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1.  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.†
doi:10.1002/ajmg.a.32162
PMCID: PMC2366099  PMID: 18203168
alleles; cleft lip; cleft palate; dietary supplements; folic acid; metabolism; humans; single nucleotide polymorphisms
2.  Oral Cleft Defects and Maternal Exposure to Ambient Air Pollutants in New Jersey 
Background
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.
Methods
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).
Results
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.
Conclusion
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.
doi:10.1002/bdra.20650
PMCID: PMC2862481  PMID: 20146378
3.  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.
doi:10.4317/medoral.19796
PMCID: PMC4259380  PMID: 25129243
4.  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.
BACKGROUND
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.
METHODS
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.
RESULTS
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.
CONCLUSIONS
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.
doi:10.1093/humrep/der144
PMCID: PMC3137385  PMID: 21576080
neural tube defects; oral facial clefts; folic acid; folate receptor; maternal autoantibodies
5.  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.
doi:10.1002/gepi.20376
PMCID: PMC2677659  PMID: 19048631
cleft lip; cleft palate; dietary supplements; folic acid; genetics; metabolism; vitamin A
6.  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.
Background
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).
Methods
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.
Results
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.
Conclusions
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.
doi:10.1186/1471-2350-13-29
PMCID: PMC3419639  PMID: 22520921
7.  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.
doi:10.1002/gepi.20314
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
8.  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.
doi:10.1158/1055-9965.EPI-09-0841
PMCID: PMC2880712  PMID: 20447924
Plasma folate; genetic variants; colorectal cancer; prospective study
9.  X-Linked Genes and Risk of Orofacial Clefts: Evidence from Two Population-Based Studies in Scandinavia 
PLoS ONE  2012;7(6):e39240.
Background
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.
Conclusions
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.
doi:10.1371/journal.pone.0039240
PMCID: PMC3378529  PMID: 22723972
10.  Association between MTHFD1 G1958A Polymorphism and Neural Tube Defects Susceptibility: A Meta-Analysis 
PLoS ONE  2014;9(6):e101169.
Objectives
The methylenetetrahydrofolate dehydrogenase (MTHFD1) gene, as one of the key genes involved in the folate pathway, has been reported to play a critical role in the pathogenesis of neural tube defects (NTDs). However, the results of published studies are contradictory and inconclusive. Thus, this meta-analysis aimed to evaluate the effect of the common polymorphism in the MTHFD1 gene, the G1958A (R653Q, dbSNP ID: rs2236225) variant, on the risk of NTDs in all eligible studies.
Methods
Relevant literature published before January 3, 2014 was retrieved from the MEDLINE, EMBASE, Cochrane Library, and CBM databases. Pooled crude odds ratios (ORs) and their corresponding 95% confidence intervals (CIs) were calculated to evaluate the association between the MTHFD1 G1958A polymorphism and NTDs risk.
Results
We performed a meta-analysis of nine studies with a total of 4,302 NTDs patients and 4,238 healthy controls. Our results demonstrated a significant correlation between the MTHFD1 G1958A polymorphism and NTDs in an overall meta-analysis. For family-based studies, the study subjects were classified as NTD cases, mothers with NTDs offspring, and fathers with NTDs offspring. We found no association between any of the fathers’ genotypes and NTDs, whereas there was a clear excess of the 1958A allele in the mothers of children with NTDs compared with controls individuals.
Conclusions
In summary, our meta-analysis strongly suggests that the MTHFD1 G1958A polymorphism might be associated with maternal risk for NTDs in Caucasian populations. However, the evidence of this association should be interpreted with caution due to the selective nature of publication of genetic association studies.
doi:10.1371/journal.pone.0101169
PMCID: PMC4076264  PMID: 24977710
11.  Evaluation of common genetic variants in 82 candidate genes as risk factors for neural tube defects 
BMC Medical Genetics  2012;13:62.
Background
Neural tube defects (NTDs) are common birth defects (~1 in 1000 pregnancies in the US and Europe) that have complex origins, including environmental and genetic factors. A low level of maternal folate is one well-established risk factor, with maternal periconceptional folic acid supplementation reducing the occurrence of NTD pregnancies by 50-70%. Gene variants in the folate metabolic pathway (e.g., MTHFR rs1801133 (677 C > T) and MTHFD1 rs2236225 (R653Q)) have been found to increase NTD risk. We hypothesized that variants in additional folate/B12 pathway genes contribute to NTD risk.
