Abstract
Objectives: Nonsyndromic cleft lip and palate (NSCLP) is genetically distinct from those with syndromic clefts, and accounts for ~70% of cases with Oral clefts. Folate, or vitamin B9, is an essential nutrient in our diet. Allelic variants in genes involved in the folate pathway might be expected to have an impact on risk of oral clefts. Given the key role of methylenetetrahydrofolate dehydrogenase 1 (MTHFD1) in folate metabolism, it would be of significant interest to assess its role in NSCLP etiology. Study Design: The present study aims at examining the association between MTHFD1 1958G>A polymorphism and NSCLP risk by conducting a case-control study in south Indian population. Our sample comprised of 142 cases with nonsyndromic clefts and 141 controls without clefts or family history of clefting. The MTHFD1 1958G>A polymorphism was genotyped using PCR-RFLP. Results: An increased risk was found for the heterozygous 1958GA (OR=2.44; P=0.020) and homozygous 1958AA (OR=2.45; P=0.012) genotypes in the children. When the dominant model (AG+AA vs GG) was applied the risk remained the same as co-dominant model, but the level of significance increased (OR=2.44; P=0.002). Conclusions: The results indicated the MTHFD1 1958G>A polymorphism to be one of the important genetic determinants of NSCLP risk in South Indian subjects. Key words:MTHFD1, orofacial cleft, SNP, genetics.
Highlights
Nonsyndromic cleft lip and palate (NSCLP) is genetically distinct from those with syndromic clefts, and accounts for ~70% of cases with Oral clefts
methylenetetrahydrofolate dehydrogenase 1 (MTHFD1) 1958G>A has not contributed to NSCLP risk in the Polish population separately or by showing epistatic interaction with other variants in genes of choline and folate metabolism [11]
In a sample of Irish population MTHFD1 1958G>A variant did not show any association between the A allele and CPO case status, but CPO case mothers were significantly more likely to be AA compared to controls
Summary
Nonsyndromic cleft lip and palate (NSCLP) is genetically distinct from those with syndromic clefts, and accounts for ~70% of cases with Oral clefts. MTHFD1 gene encodes trifunctional enzyme 5,10-methylenetetrahydrofolate dehydrogenase; 5,10-methenyltetrahydrofolate cyclohydrolase and 10-formylotetrahydrofolate synthetase [4]. This enzyme catalyzes the conversion of 1-carbon derivatives of tetrahydrofolate (THF) to form the cofactor 10formylTHF, which serves as a one-carbon donor for the de novo biosynthesis of purines [5]. Previous studies have reported the association of MTHFD1 gene variants with serum folic acid and homocysteine levels [8,9]. The common G1958A SNP, which is located in exon 20 of MTHFD1 gene is associated with folate-mediated pathologies such as congenital anomalies (neural tube defects, heart defects, oral clefts) and several cancers [10]. As the MTHFD1 is a potential candidate gene for investigation in relation to cleft palate risk, and since the previous studies have provided contradictory results [11,12,13,14], the present case-control study was undertaken to examine the association between MTHFD1 1958G>A and nonsyndromic cleft lip and palate in south Indian population
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