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1.  Is MTHFD1 polymorphisms rs 2236225 (c.1958G>A) associated with the susceptibility of NSCL/P? A systematic review and meta-analysis 
F1000Research  2015;4:142.
Aims: To investigate the association between the methylenetetrahydrofolate dehydrogenase 1 (MTHFD1) polymorphism rs 2236225 (c.1958G>A) and susceptibility to non-syndromic cleft of the lip and/or palate (NSCL/P).
Methods: An extensive literature review has been conducted using PubMed, Web of Science, Cochrane Library, Google Scholar, the China National Knowledge Infrastructure (CNKI), and Wanfang Database for eligible researches. The terms for searching were “cleft lip OR cleft palate OR CLP OR CL/P OR oral facial cleft OR OFC” AND “methylenetetrahydrofolate dehydrogenase (NADP+ dependent) 1 OR methenyltetrahydrofolate cyclohydrolase formyltetrahydrofolate synthetase OR MTHFD1 OR MTHFD”. Two independent researchers screened, evaluated and extracted the data of included studies. The pooled odds ratios (OR) with 95% confidence intervals (95% CI) were calculated by random effects model under five gene models. Subgroup, sensitivity analysis and publication bias were also assessed.
Results: Ten case-control studies have been included in the systematic review and eight studies have been considered for the meta-analysis. Overall, the MTHFD1 polymorphism rs2236225 and the risk of NSCL/P showed pooled OR (95% CI) of 1.02 (0.86-1.21) under allelic model. A higher degree of heterogeneity was observed in Asian countries (I 2 = 75.6%) compared to non-Asian countries (I 2 = 48.9%). Similar consequence appeared in the subgroup of children (I 2 = 78.6%) compared with that of mothers (I 2 = 0.0%). There was no significant difference in the publication bias by the Begg’s funnel plot (P = 0.711) and Egger’s regression test (P = 0.746).
Conclusion: Our assessment suggested there was no significant association between the MTHFD1 polymorphism rs 2236225 (c.1958G>A) and the susceptibility to NSCL/P. Further investigations using a large sample size and a more advanced technique should be adopted to reach a more precise conclusion in the future.
PMCID: PMC4722688  PMID: 26834978
MTHFD1; Polymorphisms; NSCL/P susceptibility; Meta-analysis
2.  Is MTHFD1 polymorphism rs 2236225 (c.1958G>A) associated with the susceptibility of NSCL/P? A systematic review and meta-analysis 
F1000Research  2016;4:142.
Aims: To investigate the association between the methylenetetrahydrofolate dehydrogenase 1 (MTHFD1) polymorphism rs 2236225 (c.1958G>A) and susceptibility to non-syndromic cleft of the lip and/or palate (NSCL/P).
Methods: An extensive literature review has been conducted using PubMed, Web of Science, Cochrane Library, Google Scholar, the China National Knowledge Infrastructure (CNKI), and Wanfang Database for eligible researches. The terms for searching were “cleft lip OR cleft palate OR CLP OR CL/P OR oral facial cleft OR OFC” AND “methylenetetrahydrofolate dehydrogenase (NADP+ dependent) 1 OR methenyltetrahydrofolate cyclohydrolase formyltetrahydrofolate synthetase OR MTHFD1 OR MTHFD”. Two independent researchers screened, evaluated and extracted the data of included studies. The pooled odds ratios (OR) with 95% confidence intervals (95% CI) were calculated by random effects model under five gene models. Subgroup, sensitivity analysis and publication bias were also assessed.
Results: Ten case-control studies have been included in the systematic review and eight studies have been considered for the meta-analysis. Overall, the MTHFD1 polymorphism rs2236225 and the risk of NSCL/P showed pooled OR (95% CI) of 1.02 (0.86-1.21) under allelic model. A higher degree of heterogeneity was observed in Asian countries (I 2 = 75.6%) compared to non-Asian countries (I 2 = 48.9%). Similar consequence appeared in the subgroup of children (I 2 = 78.6%) compared with that of mothers (I 2 = 0.0%). There was no significant difference in the publication bias by the Begg’s funnel plot (P = 0.711) and Egger’s regression test (P = 0.746).
Conclusion: Our assessment suggested there was no significant association between the MTHFD1 polymorphism rs 2236225 (c.1958G>A) and the susceptibility to NSCL/P. Further investigations using a large sample size and a more advanced technique should be adopted to reach a more precise conclusion in the future.
PMCID: PMC4722688  PMID: 26834978
MTHFD1; Polymorphisms; NSCL/P susceptibility; Meta-analysis
3.  Folate and One-Carbon Metabolism Gene Polymorphisms and Their Associations With Oral Facial Clefts 
Folate metabolism plays a critical role in embryonic development. Prenatal folate supplementation reduces the risk of neural tube defects and probably oral facial clefts. Previous studies of related metabolic genes have associated polymorphisms in cystathionine-beta-synthase (CBS) and 5,10-methylenetetrahydrofolate reductase (MTHFR) with cleft risk. We explored associations between genes related to one-carbon metabolism and clefts in a Norwegian population-based study that included 362 families with cleft lip with or without cleft palate (CL/P) and 191 families with cleft palate only (CPO). We previously showed a 39% reduction in risk of CL/P with folic acid supplementation in this population. In the present study we genotyped 12 polymorphisms in nine genes related to one-carbon metabolism and looked for associations of clefting risk with fetal polymorphisms, maternal polymorphisms, as well as parent-of-origin effects, using combined likelihood-ratio tests (LRT). We also stratified by maternal periconceptional intake of folic acid (>400 μg) to explore gene-exposure interactions. We found a reduced risk of CL/P with mothers who carried the CBS C699T variant (rs234706); relative risk was 0.94 with one copy of the T allele (95% CI 0.63-1.4) and 0.50 (95% CI 0.26-0.96) with two copies (P = 0.008). We found no evidence of interaction of this variant with folate status. We saw no evidence of risk from the MTHFR C677T variant (rs1801133) either overall or after stratifying by maternal folate intake. No associations were found between any of the polymorphisms and CPO. Genetic variations in the nine metabolic genes examined here do not confer a substantial degree of risk for clefts. Published 2008 Wiley-Liss, Inc.†
PMCID: PMC2366099  PMID: 18203168
alleles; cleft lip; cleft palate; dietary supplements; folic acid; metabolism; humans; single nucleotide polymorphisms
4.  First-trimester non-systemic corticosteroid use and the risk of oral clefts in Norway 
Annals of epidemiology  2014;24(9):635-640.
