Academic journal article Iranian Journal of Public Health

Analysis of MTHFR Gene C.677C>T and C.1298A>C Polymorphisms in Iranian Patients with Non-Syndromic Cleft Lip and Palate

Academic journal article Iranian Journal of Public Health

Analysis of MTHFR Gene C.677C>T and C.1298A>C Polymorphisms in Iranian Patients with Non-Syndromic Cleft Lip and Palate

Article excerpt


Non-syndromic cleftlip with or without cleftpal-ate (nsCL/P) is one of the most common congenital defects, with an occurrence rate of about 1/500 to 1/2500 in different populations worldwide (1,2). The incidence of cleftlip and pal-ate varies by ethnic origin and socioeconomic sta-tus (2). A multifactorial etiology of genetic and environmental factors likely contributes to the risk of oral clefts (3-5). Decreased incidence of orofacial clefts has been found in offspring of mothers who have received prenatal multivitamin supplementations (6-8). Deficiency of dietary folic acid during embryonic development has been suggested as a candidate environmental factor in the etiology of non-syndromic CL/P, but the results of different studies are controversial (6, 9-11). Moreover, it has been proposed that variations in the genes encoding enzymes of the folate metabolism pathway might play a role in the susceptibility to orofacial clefts. 5,10-methylenetetrahydrofolate reductase (MTHFR, MIM 236250) which is localized to chromosomal region 1p36.3, is important for a chemical reaction converting 5,10 methylenetetrahydrofolate to 5-methyl tetrahydrofolate. The latter compound is the major circulatory form of folic acid and the carbon donor for the conversion of amino acid homocysteine to methionine (3, 4, 12).

MTHFR c.677C>T polymorphism (rs1801133), which causes alanine (A) to valine (V) substitution, was the first common variant identified for this gene. The TT genotype results in lower enzymatic activity and higher thermolability than CT and CC genotypes (3,12-14). Another common polymor-phism of MTHFR, c.1298A>C (rs1801131), re-sults in glutamic acid to alanine substitution. This variant is also associated with decreased catalytic activity of the enzyme, but to a lesser extent than c.677C>T (14,15).

Since its identification, c.677C>T polymorphism of MTHFR gene has been related with many conditions and disorders including migraine, smoking behavior, vascular diseases and neural tube defects (13, 16-19). Nevertheless, findings of studies on the association between maternal or infant MTHFR polymorphism and the increased risk of oral clefts in different populations are controversial (20-26). Furthermore, no previous study has investigated the frequencies of common MTHFR polymorphisms in Iranian cleftpatients or their parents. Therefore we carried out an investigation to determine the association between two common MTHFR polymorphisms (c.677C>T and c.1298A>C) and the risk of non-syndromic cleftlip and palate in an Iranian population.

Materials and Methods

The study sample consisted of 45 non-syndromic CL/P patients, 43 mothers of patients and 101 control subjects. All cases were recruited between 2010-2012 from the Cleftlip and Palate Clinic of Mashhad Dental School, Sheikh Pediatric Hospital and Ghaem Medical Center in Mashhad, northeast of Iran. In order to exclude the syndromic vari-ants of CL/P, all patients were examined by a clinical geneticist for the presence of any associ-ated physical or developmental abnormalities. CL/P was the only disorder affecting participants. In addition, all patients and their mothers were asked questions about the medical history and fac-tors suspected to be related to clefting such as specific drugs, tobacco or alcohol consumption during the pregnancy.

Control subjects were healthy blood donors from northeast of Iran, with no family history of CL/P who enrolled the study at the same period. The cleftpatients and control subjects were from the same ethnic origin. This investigation was ap-proved by the Ethics Committee of Mashhad Uni-versity of Medical Sciences with the code number 900030. After the written informed consent was obtained, blood samples were collected from the participants.

Peripheral blood samples were collected in test tubes that contained EDTA. Standard DNA extraction from peripheral blood cells was per-formed according to Higuchi (26). …

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