title: Cystathionine β-synthase genetic variant rs2124459 is associated with a reduced risk of cleft palate in French and Belgian populations.
abstract: Orofacial cleft (OFC) is the most prevalent craniofacial birth defect. Genes involved in one-carbon, folate and vitamin B12metabolisms have been associated with OFC but no study performed a concomitant assessment on genes involved in these three pathways.
  
  
  
  We looked for potential genetic variants associated with OFC using an exhaustive gene panel of one-carbon metabolism.
  
  
  
  We performed a case-control discovery study on children with OFC (236 cases, 145 controls) and their related mothers (186 cases, 127 controls). We performed a replication study on the top significant genetic variant in an independent group from Belgium (248 cases, 225 controls).
  
  
  
  In the discovery study on 'mothers', the CBS locus reached array-wide significance (p=9.13×10-6; Bonferroni p=4.77×10-3; OR 0.47 (0.33 to 0.66)) among the 519 haplotypes tested for their association with OFC risk. Within the CBS haplotype block (rs2124459, rs6586282, rs4920037, rs234705, rs234709), the rs2124459 was the most significantly associated with a reduced risk of OFC (p=1.77×10-4; Bonferroni p=2.00×10-2; OR 0.53 (0.38 to 0.74), minor allele). The rs2124459 was associated with a reduced risk of cleft palate (CP) (p=6.78×10-5; Bonferroni p=7.80×10-3; OR 0.40 (0.25 to 0.63)). In the 'children' group, the rs2124459 was associated with a reduced risk of CP (p=0.02; OR 0.61 (0.40 to 0.93), minor allele). The association between rs2124459 and reduced risk of CP was replicated in an independent children population from Belgium (p=0.02; OR 0.64 (0.44 to 0.93), minor allele).
  
  
  