Exposure of pregnant mice to corticosteroids can produce oral clefts in offspring. While data in humans are more mixed, recent reports have suggested that dermatologic steroids are associated with oral clefts.
We investigated maternal first-trimester exposure to corticosteroids (focusing on dermatologic uses) and oral clefts in offspring using two population-based studies. The Norway Cleft Study (1996–2001) is a national case-control study including 377 infants with cleft lip +/− palate (CLP), 196 infants with cleft palate only (CPO) and 763 controls. The Norwegian Mother and Child Cohort Study (MoBa, 1998–2008), is a national birth cohort including 123 infants with CLP, 61 infants with CPO and 551 controls.
In the case-control study, there was the suggestion of an association of dermatological corticosteroids with both CLP (adjusted OR (aOR) = 2.3, 95% confidence interval = 0.71, 7.7) and CPO (aOR = 3.4, 0.87–13). There was no evidence of this association in the cohort data (OR for CLP = 1.2; 0.50, 2.8), OR for CPO = 1.0, 0.30–3.4), although exposure to dermatological steroids was less specifically ascertained. There were no associations with other types of corticosteroids.
Our data add to the suggestive but inconsistent findings for this association.
PMCID: PMC4161959  PMID: 25127739
corticosteroids; cleft lip; cleft palate; maternal exposure; pregnancy
5.  Oral Cleft Defects and Maternal Exposure to Ambient Air Pollutants in New Jersey 
Evidence links exposure to ambient air pollution during pregnancy, particularly gaseous pollutants and particulate matter, to an increased risk of adverse reproductive outcomes but the results for birth defects have been inconsistent.
We compared estimated exposure to ambient air pollutants during early pregnancy among mothers of children with oral cleft defects (cases) to that among mothers of controls, adjusting for available risk factors from birth certificates. We obtained ambient air pollutant data from air monitoring sites in New Jersey for carbon monoxide (CO), nitrogen dioxide (NO2), ozone (O3), sulfur dioxide (SO2), particulate matter less than 10 µm in aerodynamic diameter (PM10) and particulate matter less than 2.5 µm in aerodynamic diameter (PM2.5). We used values from the nearest monitor (within 40 km of the residence at birth) for controls, cleft lip with or without cleft palate (CLP) and cleft palate only (CPO).
Based on logistic regression analyses for each contaminant and all contaminants together, there were no consistent elevated associations between selected air pollutants and cleft malformations. Quartile of CO concentration showed a consistent protective association with CPO (p<.01). For other contaminants, confidence intervals (95%) of the odds ratios for some quartiles excluded one. CLP showed limited evidence of an association with increasing SO2 exposure while CPO showed weak associations with increasing O3 exposure.
There was little consistent evidence associating cleft malformations with maternal exposure to ambient air pollutants. Evaluating particular pollutants or disease subgroups would require more detailed measurement of exposure and classification of cleft defects.
PMCID: PMC2862481  PMID: 20146378
6.  Significant association of MTHFD1 1958G>A single nucleotide polymorphism with nonsyndromic cleft lip and palate in Indian population 
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.
PMCID: PMC4259380  PMID: 25129243
7.  Oral facial clefts and gene polymorphisms in metabolism of folate/one-carbon and vitamin A: a pathway-wide association study 
Genetic epidemiology  2009;33(3):247-255.
An increased risk of facial clefts has been observed among mothers with lower intake of folic acid or vitamin A around conception. We hypothesized that the risk of clefts may be further moderated by genes involved in metabolizing folate or vitamin A. We included 425 case-parent triads in which the child had either cleft lip with or without cleft palate (CL/P) or cleft palate only (CPO), and no other major defects. We analyzed 108 SNPs and one insertion in 29 genes involved in folate/one-carbon metabolism and 68 SNPs from 16 genes involved in vitamin A metabolism. Using the Triad Multi Marker (TRIMM) approach we performed SNP, gene, chromosomal region, and pathway-wide association tests of child or maternal genetic effects for both CL/P and CPO. We stratified these analyses on maternal intake of folic acid or vitamin A during the periconceptional period.
As expected with this high number of statistical tests, there were many associations with p-values < 0.05; although there were fewer than predicted by chance alone. The strongest association in our data (between fetal FOLH1 and CPO, p=0.0008) is not in agreement with epidemiologic evidence that folic acid reduces the risk of CL/P in these data, not CPO. Despite strong evidence for genetic causes of oral facial clefts and the protective effects of maternal vitamins, we found no convincing indication that polymorphisms in these vitamin metabolism genes play an etiologic role.
PMCID: PMC2677659  PMID: 19048631
cleft lip; cleft palate; dietary supplements; folic acid; genetics; metabolism; vitamin A
8.  Association between inhibited binding of folic acid to folate receptor α in maternal serum and folate-related birth defects in Norway 
Human Reproduction (Oxford, England)  2011;26(8):2232-2238.