Methods
A tagSNP approach was used to screen common variation in 82 candidate genes selected from the folate/B12 pathway and NTD mouse models. We initially genotyped polymorphisms in 320 Irish triads (NTD cases and their parents), including 301 cases and 341 Irish controls to perform case–control and family based association tests. Significantly associated polymorphisms were genotyped in a secondary set of 250 families that included 229 cases and 658 controls. The combined results for 1441 SNPs were used in a joint analysis to test for case and maternal effects.
Results
Nearly 70 SNPs in 30 genes were found to be associated with NTDs at the p < 0.01 level. The ten strongest association signals (p-value range: 0.0003–0.0023) were found in nine genes (MFTC, CDKN2A, ADA, PEMT, CUBN, GART, DNMT3A, MTHFD1 and T (Brachyury)) and included the known NTD risk factor MTHFD1 R653Q (rs2236225). The single strongest signal was observed in a new candidate, MFTC rs17803441 (OR = 1.61 [1.23-2.08], p = 0.0003 for the minor allele). Though nominally significant, these associations did not remain significant after correction for multiple hypothesis testing.
Conclusions
To our knowledge, with respect to sample size and scope of evaluation of candidate polymorphisms, this is the largest NTD genetic association study reported to date. The scale of the study and the stringency of correction are likely to have contributed to real associations failing to survive correction. We have produced a ranked list of variants with the strongest association signals. Variants in the highest rank of associations are likely to include true associations and should be high priority candidates for further study of NTD risk.
doi:10.1186/1471-2350-13-62
PMCID: PMC3458983  PMID: 22856873
Neural tube defects; Spina bifida; Folic acid; One-carbon metabolism; Candidate gene
12.  Association between MTHFR C677T and A1298C Polymorphisms and NSCL/P Risk in Asians: A Meta-Analysis 
PLoS ONE  2014;9(3):e88242.
Objective
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.
Methods
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.
Results
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.
Conclusions
The MTHFR 677T allele was associated with an increased risk of NSCL/P in Asian populations.
doi:10.1371/journal.pone.0088242
PMCID: PMC3962346  PMID: 24658649
13.  An assessment of orofacial clefts in Tanzania 
BMC Oral Health  2011;11:5.
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1186/1472-6831-11-5
PMCID: PMC3039542  PMID: 21288337
14.  Folate-related gene variants in Irish families affected by neural tube defects 
Frontiers in Genetics  2013;4:223.
Periconceptional folic acid use can often prevent neural tube defects (NTDs). Variants of genes involved in folate metabolism in mothers and children have been associated with occurrence of NTDs. We identified Irish families with individuals affected by neural tube defects. In these families, we observed that neural tube defects and birth defects overall occurred at a higher rate in the maternal lineage compared with the paternal lineage. The goal of this study was to look for evidence for genetic effects that could explain the discrepancy in the occurrence of these birth defects in the maternal vs. paternal lineage. We genotyped blood samples from 322 individuals from NTD-affected Irish families, identified through their membership in spina bifida associations. We looked for differences in distribution in maternal vs. paternal lineages of five genetic polymorphisms: the DHFR 19 bp deletion, MTHFD1 1958G>A, MTHFR 1298A>C, MTHFR 677C>T, and SLC19A1 80A>G. In addition to looking at genotypes individually, we determined the number of genotypes associated with decreased folate metabolism in each relative (“risk genotypes”) and compared the distribution of these genotypes in maternal vs. paternal relatives. Overall, maternal relatives had a higher number of genotypes associated with lower folate metabolism than paternal relatives (p = 0.017). We expected that relatives would share the same risk genotype as the individuals with NTDs and/or their mothers. However, we observed that maternal relatives had an over-abundance of any risk genotype, rather than one specific genotype. The observed genetic effects suggest an epigenetic mechanism in which decreased folate metabolism results in epigenetic alterations related to the increased rate of NTDs and other birth defects seen in the maternal lineage. Future studies on the etiology of NTDs and other birth defects could benefit from including multigenerational extended families, in order to explore potential epigenetic mechanisms.
doi:10.3389/fgene.2013.00223
PMCID: PMC3818582  PMID: 24223580
neural tube defects; folate metabolism; DHFR 19bp deletion; MTHFD1 1958G>A; MTHFR 1298A>C; MTHFR 677C>T; SLC19A1 80A>G; maternal inheritance
15.  First-Trimester Maternal Alcohol Consumption and the Risk of Infant Oral Clefts in Norway: A Population-based Case-Control Study 
American Journal of Epidemiology  2008;168(6):638-646.
