variants have been analyzed as putative genetic risk factors for oral clefts within various populations worldwide. To test the role of these polymorphisms in nonsyndromic cleft lip with or without cleft palate (NSCL/P) in the Brazilian population, we conducted a study combining a Family-Based Association Test (transmission disequilibrium test) and a structured association analysis (case-control study) based on the individual ancestry proportions. The rs1801131 and rs1801133 were initially analyzed in 197 case-parent trios by transmission disequilibrium test, and polymorphisms showing significant association with NSCL/P were subsequently studied in independent sample composed of 318 isolated samples of NSCL/P and 598 healthy controls in a case-control approach. Genomic ancestry was characterized by a set of 40 biallelic short insertion/deletion markers. A strong overtransmission of the T allele of rs1801133 was observed in case-parent trios of NSCL/P (p = 0.002), but no preferential parent-of-origin transmission was detected. No association of rs1801131 polymorphism with NSCL/P was observed. The structured case-control analysis supported that the T allele was significantly more frequent in the NSCL/P group (odds ratio: 1.37; 95% CI: 1.12-1.69; p = 0.002) than in the control group. Both polymorphisms were in linkage disequilibrium (D' = 0.94 and r(2) = 0.79), and haplotype-transmission disequilibrium test for allelic combination of rs1801131 and rs1801133 showed a significant overtransmission of haplotype A-T to the affected NSCL/P offspring (p = 0.001). Our findings provide evidences for the involvement of rs1801133 in the development of NSCL/P in the Brazilian population.