Folic acid intake during pregnancy can reduce the risk of neural tube defects (NTDs) and perhaps also oral facial clefts. Maternal autoantibodies to folate receptors can impair folic acid binding. We explored the relationship of these birth defects to inhibition of folic acid binding to folate receptor α (FRα), as well as possible effects of parental demographics or prenatal exposures.
We conducted a nested case–control study within the Norwegian Mother and Child Cohort Study. The study included mothers of children with an NTD (n= 11), cleft lip with or without cleft palate (CL/P, n= 72), or cleft palate only (CPO, n= 27), and randomly selected mothers of controls (n= 221). The inhibition of folic acid binding to FRα was measured in maternal plasma collected around 17 weeks of gestation. On the basis of prior literature, the maternal age, gravidity, education, smoking, periconception folic acid supplement use and milk consumption were considered as potential confounding factors.
There was an increased risk of NTDs with increased binding inhibition [adjusted odds ratio (aOR) = 1.4, 95% confidence interval (CI) 1.0–1.8]. There was no increased risk of oral facial clefts from inhibited folic acid binding to FRα (CL/P aOR = 0.7, 95% CI 0.6–1.0; CPO aOR = 1.1, 95% CI 0.8–1.4). No association was seen between smoking, folate supplementation or other cofactors and inhibition of folic acid binding to FRα.
Inhibition of folic acid binding to FRα in maternal plasma collected during pregnancy was associated with increased risk of NTDs but not oral facial clefts.
PMCID: PMC3137385  PMID: 21576080
neural tube defects; oral facial clefts; folic acid; folate receptor; maternal autoantibodies
9.  Genotyping of a tri-allelic polymorphism by a novel melting curve assay in MTHFD1L: an association study of nonsyndromic Cleft in Ireland 
BMC Medical Genetics  2012;13:29.
Polymorphisms within the MTHFD1L gene were previously associated with risk of neural tube defects in Ireland. We sought to test the most significant MTHFD1L polymorphisms for an association with risk of cleft in an Irish cohort. This required the development of a new melting curve assay to genotype the technically challenging MTHFD1L triallelic deletion/insertion polymorphism (rs3832406).
Melting curve analysis was used to genotype the MTHFD1L triallelic deletion/insertion polymorphism (rs3832406) and a Single Nucleotide Polymorphism rs17080476 in an Irish cohort consisting of 981 Irish case-parent trios and 1,008 controls. Tests for association with nonsyndromic cleft lip with or without cleft palate and cleft palate included case/control analysis, mother/control analysis and Transmission Disequilibrium Tests of case-parent trios.
A successful melting curve genotyping assay was developed for the deletion/insertion polymorphism (rs3832406). The TDT analysis initially showed that the rs3832406 polymorphism was associated with isolated cleft lip with or without cleft palate. However, corrected p-values indicated that this association was not significant.
Melting Curve Analysis can be employed to successfully genotype challenging polymorphisms such as the MTHFD1L triallelic deletion/insertion polymorphism (DIP) reported here (rs3832406) and is a viable alternative to capillary electrophoresis. Corrected p-values indicate no association between MTHFD1L and risk of cleft in an Irish cohort.
PMCID: PMC3419639  PMID: 22520921
10.  Genetic Variants in IRF6 and the Risk of Facial Clefts: Single-Marker and Haplotype-Based Analyses in a Population-Based Case-Control Study of Facial Clefts in Norway 
Genetic epidemiology  2008;32(5):413-424.
Mutations in the gene encoding interferon regulatory factor 6 (IRF6) underlie a common form of syndromic clefting known as Van der Woude syndrome. Lip pits and missing teeth are the only additional features distinguishing the syndrome from isolated clefts. Van der Woude syndrome, therefore, provides an excellent model for studying the isolated forms of clefting. From a population-based case-control study of facial clefts in Norway (1996–2001), we selected 377 cleft lip with or without cleft palate (CL/P), 196 cleft palate only (CPO), and 763 control infant-parent triads for analysis. We genotyped six single nucleotide polymorphisms within the IRF6 locus and estimated the relative risks (RR) conferred on the child by alleles and haplotypes of the child and of the mother. On the whole, there were strong statistical associations with CL/P but not CPO in our data. In single-marker analyses, mothers with a double-dose of the ‘a’-allele at rs4844880 had an increased risk of having a child with CL/P (RR = 1.85, 95% confidence interval: 1.04–3.25; P = 0.036). An RR of 0.38 (95% confidence interval: 0.16–0.92; P = 0.031) was obtained when the child carried a single-dose of the ‘a’-allele at rs2235371 (the p.V274I polymorphism). The P-value for the overall test was <0.001. In haplotype analyses, several of the fetal and maternal haplotype relative risks were statistically significant individually but were not strong enough to show up on the overall test (P = 0.113). Taken together, these findings further support a role for IRF6 variants in clefting of the lip and provide specific risk estimates in a Norwegian population.