Although alcohol is a recognized teratogen, evidence is limited on alcohol intake and oral cleft risk. The authors examined the association between maternal alcohol consumption and oral clefts in a national, population-based case-control study of infants born in 1996–2001 in Norway. Participants were 377 infants with cleft lip with or without cleft palate, 196 with cleft palate only, and 763 controls. Mothers reported first-trimester alcohol consumption in self-administered questionnaires completed within a few months after delivery. Logistic regression was used to calculate odds ratios and 95% confidence intervals, adjusting for confounders. Compared with nondrinkers, women who reported binge-level drinking (≥5 drinks per sitting) were more likely to have an infant with cleft lip with or without cleft palate (odds ratio = 2.2, 95% confidence interval: 1.1, 4.2) and cleft palate only (odds ratio = 2.6, 95% confidence interval: 1.2, 5.6). Odds ratios were higher among women who binged on three or more occasions: odds ratio = 3.2 for cleft lip with or without cleft palate (95% confidence interval: 1.0, 10.2) and odds ratio = 3.0 for cleft palate only (95% confidence interval: 0.7, 13.0). Maternal binge-level drinking may increase the risk of infant clefts.
doi:10.1093/aje/kwn186
PMCID: PMC2727199  PMID: 18667525
alcohol drinking; cleft lip; cleft palate
16.  Maternal Periconceptional Smoking and Alcohol Consumption and Risk for Select Congenital Anomalies 
BACKGROUND
This study examined the association between maternal smoking and alcohol use (including binge drinking) during the periconceptional period (i.e., 2 months before through 2 months after conception) and the risk of orofacial clefts, NTDs, and conotruncal heart defects in offspring.
METHODS
Data were drawn from a population-based case-control study of fetuses and live-born infants among a cohort of California births between July 1999 and June 2003. The 1,355 cases comprised of 701 orofacial clefts, 337 NTDs, and 323 conotruncal heart defects. Information on smoking and alcohol consumption was obtained via telephone interviews with mothers of 1,355 (80% of eligibles) cases and 700 (77% of eligibles) nonmalformed, live-born controls.
RESULTS
Maternal smoking of five cigarettes or less per day was associated with reduced risks of NTDs (OR 0.7; 95% CI: 0.3, 1.4), whereas the risk associated with higher cigarette consumption was lower for conotruncal heart defects (OR 0.5; 95% CI: 0.2, 1.2). Maternal intake of alcohol less than 1 day per week was associated with a 1.6- to 2.1-fold higher risk of NTDs (95% CI: 0.9, 2.6), d-transposition of the great arteries (95% CI: 1.1, 3.2), and multiple cleft lip with or without cleft palate (CLP) (95% CI: 0.8, 4.5). Risks associated with more frequent alcohol intake were 2.1 for NTDs (95% CI: 1.1, 4.0) and 2.6 for multiple CLP (95% CI: 1.1, 6.1).
CONCLUSIONS
This study observed that maternal alcohol intake increased the risk for d-transposition of the great arteries, NTDs, and multiple CLP in infants. By contrast, smoking was associated with a lower risk of NTDs and conotruncal heart defects.
doi:10.1002/bdra.20461
PMCID: PMC2861577  PMID: 18481814
smoking; alcohol; drinking; conotruncal heart defect; NTDs; clefts; congenital anomalies; pregnancy
17.  MTHFR rs1801133 C>T polymorphism is associated with an increased risk of tetralogy of Fallot 
Biomedical Reports  2014;2(2):172-176.
