Studies of reduced folate carrier 1 (<i>RFC1</i>) A80G and 5,10‐methylenetetrahydrofolate reductase (<i>MTHFR</i>) C677T polymorphisms with neural tube and orofacial cleft defects

Vieira, Alexandre R.; Murray, Jeffrey C.; Trembath, Dimitri G.; Orioli, Iêda M.; Castilla, Eduardo E.; Cooper, Margaret E.; Marazita, Mary L.; Lennon-Graham, Felicia; Speer, Marcy C.

doi:10.1002/ajmg.a.30705

Cited by 48 publications

(41 citation statements)

References 36 publications

(24 reference statements)

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“…The reanalysis of the MTHFR data based on maternal origin confirms our previous results in which no association between MTHFR and cleft lip and palate was found (2). On the other hand, it appears that the association between cleft lip only and RFC1 in South Americans relates to ancestral origin that is independent among individuals with maternal lineage containing the mitochondrial DNA haplotype D. The mitochondrial DNA haplotype D is more frequently found among the Aleuts, Amazonian Amerindians, Andean Amerindians, and Patagonian Amerindians.…”

Section: Discussionsupporting

confidence: 77%

“…www.bjournal.com.br this same population was evaluated for genes related to the folate pathway, no association was found between genetic markers in MTHFR (5,10-methylenetetrahydrofolate reductase) or RFC1 (reduced folate carrier 1) and oral clefts (2). Conflicting results have been published regarding the association between cleft lip and palate and MTHFR (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13).…”

Section: Introductionmentioning

confidence: 49%

“…With the exception of our previous report (2), none of the previous studies that investi- Although the biochemical evidence and clinical trial results are nowhere near being consistent and persuasive for a folate effect on oral clefts as they are for a folate effect on neural tube defects, studies such as ours suggest that mutations in genes involved in the folate pathway exist. The relevance of this finding may be dependent on individuals' specific genetic background, in this case, maternal mitochondrial origin.…”

Section: Discussionmentioning

confidence: 81%

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Reduced folate carrier 1 (RFC1) is associated with cleft of the lip only

Vieira

Cooper

Marazita

et al. 2008

Braz J Med Biol Res

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In this report, we have reanalyzed genotyping data in a collection of families from South America based on maternal origin. Genotyping analysis was performed at the Craniofacial Anomalies Research Center at the University of Iowa. These genotypes were derived from genomic DNA samples obtained from blood spots from children born with isolated orofacial clefts in 45 hospitals located in eight countries (Argentina, Bolivia, Brazil, Chile, Ecuador, Paraguay, Uruguay, and Venezuela) collaborating with ECLAMC (Latin American Collaborative Studies of Congenital Malformations) between January 1998 and December 1999. Dried blood samples were sent by regular mail to the Laboratory of Congenital Malformations, Federal University of Rio de Janeiro. Previous findings suggested that mitochondrial haplotype D is more commonly found among cleft cases born in South America. We hypothesized that association of certain genes may depend upon the ethnic origin, as defined by populationspecific markers. Therefore, we tested if markers in MTHFR (5,10-methylenetetrahydrofolate reductase) and RFC1 (reduced folate carrier 1) were associated with oral clefts, depending on the maternal origin defined by the mitochondrial haplotype. Transmission distortion of alleles in MTHFR C677T and RFC1 G80A polymorphic variants was tested in 200 mother/affected child pairs taking into consideration maternal origin. RFC1 variation was over-transmitted to children born with cleft lip only (P = 0.017) carrying mitochondrial DNA haplotypes other than haplotype D. Our results provide a new indication that variation in RFC1 may contribute to cleft lip only. Future studies should investigate the association between oral clefts and RFC1 based on more discrete phenotypes.