PMCID: PMC2680842  PMID: 18278815
birth defects; facial clefts; genetic epidemiology; IRF6; case-control; case-parent triad; log-linear model; association analysis; haplotype analysis; haplotype relative risk; HAPLIN; HapMap
11.  Plasma folate, related genetic variants and colorectal cancer risk in EPIC 
A potential dual role of folate in colorectal cancer (CRC) is currently subject to debate. Previous studies on plasma folate and CRC risk were small and inconclusive. We therefore investigate associations between plasma folate, a number of relevant folate-related polymorphisms and CRC risk. In this nested case-control study within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, 1367 incident CRC cases were matched to 2325 controls for study center, age and sex. Risk ratios (RR) were estimated with conditional logistic regression and further adjusted for smoking, education, physical activity, and intake of alcohol and fiber. Overall analyses did not reveal associations of plasma folate with CRC. The RR (95% CI), Ptrend) for the fifth vs. the first quintile of folate status was 0.94 ((0.74; 1.20), 0.44). The polymorphisms MTHFR 677C→T, MTHFR 1298A→C, MTR 2756A→G, MTRR 66A→G, and MTHFD1 1958G→A were not associated with CRC risk. However, in individuals with the lowest plasma folate concentrations, the MTHFR 677TT genotype showed a statistically non-significant increased CRC risk (RR (95% CI, Ptrend) TT vs. CC =1.39 (0.87; 2.21), 0.12), whereas in those with the highest folate concentrations showed a non-significant decreased CRC risk (RR TT vs. CC=0.74 (0.39; 1.37), 0.34). The SLC19A1 80G→A showed a positive association with CRC risk (RR AA vs. GG1.30 (1.06; 1.59), <0.01).
Within this large European prospective multicenter study we did not observe an association of CRC risk with plasma folate status, nor with the MTHFR polymorphisms.
PMCID: PMC2880712  PMID: 20447924
Plasma folate; genetic variants; colorectal cancer; prospective study
12.  Association between Maternal MTHFR Polymorphisms and Nonsyndromic Cleft Lip with or without Cleft Palate in Offspring, A Meta-Analysis Based on 15 Case-Control Studies 
The methylenetetrahydrofolate reductase (MTHFR) is thought to be involved in the development of nonsyndromic cleft lip with or without cleft palate (NSCL/P). However, conflicting results have been obtained when evaluating the association between maternal MTHFR C677T and A1298C polymorphisms and the risk of NSCL/P. In light of this gap, a meta-analysis of all eligible case-control studies was conducted in the present study.
Materials and Methods
A total of 15 case-control studies were ultimately identified after a comprehensive literature search and Hardy-Weinberg equilibrium (HWE) examination. Cochrane’s Q test and index of heterogeneity (I2) indicated no obvious heterogeneity among studies.
Fixed or random-effects models were used to calculate the pooled odds ratios (ORs). The results showed that the TT genotype in mothers increased the likelihood of having NSCL/P offspring 1.25 times (95% CI: 1.047-1.494) more than the CC homozygotes. Meanwhile, maternal TT genotype increased the risk of producing NSCL/P offspring in recessive model (OR=1.325, 95% CI: 1.124-1.562). However, the CT heterozygote and the CT+TT dominant models had no association with NSCL/P offspring compared with the CC wild-type homozygote model. Subgroup analyses based on ethnicity indicated that maternal TT genotype increased the likelihood of having NSCL/P offspring in Whites (OR=1.308, 95% CI: 1.059-1.617) and Asians (OR=1.726, 95% CI: 1.090-2.733) in recessive model. Also, subgroup analyses based on source of control showed that mothers with the 677TT genotype had a significantly increased susceptibility of having NSCL/P children in hospital based population (HB) when compared with CC homozygotes (OR=1.248, 95% CI: 1.024-1.520) and un- der the recessive model (OR=1.324, 95% CI: 1.104-1.588). Furthermore, maternal A1298C polymorphism had no significant association with producing NSCL/P offspring (dominant model OR=0.952, 95% CI: 0.816-1.111, recessive model OR=0.766, 95% CI: 0.567-1.036).
MTHFR C677T polymorphism is associated with the risk of generating NSCL/P offspring, and being a 677TT homozygote is a risk factor. MTHFR A1298C polymorphism was not associated with generating NSCL/P offspring. However, further work should be performed to confirm these findings.
PMCID: PMC4355933  PMID: 25780529
Methylenetetrahydrofolate Reductase; Cleft Lip; Meta-Analysis
13.  Psychotropic drug use in adolescents born with an orofacial cleft: a population-based study 
BMJ Open  2015;5(4):e005306.
Being born with an orofacial cleft (OFC) can, due to an incomplete closure of the lip and/or palate, convey a deviant speech and/or deviant facial aesthetics, which may in turn increase the risk for poor psychological health later in life. Previous investigations have been based on small samples and self-reports, not distinguishing between the three different types of OFC: cleft lip (CL), CL and palate (CLP) and cleft palate only (CPO). We present a large population-based study, considering psychotropic drug use as a proxy for poor psychological health and distinguishing between three different types of OFC.
Design and methods
Using the Swedish Medical Birth Register, and linking to it the Swedish Prescribed Drug Register, the National Mortality Register, the Emigration Register and the National Inpatient Register, we identified all singletons born to native mothers in Sweden between 1987 and 1993, alive and residing in Sweden at the end of an 18-year follow-up period (N=626 109). We compared psychotropic drug use among individuals with and without OFC during the individuals’ adolescence (2005–2008) by multiple logistic regressions, using ORs with 95% CIs.
When adjusted for potential confounders, having a CL (OR=1.63, 95% CI 1.08 to 2.46) or a CPO (OR=1.54, 95% CI 1.18 to 2.01) increased the risk of psychotropic drug use. Results were not significant regarding adolescents who had a CLP (OR=1.21, 95% CI 0.81 to 1.80).
Being born with a CL or a CPO increases the risk for psychotropic drug use in adolescence, but not for adolescents born with a CLP. Our findings suggest that, since the three OFC types are associated with different long-term risks of poor psychological health, the three groups should be studied separately concerning long-term psychosocial consequences.