Abnormal folate metabolism and common variants of folate-metabolizing enzymes have been described as possible risk factors for congenital heart disease (CHD). Two important folate-metabolizing enzymes involved in the folate/homocysteine metabolic pathway are 5,10-methylenetetrahydrofolate reductase (MTHFR) and methylenetetrahydrofolate dehydrogenase 1 (MTHFD1). MTHFR and MTHFD1 polymorphisms may be associated with CHD susceptibility. To evaluate the impact of MTHFR and MTHFD1 single-nucleotide polymorphisms (SNPs) on CHD susceptibility, we genotyped functional MTHFR SNPs rs1801133 C>T, rs1801131 A>C and rs2274976 G>A, and MTHFD SNPs rs2236225 C>T, rs1950902 G>A and rs1076991 A>G in a hospital-based case-control study of 173 tetralogy of Fallot (TOF) cases and 207 non-CHD controls. When MTHFR rs1801133 CC homozygote genotype was used as the reference group, the TT genotype was associated with a significantly increased risk for TOF [TT vs. CC: odds ratio (OR)=1.67; 95% confidence interval (CI): 1.01–2.75; P=0.046]. In the recessive model, when MTHFR rs1801133 CC/CT genotype was used as the reference group, the TT homozygote genotype was associated with a significantly increased risk for TOF (OR=1.81, 95% CI: 1.15–2.84; P=0.010). In conclusion, our findings suggest that MTHFR rs1801133 C>T polymorphism may play a role in susceptibility for TOF. Large-scale studies with a more rigorous study design including diverse ethnic populations are required to confirm these findings.
doi:10.3892/br.2014.222
PMCID: PMC3917760  PMID: 24649091
5,10-methylenetetrahydrofolate reductase; congenital heart disease; polymorphisms; tetralogy of Fallot; molecular epidemiology
18.  Anatomical Variations in Clefts of the Lip with or without Cleft Palate 
Plastic Surgery International  2012;2012:542078.
Objective. Few orofacial cleft (OFC) studies have examined the severity of clefts of the lip or palate. This study examined associations between the severity of cleft of the lip with cleft type, laterality, and sex in four regional British Isles cleft registers whilst also looking for regional variations. Design. Retrospective analysis of cleft classification in the data contained in these four cleft registers. Sample. Three thousand and twelve patients from cleft registers based in Scotland, East England, Merseyside, and Belfast were sourced from the period 2002–2010. Submucous clefts and syndromic clefts were included whilst stillbirths, abortuses, and atypical orofacial clefts were excluded. Results. A cleft of the lip in CLP patients is more likely to be complete in males. A cleft of the lip in isolated CL patients is more likely to be complete in females. Variation in the proportion of cleft types was evident between Scotland and East England. Conclusions. Association between severity of cleft of the lip and sex was found in this study with females having a significantly greater proportion of more severe clefts of the lip (CL) and CLP males being more severe (P < 0.0003). This finding supports a fundamental difference between cleft aetiology between CL and CLP.
doi:10.1155/2012/542078
PMCID: PMC3517834  PMID: 23251795
19.  Association of Methylenetetrahydrofolate Dehydrogenase 1 Polymorphisms with Cancer: A Meta-Analysis 
PLoS ONE  2013;8(7):e69366.
Background
Studies investigating the association between single-nucleotide polymorphisms (SNPs) of the methylenetetrahydrofolate dehydrogenase 1 (MTHFD1) and cancer risk report conflicting results. To derive a more precise estimation of the relationship between MTHFD1 polymorphisms and cancer risk, the present meta-analysis was carried out.
Methodology/Principal Findings
A comprehensive search was conducted to determine all the eligible studies about MTHFD1 polymorphisms and cancer risk. Combined odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the strength of the association between the MTHFD1 polymorphisms and cancer risk. We investigated by meta-analysis the effects of 2 polymorphisms in MTHFD1: G1958A (17 studies, 12348 cases, 44132 controls) and G401A (20 studies, 8446 cases, 14020 controls). The overall results indicated no major influence of these 2 polymorphisms on cancer risk. For G1958A, a decreased cancer risk was found in acute lymphoblastic leukemia (ALL)/Asians (the dominant: OR = 0.74, 95% CI = 0.58–0.94, P = 0.01; allelic: OR = 0.80, 95% CI = 0.65–0.99, P = 0.04) and other cancers (recessive: OR = 0.80, 95% CI = 0.66–0.96, P = 0.02). For G401A, the data showed that MTHFD1 G401A polymorphism was associated with a decreased colon cancer risk under dominant model (OR = 0.89, 95% CI = 0.80–0.99, P = 0.04).
