The 19-bp deletion polymorphism of dihydrofolate reductase (DHFR) and nonsyndromic cleft lip with or without cleft palate: evidence for a protective role

Abstract

Objective Nonsyndromic cleft lip with or without cleft palate (NS-CL/P) are among the most common congenital birth defects worldwide. Several lines of evidence point to the involvement of folate, as well as folate metabolizing enzymes in risk reduction of orofacial clefts. Dihydrofolate reductase (DHFR) enzyme participates in the metabolic cycle of folate and has a crucial role in DNA synthesis, a fundamental feature of gestation and development. A functional polymorphic 19-bp deletion within intron-1 of DHFR has been associated with the risk of common congenital malformations. The present study aimed to evaluate the possible association between DHFR 19-bp deletion polymorphism and susceptibility to NS-CL/P in an Iranian population.Material and Methods The current study recruited 100 NS-CL/P patients and 100 healthy controls. DHFR 19-bp deletion was determined using an allele specific-PCR method.Results We observed the DHFR 19-bp homozygous deletion genotype (D/D) vs. homozygous wild genotype (WW) was more frequent in controls than in NS-CL/P patients (25% vs. 13%), being associated with a reduced risk of NS-CL/P in both codominant (OR=0.33, P=0.027) and recessive (OR=0.45, P=0.046) tested inheritance models. We also stratified the cleft patients and reanalyzed the data. The association trend for CL+CL/P group compared to the controls revealed that the DD genotype in both codominant (OR=0.30, P=0.032) and recessive models (OR=0.35, P=0.031) was associated with a reduced risk of CL+CL/P.Conclusions Our results for the first time suggested the DHFR 19-bp D/D genotype may confer a reduced risk of NS-CL/P and might act as a protective factor against NS-CL/P in the Iranian subjects.

Association of FOLH1, DHFR, and MTHFR gene polymorphisms with susceptibility of Neural Tube Defects: A case control study from Eastern India

“…Our result was similar to the previous reported studies on Dutch and mixed UK populations (Van der Linden et al, ; Doudney et al, ), whereas a report from Irish population showed protective role of rs70991108 (Parle McDermott et al, 2007). It is assumed that rs70991108/19 bp deletion within intron 1 of DHFR affects the transcription and as well the translational process of the protein, however the direct role of the polymorphism is controversial (Rafighdoost et al, ). Extensive genetic and functional study is necessary to conclude the role of rs70991108 in NTD patients.…”

Association of single nucleotide polymorphisms in AXIN2, BMP4, and IRF6 with Non-Syndromic Cleft Lip with or without Cleft Palate in a sample of the southeast Iranian population

“…A total of 288 subjects, including 132 NSCL/P and 156 healthy subjects, were recruited for this case-control study. The criteria for participants with NSCL/P and healthy individuals were previously described 22 - 24 . The local Ethics Committee of the Zahedan University of Medical Sciences approved the project (IR.ZAUMS.Rec.1393.6923) and informed consent forms were collected from all participants (or their legal guardians).…”

“…The interferon regulatory factor 6 (IRF6) gene is located on chromosome 1q32.2. It has been shown that variants of the IRF6 gene increased the risk of NSCL/P as well as tooth agenesis 20 , 22 , 26 .…”

DHFR (dihydrofolate reductase)

“…In contrast, Parle-McDermott et al (2007), demonstrated that 19-bp deletion allele (D) may be a protective genetic factor against NTD by increasing DHFR mRNA levels in pregnant women. Moreover, a study by Rafighdoost also suggests that DHFR 19bp D/D genotype reduce the risk of Nonsyndromic cleft lip with or without cleft palate (NS-CL/P) in Iranian subjects (Rafighdoost et al 2015). Ongaro et al (2009) and Vagace et al (2011) reported that homozygosity for DHFR 19 bp deleted allele polymorphism has been associated with increased hepatotoxicity in leukemia patients treated with MTX.…”