PMCID: PMC4390737  PMID: 25838502
14.  Common Mutations of the Methylenetetrahydrofolate Reductase (MTHFR) Gene in Non-Syndromic Cleft Lips and Palates Children in North-West of Iran 
Cleft lips and cleft palates are common congenital abnormalities in children. Various chromosomal loci have been suggested to be responsible the development of these abnormalities. The present study was carried out to investigate the association between the suspected genes (methylenetetrahydrofolate reductase [MTHFR] A1298C and C677T) that might contribute into the etiology of these disorders through application of molecular methods.
Materials and Methods:
This cross-sectional and explanatory study was carried out on a study population of 65 affected children, 130 respective parents and 50 healthy individuals between 2009 and 2012 at Tabriz University of Medical Sciences, IR Iran. After DNA extraction, amplification refractory mutation system–polymerase chain reaction (ARMS-PCR) and restriction fragment length polymorphism (RFLP)-PCR were used respectively to investigate the C677T and A1298C mutations for the MTHFR gene.
There was a significant difference in the rates of the C677T mutation when affected patients and their fathers were compared with the control group (odds ratio [OR]=0.44) (OR=0.64). However, there was no significant difference observed in the rate of this mutation between the patients’ mothers and the control group (OR=1.35). In addition, the abnormality rate was higher in patients with the A1298C mutation and their parents, when compared with the control group. This abnormality rate was higher for the affected children and their fathers in comparison with their mothers (Fathers, OR=0.26; Mothers, OR=0.65; Children, OR=0.55). No significant difference was seen in the rate of the polymorphism C677T in its CC, when the affected children and their parents were compared with the control group. However, there was a significant difference in the A1298C mutation.
An association was seen between the A1298C mutation and cleft lip and cleft palate abnormalities in Iran. However, there seems to be a stronger relationship between the C67TT mutation and these abnormalities in other countries, which could be explained by racial differences. Moreover, this association was more notable between the affected children and their fathers than their mothers. The findings in this study may be helpful in future studies and screening programs.
PMCID: PMC4344969  PMID: 25745606
A1298C mutation; Cleft lip; Cleft palate; C677T mutation; MTHFR
15.  Late detection of cleft palate 
Cleft palate only (CPO) is a common congenital malformation, and most patients are diagnosed within the first weeks after birth. Late diagnosis of the cleft palate (CP) could initially result in feeding and growth impairment, and subsequently speech and hearing problems later in life. The purpose of this study is to retrospectively investigate (1) at which age CPO is diagnosed and (2) how the presence of syndromes and other factors relate to the age at diagnosis. The mean age of all children at our centre with CPO included between 1997 and 2014 at diagnosis (n = 271) was 1 year and 4 months. In all, 24.8 % (n = 67) was older than 12 months when diagnosed, and 37.3 % (n = 101) of all children had been diagnosed >30 days. These findings remain valid when a cut-off point of 14 days is used (44.3 % late). Moreover, the grade of the cleft was a determining factor for successful diagnosis; submucous clefts were detected much later on average (89.3 % > 30 days; p = .000). Similar results were found using Kaplan-Meier survival analyses.
Conclusion: CPO is often diagnosed late. Patients diagnosed ≤30 days after birth more often presented with an associated disorder. Early diagnoses became more frequent as the severity of the cleft increased (grades 1–4). Professionals should perform more thorough intra-oral investigations, including manual palpations and visual inspections of the palate; they should be made more aware of the frequent accompanying symptoms. What is Known: • The presence of cleft palate only (CPO) is known to negatively affect feeding, hearing, speech and (social) development. • Submucous clefts are often underdiagnosed due to their difficulty to detect. As far as we know the literature shows that symptomatic submucous CPs are often diagnosed at an average age of 4.9 years. What is New: • 37.3 % respectively of all children with CPO were diagnosed relatively late (>30 days after birth), 24.8 % was older than 12 months when diagnosed. Mean age of all children with CPO was 1 year and 4 months. • We conclude that midwives and pediatricians should perform more through intra-oral investigations of all new-borns, including both a manual palpation, als well a visual inspection of the palate.
PMCID: PMC4709386  PMID: 26231683
Cleft palate only; Diagnosis; Children; Age; Feeding difficulties; Nasal regurgitation
16.  X-Linked Genes and Risk of Orofacial Clefts: Evidence from Two Population-Based Studies in Scandinavia 
PLoS ONE  2012;7(6):e39240.
Orofacial clefts are common birth defects of complex etiology, with an excess of males among babies with cleft lip and palate, and an excess of females among those with cleft palate only. Although genes on the X chromosome have been implicated in clefting, there has been no association analysis of X-linked markers.
Methodology/Principal Findings
We added new functionalities in the HAPLIN statistical software to enable association analysis of X-linked markers and an exploration of various causal scenarios relevant to orofacial clefts. Genotypes for 48 SNPs in 18 candidate genes on the X chromosome were analyzed in two population-based samples from Scandinavia (562 Norwegian and 235 Danish case-parent triads). For haplotype analysis, we used a sliding-window approach and assessed isolated cleft lip with or without cleft palate (iCL/P) separately from isolated cleft palate only (iCPO). We tested three statistical models in HAPLIN, allowing for: i) the same relative risk in males and females, ii) sex-specific relative risks, and iii) X-inactivation in females. We found weak but consistent associations with the oral-facial-digital syndrome 1 (OFD1) gene (formerly known as CXORF5) in the Danish iCL/P samples across all models, but not in the Norwegian iCL/P samples. In sex-specific analyses, the association with OFD1 was in male cases only. No analyses showed associations with iCPO in either the Norwegian or the Danish sample.
The association of OFD1 with iCL/P is plausible given the biological relevance of this gene. However, the lack of replication in the Norwegian samples highlights the need to verify these preliminary findings in other large datasets. More generally, the novel analytic methods presented here are widely applicable to investigations of the role of X-linked genes in complex traits.