Conclusions
The results suggest that MTHFD1 G1958A polymorphism might be associated with a decreased risk of ALL and other cancers. Meanwhile, the MTHFD1 G401A might play a protective role in the development of colon cancer. Large-scale and well-designed case-control studies are necessary to validate the risk identified in the present meta-analysis.
doi:10.1371/journal.pone.0069366
PMCID: PMC3716643  PMID: 23894459
20.  The Folate Pathway and Nonsyndromic Cleft Lip and Palate 
Nonsyndromic cleft lip with or without cleft palate (NSCLP) is a common birth malformation caused by genetic, environmental and gene-environment interactions. Periconceptional supplementation with folic acid, a key component in DNA synthesis and cell division, has reduced the birth prevalence of neural tube defects (NTDs) and may similarly reduce the birth prevalence of other complex birth defects including NSCLP. Past studies investigating the role of two common methylenetetrahydrofolate reductase (MTHFR) SNP polymorphisms, C677T (rs1801133) and A1298C (rs1801131), in NSCLP have produced conflicting results. Most studies of folate pathway genes have been limited in scope, as few genes/SNPs have been interrogated. In this study, we asked whether variations in a more comprehensive group of folate pathway genes were associated with NSCLP and, if so, were there detectable interactions between these genes and environmental exposures. In addition, we evaluated the data for a sex effect. Fourteen folate metabolism related genes were interrogated using eighty-nine SNPs in multiplex and simplex non-Hispanic White (NHW) (317) and Hispanic (128) NSCLP families. Evidence for a risk association between NSCLP and SNPs in nitrous oxide 3 (NOS3) and thymidylate synthetase (TYMS) was detected in the NHW group, whereas associations with methionine synthase (MTR), betaine-homocysteine methyltransferase (BHMT2), MTHFS and SLC19A1 were detected in the Hispanic group. Evidence for over-transmission of haplotypes and gene interactions in the methionine arm was detected. These results suggest that perturbations of the genes in the folate pathway may contribute to NSCLP. There was evidence for an interaction between several SNPs and maternal smoking, and for one SNP with sex of the offspring. These results provide support for other studies that suggest that high maternal homocysteine levels may contribute to NSCLP and should be further investigated.
doi:10.1002/bdra.20740
PMCID: PMC4098909  PMID: 21254359
Nonsyndromic cleft lip and palate; NSCLP; folate metabolism; association; genetics; homocysteine; methionine
21.  Gene–gene interaction in folate-related genes and risk of neural tube defects in a UK population 
Journal of Medical Genetics  2004;41(4):256-260.
Objective: To investigate the contribution of polymorphic variation in genes involved in the folate-dependent homocysteine pathway in the aetiology of neural tube defects (NTD).
Design: Case-control association study.
Subjects: A total of 530 individuals from families affected by NTD, 645 maternal controls, and 602 healthy newborn controls from the northern UK.
Main outcome measures: Seven polymorphisms in six genes coding for proteins in the folate-dependent homocysteine pathway (MTHFR 677C→T, MTHFR 1298A→C, MTRR 66A→G, SHMT 1420C→T, CßS 844ins68, GCPII 1561C→T, RFC-1 80G→A). The impact of each polymorphism and the effect of gene–gene interactions (epistasis) upon risk of NTD were assessed using logistic regression analysis.
Results: The MTHFR 677C→T polymorphism was shown to represent a risk factor in NTD cases (CC v CT+TT odds ratio (OR) 2.03 [95% confidence interval (CI) 1.09, 3.79] p = 0.025) and the MTRR 66A→G polymorphism was shown to exert a protective effect in NTD cases (AA v AG+GG OR 0.31 [95% CI 0.10, 0.94] p = 0.04). When statistical tests for interaction were conducted, three genotype combinations in cases (MTRR/GCPII; MTHFR 677/CßS; MTHFR 677/MTRR) and one combination in case mothers (CßS/RFC-1) were shown to elevate NTD risk. Maternal–fetal interaction was also detected when offspring carried the MTHFR 677C→T variant and mothers carried the MTRR 66A→G variant, resulting in a significantly elevated risk of NTD.