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Section: Discussionsupporting

confidence: 77%

Section: Introductionmentioning

confidence: 49%

Section: Discussionmentioning

confidence: 81%

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Reduced folate carrier 1 (RFC1) is associated with cleft of the lip only

Vieira

Cooper

Marazita

et al. 2008

Braz J Med Biol Res

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“…It is well recognized that alcohol [56] and smoking [57] increase the risk for CL/P, and there is evidence that folate supplementation decreases the risk [58]. Clearly it is likely that the environment interacts with both the maternal and fetal gene products, supporting the hypothesis that genetic variation in involved pathways modulates CL/P risk.…”

Section: Genes In Environmental Pathwaysmentioning

confidence: 99%

“…Most studies have focused on two MTHFR polymorphisms (C677T or A298C), both of which cause reduced enzymatic activity. Results of several association studies have been contradictory, which may be due to different analytic strategies, specifically whether the analysis focused on the proband or maternal genotype [58]. Alternately, assuming that MTHFR is not sufficient but necessary to cause CL/P, analytical strategies that consider the simultaneous effects of different loci or that take into account environmental covariates may be more powerful for detecting the relation between MTHFR and CL/P [61].…”

Section: Genes In Environmental Pathwaysmentioning

confidence: 99%

Progress toward discerning the genetics of cleft lip

Lidral

Moreno

2005

Current Opinion in Pediatrics

111

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Purpose of review-Orofacial clefts are common birth defects with a known genetic component to their etiology. Most orofacial clefts are nonsyndromic, isolated defects, which can be separated into two different phenotypes: (1) cleft lip with or without cleft palate and (2) cleft palate only. Both are genetically complex traits, which has limited the ability to identify disease loci or genes. The purpose of this review is to summarize recent progress of human genetic studies in identifying causal genes for isolated or nonsyndromic cleft lip with or without cleft palate.Recent findings-The results of multiple genome scans and a subsequent meta-analysis have significantly advanced our knowledge by revealing novel loci. Furthermore, candidate gene approaches have identified important roles for IRF6 and MSX1. To date, causal mutations with a known functional effect have not yet been described.Summary-With the implementation of genome-wide association studies and inexpensive sequencing, future studies will identify disease genes and characterize both gene-environment and gene-gene interactions to provide knowledge for risk counseling and the development of preventive therapies.

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Fetal and maternalMTHFR C677Tgenotype, maternal folate intake and the risk of nonsyndromic oral clefts

Chevrier

Perret

Bahuau

et al. 2007

American J of Med Genetics Pt A

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The association between maternal folate intake and risk of nonsyndromic oral clefts has been studied among many populations with conflicting results. The methylenetetrahydrofolate reductase gene (MTHFR) plays a major role in folate metabolism, and several polymorphisms, including C677T, are common in European populations. Data from a French study (1998-2001) let us investigate the roles of maternal dietary folate intake and the MTHFR polymorphism and their interaction on the risk of cleft lip with/without cleft palate (CL/P) and cleft palate only (CP). We used both case-control (164 CL/P, 76 CP, 236 controls; 148, 59, 168 of whom, respectively, had an available genotype) and case-parent (143 CL/P and 56 CP families) study designs and distinguished the role of the child's genotype and maternally mediated effects on risks. This study observed a beneficial effect of mothers' dietary folate intake on their offspring's risk (odds ratio (OR)(< or = 230 microg/day) = ref; for CL/P, OR([230-314 microg/day]) = 0.56, 95% confidence interval = 0.3-0.9, OR(>314 microg/day) = 0.64, 0.4-1.1; for CP, OR([230-314 microg/day]) = 1.15, 0.6-2.2, OR(>314 microg/day) = 0.70, 0.3-1.4). We observed a reduced risk associated with the TT genotype of the child in the case-control analysis (OR(CC) = ref; for CL/P, OR(TT) = 0.54, 0.3-1.1; for CP, OR(TT) = 0.33, 0.1-1.0); this genotype, either fetal or maternal, was not statistically significant in the case-parent analysis. A frequency of TT genotype higher in our control group than previously reported in France can partly explain the risk reduction observed in case-control comparison. Interactions were not statistically significant. Stratified case-parent analysis showed, however, slight heterogeneity in the role of TT genotype according to folate intake. The modest sample size limits this study, which nonetheless provides new estimate of the possible impact of dietary folate intake and MTHFR polymorphism on oral clefts.

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Studies of reduced folate carrier 1 (RFC1) A80G and 5,10‐methylenetetrahydrofolate reductase (MTHFR) C677T polymorphisms with neural tube and orofacial cleft defects

Cited by 48 publications

References 36 publications

Reduced folate carrier 1 (RFC1) is associated with cleft of the lip only

Reduced folate carrier 1 (RFC1) is associated with cleft of the lip only

Progress toward discerning the genetics of cleft lip

Fetal and maternalMTHFR C677Tgenotype, maternal folate intake and the risk of nonsyndromic oral clefts

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