PMCID: PMC3378529  PMID: 22723972
17.  Association between MTHFR C677T and A1298C Polymorphisms and NSCL/P Risk in Asians: A Meta-Analysis 
PLoS ONE  2014;9(3):e88242.
Several studies have reported the association between methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms and nonsyndromic cleft lip with or without palate (NSCL/P) in Asian populations. However, findings have been conflicting. In order to investigate the association, a meta-analysis was performed.
We searched Pubmed, MedLine and EmBase database to selected eligible studies. The pooled odds ratios (ORs) with 95% confidence intervals (95%CIs) were calculated using fixed effects model or random effects model to assess the association between MTHFR polymorphisms and NSCL/P in both Asian children and mothers.
Finally, nine case-control studies were included. Overall, the MTHFR C677T polymorphism and NSCL/P showed pooled ORs (95%CI) of 1.41(1.23–1.61) in Asian children, and 1.70(1.19–2.42) in Asian mothers. Subgroup analyses by geographical locations further identified the association in Eastern Asian children, Western/Central Asian children and mothers, but not in Eastern Asian mothers. However, no significant relationship between MTHFR A1298C polymorphism and NSCL/P was found in this meta-analysis.
The MTHFR 677T allele was associated with an increased risk of NSCL/P in Asian populations.
PMCID: PMC3962346  PMID: 24658649
18.  Maternal Supplementary Folate Intake, Methylenetetrahydrofolate Reductase (MTHFR) C677T and A1298C Polymorphisms and the Risk of Orofacial Cleft in Iranian Children 
The purpose of this study was to describe the association of MTHFR gene single nucleotide polymorphisms (C677T and A1298C) and maternal supplementary folate intake with orofacial clefts in the Iranian population.
In this case-control study, peripheral venous blood was taken from 65 patients with orofacial clefts and 215 unaffected controls for DNA extraction and kept in EDTA for further analysis. The genotyping was carried out using Polymerase Chain Reaction (PCR) followed by Restriction Fragment Length Polymorphism (RFLP) and gel electrophoresis. Data were analyzed using Chi square test and logistic regression tests.
Genotype frequencies of 677TT were reported to be 13.5 and 36.1% in controls and CL/P patients, respectively, which showed a significant difference compared to CC as reference (OR=4.118; 95% CI=1.997–8.492; p=0.001). Conversely, 1298CC with frequencies of 10.8 and 12.7% in controls and patients, respectively, showed no significant difference compared to AA (OR=2.359; 95% CI=0.792–7.023; p=0.123). Comparing patients whose mothers did not report the folate supplement intake during pregnancy, to controls, it was observed that lack of folate intake was a predisposing factor for having a child with oral clefts (OR=5/718, p=0.000).
Children carrying the 677TT variant of the MTHFR gene may have an increased risk of CL/P. In addition, the finding that the risk associated with this allele was obviously higher when the mothers didn’t use folic acid, supports the hypothesis that folic acid may play a role in the etiology of CL/P.
PMCID: PMC4483319  PMID: 26140186
Cleft lip; Cleft palate; Genes; Polymorphism
19.  Oral Clefts and Maternal Biomarkers of Folate-Dependent One-Carbon Metabolism in Utah 
Maternal folate intake and related biomarkers have been inconsistently associated with a risk of oral clefts.
Maternal concentrations of plasma folate (PF) and erythrocyte folate (EF), plasma pyridoxal-5′-phosphate (PLP; active vitamin B6) and total plasma homocysteine (tHcy) were measured in a Utah study with 347 cases and 469 controls.
Risk of all clefts combined, including cleft lip with or without cleft palate (CL/P) and cleft palate only (CP), was 65% lower in the highest versus lowest PF quartile (odds ratio [OR], 0.35; 95% confidence interval [CI], 0.23–0.53; p-trend < 0.001). Results remained significant in the subgroups with isolated CL/P and CP (p-trend < 0.001 in each). EF results were similar. In the highest versus lowest PLP quartile, risk of CP with other malformations was lower (OR, 0.25; 95% CI, 0.07–0.95); however, no other associations were significant for PLP or tHcy. Differences in mean bio-marker levels between cases and controls widened with an increasing interval between delivery and maternal blood collection. Decreased cleft risk with increasing quartiles of PF, EF, and PLP and decreasing tHcy was more apparent in mothers with a longer versus shorter interval between the index child delivery and blood collection.
Low maternal blood folate concentration was associated with an increased risk of clefts, and the differences in mean case and control PF, EF, PLP, and tHcy concentrations widened over time. Additional mechanistic studies are warranted to elucidate whether an acquired or inherited disorder of folate metabolism plays a role in the etiology of clefts.
PMCID: PMC4703080  PMID: 21290562
oral cleft; folate; vitamin B6; homocysteine; case-control study
20.  A Multisite Study of Oral Clefts and Associated Abnormalities in Thailand: The Epidemiologic Data 
This study aimed to obtain epidemiological data of birth incidences of cleft lips and/or cleft palates (CLP) in the Thai population with associated risk factors.
The data were collected for a period of 12 months between 2003 and 2004 for infants’ deliveries with CLP and associated risk factors in all hospitals of 6 provinces from 4 regions of Thailand. The birth incidence, related factors with cleft birth, and linkage with geographical area were analyzed by the geographic information system.
Phitsanulok, Saraburi, and Khon Kaen had higher birth incidences for CLP of 2.01, 1.69, and 1.66 per 1000 live births, respectively, and the overall birth incidence was 1.51 per 1000 live births. There were a total of 112 cleft births (61 males and 51 females) with 43 cleft lips, 18 cleft palates, and 51 cleft lips + cleft palates. The northeast region had infants with different gestational ages at birth and mothers with higher intakes of vitamins and a use of vitamin A supplement or retinoic acid than others. A use of folic acid supplement was low in all 4 regions.
