5,10‐Methylenetetrahydrofolate reductase single nucleotide polymorphisms and gene–environment interaction analysis in non‐syndromic cleft lip/palate

Estandía-Ortega, Bernardette; Velázquez-Aragón, José A.; Alcántara-Ortigoza, Miguel Ángel; Reyna-Fabián, Miriam E.; Villagómez-Martínez, Sandra; Ángel, Ariadna González-del

doi:10.1111/eos.12114

Cited by 18 publications

(18 citation statements)

References 31 publications

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“…This result reflects the complexity of the model where two copies of the risk allele could be necessary to increase the phenotype susceptibility. Both positive and negative results of association have been previously described in other Latin American case–control populations (Gaspar et al , ; Sözen et al , ; Estandia‐Ortega et al , ; Bezerra et al , ). Multiethnic meta‐analyses for genotypes (TT vs CC) present highly similar results to ours showing overall ORs of 1.21 (95% CI 0.97–1.53; Pan et al , ) and 1.22 (95% CI 0.97–1.55; Luo et al , ).…”

Section: Discussionsupporting

confidence: 53%

MTHFR c.677C>T is a risk factor for non‐syndromic cleft lip with or without cleft palate in Chile

et al. 2016

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Section: Discussionsupporting

confidence: 53%

MTHFR c.677C>T is a risk factor for non‐syndromic cleft lip with or without cleft palate in Chile

et al. 2016

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“…Out of 31 studies included in the present meta-analysis, six studies 27,34,39,44,45,52 , five studies 34,39,44,46,52 , and four studies 34,39,46,52 reported significantly increased risk of T allele, TT genotype, and CT genotype in NSCL/P patients compared with controls, respectively. Also, five studies 36,47,49,55,57 , two studies 47,57 , and four studies 28,36,47,57 reported a significantly decreased risk of T allele, TT genotype and CT genotype in NSCL/P patients compared with controls, respectively. In addition, TT + CT genotype was reported to have a significantly increased risk in five studies 34,39,44,46,52 and significantly decreased risk in four studies 36,47,55,57 in NSCL/P patients compared with controls.…”

Section: Discussionmentioning

confidence: 98%

“…Also, five studies 36,47,49,55,57 , two studies 47,57 , and four studies 28,36,47,57 reported a significantly decreased risk of T allele, TT genotype and CT genotype in NSCL/P patients compared with controls, respectively. In addition, TT + CT genotype was reported to have a significantly increased risk in five studies 34,39,44,46,52 and significantly decreased risk in four studies 36,47,55,57 in NSCL/P patients compared with controls. Based on the recessive model, three studies 39,46,54 reported significantly increased risk of TT genotype and one study 57 reported its significantly decreased risk in NSCL/P patients compared with controls.…”

Section: Discussionmentioning

confidence: 98%

Methylenetetrahydrofolate reductase C677T polymorphism is not associated with the risk of nonsyndromic cleft lip/palate: An updated meta-analysis

Imani

Golchin

Safaei

et al. 2020

Sci Rep

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Both genetic and environmental factors affect the risk of orofacial clefts. The present meta-analysis aimed to evaluate the association between methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and risk of nonsyndromic cleft lip/palate (NSCL/P) in cases-control studies. The PubMed/ Medline, Scopus, Web of Science, and Cochrane Library databases were searched up to April 2019 with no restrictions. The odds ratios (ORs) and 95% confidence intervals (CIs) in all analyses were calculated by Review Manager 5.3 software. The funnel plot analysis was carried out by the Comprehensive Meta-Analysis version 2.0 software. Subgroup analysis, meta-regression, and sensitivity analysis were performed for the pooled analyses. Thirty-one studies reviewed in this meta-analysis included 4710 NSCL/P patients and 7271 controls. There was no significant association between MTHFR C677T polymorphism and NSCL/P susceptibility related to allelic model (OR = 1.04; P = 0.49), homozygote model (OR = 1.11; P = 0.35), heterozygote model (OR = 0.99; P = 0.91), dominant model (OR = 1.00; p = 0.96), or recessive model (OR = 1.08; P = 0.23). There was no significant association between MTHFR C677T polymorphism and NSCL/P susceptibility based on the ethnicity or the source of cases. There was a significant linear relationship between the year of publication and log ORs for the allele model. The results of the present meta-analysis failed to show an association between MTHFR C677T polymorphism and NSCL/P susceptibility. The subgroup analyses based on the ethnicity and the source of cases further confirmed this result.Non-syndromic cleft lip/palate (NSCL/P) is a common birth defect worldwide 1 . In low-and middle-income countries, around 1/730 children is born with cleft lip/palate 2 . A multifactorial model of genetic inheritance has been recommended for NSCL/P based on the interaction of genetic and environmental factors 1 . Several lines of evidence have proven a significant association between polymorphism of genes connected to folate metabolism and increased risk of orofacial clefts 3 . Among genes related to folate metabolism, 5,10-methylenetetrahydrofolate reductase (MTHFR) reportedly has the highest association with NSCL/P. This gene is located on chromosome 1 at 1p36.3 and translates to MTHFR enzyme that catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a cosubstrate for homocysteine remethylation to methionine 4,5 . MTHFR is a fundamental enzyme in folate metabolism and DNA synthesis, and MTHFR rs1801133 (C677T) is one of the most common polymorphisms which diminishes the enzyme activity 6-8 . Regulation of MTHFR activity is pivotal to maintain optimal cellular levels of methionine and S-adenosylmethionine 5 . Folate supplementation or its adequate dietary intake during pregnancy has been shown to prevent or decrease NSCL/P susceptibility 9 . Nutritional factors, such as the adequacy of folic acid in the mother's diet, are clearly important, but other potential disturbances in ovulation or ...

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“…The development of craniofacial structures is the product of social environmental, and nutritional factors such as tobacco smoke, alcohol consumption, and maternal folic acid deficiency due to exposure to folic acid antagonists – such as anticonvulsants 26 – appear to play a role in the development of OFC during pregnancy 8 . Folic acid is a water soluble B-vitamin that plays a crucial role in embryonic development because it is essential for DNA stability maintenance, being involved in DNA synthesis, repair, and methylation 4 , 22 .…”

Section: Introductionmentioning

confidence: 99%

“…The metabolic cycle of folate is complex, with multiple genes participating in the transformation of folate into various compounds 8 . One of these genes is dihydrofolate reductase (DHFR), known as a strong candidate for a teratogenic locus which synthesizes the DHFR enzyme.…”

Section: Introductionmentioning

confidence: 99%

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

Rafighdoost

et al. 2015

J. Appl. Oral Sci.

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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.

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5,10‐Methylenetetrahydrofolate reductase single nucleotide polymorphisms and gene–environment interaction analysis in non‐syndromic cleft lip/palate

Cited by 18 publications

References 31 publications

MTHFR c.677C>T is a risk factor for non‐syndromic cleft lip with or without cleft palate in Chile

MTHFR c.677C>T is a risk factor for non‐syndromic cleft lip with or without cleft palate in Chile

Methylenetetrahydrofolate reductase C677T polymorphism is not associated with the risk of nonsyndromic cleft lip/palate: An updated meta-analysis

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

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