Conclusion: Both independent genetic effects and gene–gene interaction were observed in relation to NTD risk. Multi-locus rather than single locus analysis might be preferable to gain an accurate assessment of genetic susceptibility to NTD.
doi:10.1136/jmg.2003.010694
PMCID: PMC1735724  PMID: 15060097
22.  Gene Variants in the Folate-mediated One-carbon Metabolism (FOCM) Pathway as Risk Factors for Conotruncal Heart Defects 
We evaluated 35 variants among four folate-mediated one-carbon metabolism pathway genes, MTHFD1, SHMT1, MTHFR, and DHFR as risk factors for conotruncal heart defects. Cases with a diagnosis of single gene disorders or chromosomal aneusomies were excluded. Controls were randomly selected from area hospitals in proportion to their contribution to the total population of live-born infants. Odds Ratios (OR) and the 95% confidence intervals were computed for each genotype (homozygous variant or heterozygote, versus homozygous wildtype) and for increase of each less common allele (log-additive model). Interactions between each variant and three folate intake variables (maternal multivitamin use, maternal dietary folate intake, and combined maternal folate intake) were also evaluated under the log-additive model. In general, we did not identify notable associations. The A allele of MTHFD1 rs11627387 was associated with a 1.7-fold increase in conotruncal defects risk in both Hispanic mothers (OR=1.7, 95% CI=1.1∼2.5) and Hispanic infants (OR=1.7, 95% CI=1.2∼2.3). The T allele of MTHFR rs1801133 was associated with a 2.8-fold increase of risk among Hispanic women whose dietary folate intake was ≤ 25th centile. The C allele of MTHFR rs1801131 was associated with a two-fold increase of risk (OR=2.0, 95%CI=1.0∼3.9) only among those whose dietary folate intake was >25th centile. Our study suggested that MTHFD1 rs11627387 may be associated with risk of conotruncal defects through both maternal and offspring genotype effect among the Hispanics. Maternal functional variants in MTHFR gene may interact with dietary folate intake and modify the conotruncal defects risk in the offspring.
doi:10.1002/ajmg.a.35313
PMCID: PMC3331895  PMID: 22495907
conotruncal defects; one carbon metabolism; folate; MTHFR; MTHFD1; DHFR; SHMT1
23.  Testing reported associations of genetic risk factors for oral clefts in a large Irish study population 
BACKGROUND
Suggestive, but not conclusive, studies implicate many genetic variants in oral cleft etiology. We used a large, ethnically homogenous study population to test whether reported associations between nonsyndromic oral clefts and 12 genes (CLPTM1, CRISPLD2, FGFR2, GABRB3, GLI2, IRF6, PTCH1, RARA, RYK, SATB2, SUMO1, TGFA) could be confirmed.
METHODS
Thirty-one single nucleotide polymorphisms (SNPs) in exons, splice sites, and conserved non-coding regions were studied in 509 patients with cleft lip with or without cleft palate (CLP), 383 with cleft palate only (CP), 838 mothers and 719 fathers of patients with oral clefts, and 902 controls from Ireland. Case-control and family-based statistical tests were performed using isolated oral clefts for the main analyses.
RESULTS
In case-control comparisons, the minor allele of PTCH1 A562A (rs2066836) was associated with reduced odds of CLP (OR: 0.29, 95% CI: 0.13–0.64 for homozygotes) whereas the minor allele of PTCH1 L1315P (rs357564) was associated with increased odds of CLP (OR: 1.36, 95% CI: 1.07–1.74 for heterozygotes and OR: 1.56, 95% CI: 1.09–2.24 for homozygotes). The minor allele of one SUMO1 SNP, rs3769817 located in intron 2, was associated with increased odds of CP (OR: 1.45, 95% CI: 1.06–1.99 for heterozygotes). Transmission disequilibrium was observed for the minor allele of TGFA V159V (rs2166975) which was over-transmitted to CP cases (P=0.041).
CONCLUSIONS
For 10 of the 12 genes, this is the largest candidate gene study of nonsyndromic oral clefts to date. The findings provide further evidence that PTCH1, SUMO1, and TGFA contribute to nonsyndromic oral clefts.
doi:10.1002/bdra.20639
PMCID: PMC3503531  PMID: 19937600
cleft lip; cleft palate; congenital abnormalities
24.  MTHFR Genetic Polymorphism As a Risk Factor in Egyptian Mothers with Down Syndrome Children 
Disease markers  2007;24(1):19-26.