The varied incidence of CLP may reflect the incomplete accuracy of case ascertainment. A number of challenges were addressed. The geographic information system was helpful for more background investigation and planning of cleft care management. Our study enables future studies of etiological factors and future birth registries.
PMCID: PMC4727692  PMID: 26894008
21.  Cleft lip and Palate: A 30-year Epidemiologic Study in North-East of Iran 
Cleft lip and palate are among the most common congenital anomalies worldwide. This study was conducted in order to explore the incidence and related factors of cleft lip and/or palate (CL/P) among live births in Mashhad, North-Eastern Iran.
Materials and Methods:
In this cross-sectional study, records of 28,519 infants born between March 1982 and March 2011 at three major hospitals in Mashhad were screened for oral clefts. Clinical and demographic factors relating to diagnosed cases, including birth date, gender, birth weight, maternal age, number of pregnancies, type and side of cleft and presence of other congenital anomalies were recorded for analysis.
The overall incidence of CL/P was 1.9 per 1,000 live births. Cleft lip associated with cleft palate (CLP) was the most prevalent type of cleft (50%), followed by isolated cleft lip (35.2%) and isolated cleft palate (14.8%). A total of 92.6% of oral clefts were bilateral and 5.5% were located on the right side. In addition, clefts were found to be more common in male than female births (male/female ratio=2.3). The rate of associated congenital anomalies in CL/P newborns was 37%. No significant differences were observed in the incidence of oral clefts across three decades of study; except for CLP which was significantly more prevalent between 2002–2011 (P=0.027). There were no significant differences with regard to season of birth, associated anomalies or maternal age of affected newborns in the three time periods of the study. Furthermore, maternal age and number of pregnancies were not significantly different among the three types of cleft (P=0.43 and P=0.91, respectively). Although the mean birth weight of patients affected with isolated cleft palate was considerably lower than that of the other two types of cleft, the difference was not statistically significant (P=0.05).
This study indicates a frequency of CL/P close to the findings in East Asian countries and higher than some previous reports from Iran, European and American countries. Ethnicity-related genetic factors may have a role in the conflicting results obtained from different populations.
PMCID: PMC4344973  PMID: 25745610
Cleft lip; Cleft palate; Epidemiology; Incidence; Iran
22.  An assessment of orofacial clefts in Tanzania 
BMC Oral Health  2011;11:5.
Clefts of the lip (CL), the palate (CP), or both (CLP) are the most common orofacial congenital malformations found among live births, accounting for 65% of all head and neck anomalies. The frequency and pattern of orofacial clefts in different parts of the world and among different human groups varies widely. Generally, populations of Asian or Native American origin have the highest prevalence, while Caucasian populations show intermediate prevalence and African populations the lowest. To date, little is known regarding the epidemiology and pattern of orofacial clefts in Tanzania.
A retrospective descriptive study was conducted at Bugando Medical Centre to identify all children with orofacial clefts that attended or were treated during a period of five years. Cleft lip and/or palate records were obtained from patient files in the Hospital's Departments of Surgery, Paediatrics and medical records. Age at presentation, sex, region of origin, type and laterality of the cleft were recorded. In addition, presence of associated congenital anomalies or syndromes was recorded.
A total of 240 orofacial cleft cases were seen during this period. Isolated cleft lip was the most common cleft type followed closely by cleft lip and palate (CLP). This is a departure from the pattern of clefting reported for Caucasian and Asian populations, where CLP or isolated cleft palate is the most common type. The distribution of clefts by side showed a statistically significant preponderance of the left side (43.7%) (χ2 = 92.4, p < 0.001), followed by the right (28.8%) and bilateral sides (18.3%). Patients with isolated cleft palate presented at very early age (mean age 1.00 years, SE 0.56). Associated congenital anomalies were observed in 2.8% of all patients with orofacial clefts, and included neural tube defects, Talipes and persistent ductus arteriosus.
Unilateral orofacial clefts were significantly more common than bilateral clefts; with the left side being the most common affected side. Most of the other findings did not show marked differences with orofacial cleft distributions in other African populations.
PMCID: PMC3039542  PMID: 21288337
23.  5,10-Methylenetetrahydrofolate Reductase 677 and 1298 Polymorphisms, Folate Intake, and Microsatellite Instability in Colon Cancer 
The 5,10-methylenetetrahydrofolate reductase (MTHFR) gene plays a critical role in folate metabolism. Studies on the association between MTHFR polymorphisms and length changes in short tandem repeat DNA sequences [microsatellite instability (MSI)] are inconsistent. Using data from colon cancer cases (n = 503) enrolled as part of an existing population-based case-control study, we investigated the association between MTHFR 677 and MTHFR 1298 polymorphisms and MSI. We also examined whether the association was modified by folate intake. Participants were case subjects enrolled as part of the North Carolina Colon Cancer Study. Consenting cases provided information about lifestyle and diet during in-home interviews as well as blood specimens and permission to obtain tumor blocks. DNA from normal and tumor tissue sections was used to determine microsatellite status (MSI). Tumors were classified as MSI if two or more microsatellite markers (BAT25, BAT26, D5S346, D2S123, and D17S250) had changes in the number of DNA sequence repeats compared with matched nontumor tissue. Tumors with one positive marker (MSI-low) or no positive markers (microsatellite stable) were grouped together as non-MSI tumors (microsatellite stable). MTHFR 677 and MTHFR 1298 genotypes were determined by real-time PCR using the 5′ exonuclease (Taqman) assay. Logistic regression was used to calculate odds ratio (OR) and 95% confidence intervals (95% CI). MSI was more common in proximal tumors (OR, 3.8; 95% CI, 1.7–8.4) and in current smokers (OR, 4.0; 95% CI, 1.6–9.7). Compared with MTHFR 677 CC referent, MTHFR 677 CT/TT genotype was inversely associated with MSI among White cases (OR, 0.36; 95% CI, 0.16–0.81) but not significant among African Americans. Although not statistically significant, a similar inverse association was observed between MTHFR 677 CT/TT genotype and MSI among the entire case subjects (OR, 0.54; 95% CI, 0.26–1.10). Among those with adequate folate intake (>400 μg total folate), we found strong inverse associations between combined MTHFR genotypes and MSI (677 CC + 1298 AC/CC, OR, 0.09; 95% CI, 0.01–0.59; 677 CT/TT + 1298 AA, OR, 0.13; 95% CI, 0.02–0.85) compared with the combined wild-type genotypes (677 CC + 1298 AA). This protective effect was not evident among those with low folate (<400 μg total folate) intake. Our results suggest that MTHFR variant genotypes are associated with reduced risk of MSI tumors under conditions of adequate folate intake, although the data are imprecise due to small numbers. These results indicate that the relationship between MTHFR genotypes and MSI is influenced by folate status.
