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

Abstract

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.

Maternal polymorphisms in folic acid metabolic genes are associated with nonsyndromic cleft lip and/or palate in the Brazilian population

“…Investigating genetic variations that influence cellular absorption, transport, and metabolism of folic acid may offer insights into the role of this vitamin on NSCL/ P pathogenesis. Previous investigations of genes that are involved with folic acid metabolism, including 5,10-methylenetetrahydrofolate reductase (MTHFR), methylenetetrahydrofolate dehydrogenase 1 (MTHFD1), 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR), and solute carrier family 19-member 1 (SLC19A1), have demonstrated an association of functional polymorphisms with increased maternal risk of NSCL/P (Shotelersuk et al, 2003;Mostowska et al, 2006;Mills et al, 2008;Vieira et al, 2008).…”

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

“…The aim of the current report was to assess the possible role of MTHFR c.677C>T in the expression of NSCL/P phenotype in a Chilean population, based on two complementary stages: a case–control study (stage 1) and a case–parent trio study (stage 2). We have considered as reference the results of two previous studies from the ECLAMC including lower number of OFC Chilean subjects and analyzed jointly with other samples from South American countries (Vieira et al , , ). Both reports did not show association between MTHFR c.677C>T and non‐syndromic OFCs.…”

“…The aim of this study was to evaluate the possible role of MTHFR c.677C>T in the expression of NSCL/P in the Chilean population. As reference, the literature shows two previous studies including Chilean OFC subjects and their mothers from the Latin American Collaborative Study of Congenital Malformations (ECLAMC) (Vieira et al , , ). In these reports, Chilean samples were grouped with other South American subjects and no associations between this variant and OFCs were detected.…”

Association studies of candidate genes and cleft lip and palate taking into consideration geographical origin

“…To the best of our knowledge, this study is the first to stratify the results of genotyping based on mtDNA haplotypes in Europeans. Initial work performed using data based on South American individuals suggested that association with specific genes is detected only when data are stratified by mtDNA haplotype (22, 23). It is unlikely that mtDNA variants play a direct role in the development of CL/CLP.…”