Recent reports linking Down syndrome (DS) to maternal polymorphisms at the methylenetetrahydrofolate reductase (MTHFR) gene locus have generated great interest among investigators in the field. The present study aimed at evaluation of MTHFR 677C/T and 1298A/C polymorphisms in the MTHFR gene as maternal risk factors for DS. Forty two mothers of proven DS outcomes and forty eight control mothers with normal offspring were included. Complete medical and nutritional histories for all mothers were taken with special emphasis on folate intake. Folic acid intake from food or vitamin supplements was significantly low (below the Recommended Daily Allowance) in the group of case mothers compared to control mothers. Frequencies of MTHFR 677T and MTHFR 1298C alleles were significantly higher among case mothers (32.1% and 57.1%, respectively) compared to control mothers (18.7% and 32.3%, respectively). Heterozygous and homozygous genotype frequencies of MTHFR at position 677 (CT and TT) were higher among case mothers than controls (40.5% versus 25% and 11.9% versus 6.2%, respectively) with an odds ratio of 2.34 (95% confidence interval [CI] 0.93–5.89) and 2.75 (95% CI 0.95–12.77), respectively. Interestingly, the homozygous genotype frequency (CC) at position 1298 was significantly higher in case mothers than in controls (33.3% versus 2.1% respectively) with an odds ratio of 31.5 (95% CI 3.51 to 282.33) indicating that this polymorphism may have more genetic impact than 677 polymorphism. Heterozygous genotype (AC) did not show significant difference between the two groups. We here report on the first pilot study of the possible genetic association between DS and MTHFR 1298A/C genotypes among Egyptians. Further extended studies are recommended to confirm the present work.
doi:10.1155/2008/214027
PMCID: PMC3850629  PMID: 18057532
Methylenetetrahydrofolate reductase (MTHFR); Down syndrome; polymorphism; MTHFR 677C/T polymorphism; MTHFR 1298A/C polymorphism; Egyptian
25.  Maternal and Infant Gene-Folate Interactions and the Risk of Neural Tube Defects 
Neural tube defects (NTDs) are common, serious malformations with a complex etiology that suggests involvement of both genetic and environmental factors. The authors evaluated maternal or offspring folate-related gene variants and interactions between the gene variants and maternal intake of folates on the risk of NTDs in their offspring. A case-control study was conducted on mothers and/or their fetuses and infants who were born in California from 1999–2003 with an NTD (cases n = 222, including 24 mother-infant pairs) or without a major malformation (controls n = 454, including 186 mother-infant pairs). Maternal intake of folates was assessed by food frequency questionnaire and genotyping was performed on samples from mothers and infants. For mothers in the lowest folate-intake group, risk of NTDs in offspring was significantly decreased for maternal MTHFR SNPs rs1476413, rs1801131 and rs1801133 (odds ratio (OR) = 0.55, 80% confidence interval (CI): 0.20, 1.48; OR = 0.58, 80% CI: 0.24, 1.43; OR = 0.69, 80% CI: 0.41, 1.17, respectively), and TYMS SNPs rs502396 and rs699517 (OR= 0.91, 80% CI: 0.53, 1.56; OR = 0.70, 80% CI: 0.38, 1.29). A gene-only effect was observed for maternal SHMT1 SNP rs669340 (OR = 0.69, 95% CI: 0.49, 0.96). When there was low maternal folate intake, risk of NTDs was significantly increased for infant MTHFD1 SNPs rs2236224, rs2236225 and rs11627387 (OR = 1.58, 80% CI: 0.99, 2.51; OR = 1.53, 80% CI: 0.95, 2.47; OR = 4.25, 80% CI: 2.33, 7.75, respectively) and SHMT1 SNP rs12939757 (OR = 2.01, 80% CI: 1.20, 3.37), but decreased for TYMS SNP rs2847153 (OR = 0.73, 80% CI: 0.37, 1.45). Although power to detect interaction effects was low for this birth defects association study, the gene-folate interactions observed in this study represent preliminary findings that will be useful for informing future studies on the complex etiology of NTDs.
doi:10.1002/ajmg.a.35552
PMCID: PMC3448841  PMID: 22903727
Congenital Abnormalities; Folic Acid; Genetic Association Studies; Molecular Epidemiology; Neural Tube Defects; Maternal Nutritional Physiological Phenomena; Nervous System Malformations; Nutrigenomics

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