PMCID: PMC4540476  PMID: 16103455
24.  MTHFD1 gene polymorphisms as risk factors involved in orofacial cleft: an independent case-control study and a meta-analysis 
Background: Orofacial clefts (OFCs) were among the most familiar birth defects in the world, which had been reported to be influenced by the folic acid ingestion in pregnancy previously. Methylenetetrahydrofolate dehydrogenase1 (MTHFD1) gene was associated with the susceptibility of OFCs through a complex metabolism correlate with folic acid. The aim of our study was to evaluate the correlation of five single-nucleotide polymorphisms (SNPs) within MTHFD1 related to the OFCs risk in a Chinese population. Methods: By the use of polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), we genotyped 5 filtered SNPs (identified by Haploview 4.2 software with HapMap databases) on MTHFD1 gene: 118913T>C, 31136A>G, 58893A>G, 1958G>A and 61869T>C of 216 subjects (108 OFCs cases and 108 healthy controls) from a Chinese population. The association between these SNPs and OFCs risk was investigated by student t-test, one-way analysis of variance (ANOVA) and chi-square test with GraphPad Prism 5.0 software. Furthermore, we also performed a meta-analysis of relevant studies to investigate the association between MTHFD1 1958G>A and the susceptibility of OFCs. Results: Through the genotyping, the AA genotype was found significantly correlated with the susceptibility of OFCs compared with other SNPs on MTHFD1, yielding an OR of 2.71 (95% CI = 1.12-6.58, P = 0.025) under the homozygous model and an OR of 2.37 (95% CI = 1.06-5.30, P = 0.033) under the recessive model. While other selected SNPs 118913T>C and 31136A>G were also associated with an increased OFC risk, the results were not statistically significant (all P > 0.05). However, the overall result of meta-analysis did not support the conclusion that the 1958G>A variant could be a genetic susceptible factor for OFCs (A allele vs. G allele: OR = 1.02, 95% CI = 0.85-1.23, AA vs. GG: OR = 1.06, 95% CI = 0.69-1.63, GA vs. GG: OR = 1.02, 95% CI = 0.81-1.27, AA vs. GG+GA: OR = 0.94, 95% CI = 0.61-1.46, AA+GA vs. GG: OR = 0.94, 95% CI = 0.74-1.19). Conclusions: The MTHFD1 1958G>A variant was significantly associated with the increased OFCs risk in Chinese population. However, this association was not supported by meta-analysis of all relevant studies. Further investigations about functional impact of this polymorphism were needed.
PMCID: PMC4509269  PMID: 26221324
Orofacial cleft; methylenetetrahydrofolate dehydrogenase (MTHFD1); polymorphism; folate metabolism
25.  Analysis of MTHFR Gene C.677C>T and C.1298A>C Polymorphisms in Iranian Patients with Non-Syndromic Cleft Lip and Palate 
Iranian Journal of Public Health  2014;43(6):821-827.
Non-syndromic cleft lip with or without cleft palate (nsCL/P) is one of the most common congenital abnormalities of the orofacial region with a multifactorial etiology. The present study aimed to investigate the association of two common polymorphisms of methylenetetrahydrofolate reductase (MTHFR) gene (c.677C>T and c.1298A>C) with the occurrence of nsCL/P in an Iranian population.
Forty-five nsCL/P patients, 43 mothers of patients, and 101 unrelated controls participated in the present study. Analysis of c.677C>T and c.1298A>C polymorphisms in MTHFR gene was conducted using polymerase chain reaction and restriction enzyme digestions.
There was no statistical difference in genotype and allele frequencies for c.677C>T variants between patients or their mothers and the control group. However, differences in the frequencies of alleles and genotypes of c.1298A>C polymorphism were statistically significant between patients and control group (P=0.01 for alleles and P=0.005 for genotypes). The odds ratios (OR) for the CC versus AA homozygotes were 6.1 (95% CI 1.8-20.5) and 4.2 (95% CI 1.1-15.4), in patients and mothers, respectively.
We found no association between genetic polymorphism of MTHFR c.677C>T and the risk of nsCL/P in the population studied. Yet the results suggested that c.1298A>C polymorphism of MTHFR gene may be a risk factor for the occurrence of nsCL/P in the Iranian population.
PMCID: PMC4475601  PMID: 26110153
MTHFR; Folic acid; Methylenetetrahydrofolate reductase; Cleft Lip; Cleft palate; Non-syndromic cleft

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