  The CBS rs2124459 was associated with a reduced risk of CP in both French and Belgian populations. These results highlight the prominent involvement of the vitamin B6-dependent transsulfuration pathway of homocysteine in OFC risk and the interest for evaluating vitamin B6 status in further population studies.
authors.affiliation: Faculty of Medicine of Nancy, INSERM U954, NGERE-Nutrition, Genetics, and Environmental Risk Exposure, University of Lorraine, Vandoeuvre-lès-Nancy, France.|Department of Pediatric Surgery, University Hospital of Nancy, Vandoeuvre-lès-Nancy, France.
authors.forename: Laetitia
authors.initials: L
authors.lastname: Goffinet
authors.affiliation: Faculty of Medicine of Nancy, INSERM U954, NGERE-Nutrition, Genetics, and Environmental Risk Exposure, University of Lorraine, Vandoeuvre-lès-Nancy, France.|Department of Molecular Medicine and Personalized Therapeutics, University Hospital of Nancy, Vandoeuvre-lès-Nancy, France.|Division of Biochemistry, Molecular Biology, Nutrition, and Metabolism, University Hospital of Nancy, Vandoeuvre-lès-Nancy, France.
authors.forename: Abderrahim
authors.initials: A
authors.lastname: Oussalah
authors.affiliation: Faculty of Medicine of Nancy, INSERM U954, NGERE-Nutrition, Genetics, and Environmental Risk Exposure, University of Lorraine, Vandoeuvre-lès-Nancy, France.|Department of Molecular Medicine and Personalized Therapeutics, University Hospital of Nancy, Vandoeuvre-lès-Nancy, France.|Division of Biochemistry, Molecular Biology, Nutrition, and Metabolism, University Hospital of Nancy, Vandoeuvre-lès-Nancy, France.
authors.forename: Rosa-Maria
authors.initials: RM
authors.lastname: Guéant-Rodriguez
authors.affiliation: Faculty of Medicine of Nancy, INSERM U954, NGERE-Nutrition, Genetics, and Environmental Risk Exposure, University of Lorraine, Vandoeuvre-lès-Nancy, France.|Department of Molecular Medicine and Personalized Therapeutics, University Hospital of Nancy, Vandoeuvre-lès-Nancy, France.|Division of Biochemistry, Molecular Biology, Nutrition, and Metabolism, University Hospital of Nancy, Vandoeuvre-lès-Nancy, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Chery
authors.affiliation: Human Molecular Genetics (GEHU), de Duve Institute-Université catholique de Louvain, Brussels, Belgium.
authors.forename: Mirta
authors.initials: M
authors.lastname: Basha
authors.affiliation: Faculty of Medicine of Nancy, INSERM U954, NGERE-Nutrition, Genetics, and Environmental Risk Exposure, University of Lorraine, Vandoeuvre-lès-Nancy, France.
authors.forename: Patrice Hodonou
authors.initials: PH
authors.lastname: Avogbe
authors.affiliation: Faculty of Medicine of Nancy, INSERM U954, NGERE-Nutrition, Genetics, and Environmental Risk Exposure, University of Lorraine, Vandoeuvre-lès-Nancy, France.|Department of Molecular Medicine and Personalized Therapeutics, University Hospital of Nancy, Vandoeuvre-lès-Nancy, France.|Division of Biochemistry, Molecular Biology, Nutrition, and Metabolism, University Hospital of Nancy, Vandoeuvre-lès-Nancy, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Josse
authors.affiliation: Faculty of Medicine of Nancy, INSERM U954, NGERE-Nutrition, Genetics, and Environmental Risk Exposure, University of Lorraine, Vandoeuvre-lès-Nancy, France.|Department of Molecular Medicine and Personalized Therapeutics, University Hospital of Nancy, Vandoeuvre-lès-Nancy, France.|Division of Biochemistry, Molecular Biology, Nutrition, and Metabolism, University Hospital of Nancy, Vandoeuvre-lès-Nancy, France.
authors.forename: Elise
authors.initials: E
authors.lastname: Jeannesson
authors.affiliation: Faculty of Medicine of Nancy, INSERM U954, NGERE-Nutrition, Genetics, and Environmental Risk Exposure, University of Lorraine, Vandoeuvre-lès-Nancy, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Rouyer
authors.affiliation: Faculty of Medicine of Nancy, INSERM U954, NGERE-Nutrition, Genetics, and Environmental Risk Exposure, University of Lorraine, Vandoeuvre-lès-Nancy, France.
authors.forename: Justine
authors.initials: J
authors.lastname: Flayac
authors.affiliation: Faculty of Medicine of Nancy, INSERM U954, NGERE-Nutrition, Genetics, and Environmental Risk Exposure, University of Lorraine, Vandoeuvre-lès-Nancy, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Gerard
authors.affiliation: Department of Pediatric Visceral Surgery, Francois Rabelais University, and University Hospital of Tours, Tours, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Le Touze
authors.affiliation: Department of Maxillofacial Surgery, Hospital Trousseau, CHRU Tours, Tours, France.
authors.forename: Béatrice
authors.initials: B
authors.lastname: Bonin-Goga
authors.affiliation: Department of Maxillofacial Surgery, Hospital Trousseau, CHRU Tours, Tours, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Goga
authors.affiliation: Department of Maxillofacial, Plastic, Reconstructive and Cosmetic Surgery, University Hospital of Nancy, Nancy, France.|University of Lorraine, Vandoeuvre-lès-Nancy, Lorraine, France.
authors.forename: Etienne
authors.initials: E
authors.lastname: Simon
authors.affiliation: Faculty of Medicine of Nancy, INSERM U954, NGERE-Nutrition, Genetics, and Environmental Risk Exposure, University of Lorraine, Vandoeuvre-lès-Nancy, France.
authors.forename: François
authors.initials: F
authors.lastname: Feillet
authors.affiliation: Human Molecular Genetics (GEHU), de Duve Institute-Université catholique de Louvain, Brussels, Belgium.
authors.forename: Miikka
authors.initials: M
authors.lastname: Vikkula
authors.affiliation: Faculty of Medicine of Nancy, INSERM U954, NGERE-Nutrition, Genetics, and Environmental Risk Exposure, University of Lorraine, Vandoeuvre-lès-Nancy, France.|Department of Molecular Medicine and Personalized Therapeutics, University Hospital of Nancy, Vandoeuvre-lès-Nancy, France.|Division of Biochemistry, Molecular Biology, Nutrition, and Metabolism, University Hospital of Nancy, Vandoeuvre-lès-Nancy, France.
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Guéant
mesh_terms: D000328:Adult; D001530:Belgium; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D002971:Cleft Lip / Q000150:complications / Q000235:genetics* / Q000378:metabolism; D002972:Cleft Palate / Q000150:complications / Q000235:genetics* / Q000378:metabolism; D003541:Cystathionine beta-Synthase / Q000235:genetics*; D005260:Female; D005602:France; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D007223:Infant; D008297:Male; D020641:Polymorphism, Single Nucleotide
chemical_list: D003541:Cystathionine beta-Synthase
keywords: cleft palate; cystathionine beta-synthase; homocysteine transsulfuration pathway; one-carbon metabolism; orofacial cleft