Laetitia Goffinet1,2, Abderrahim Oussalah1,3,4, Rosa-Maria Guéant-Rodriguez1,3,4, Céline Chery1,3,4, Mirta Basha5, Patrice Hodonou Avogbe1, Thomas Josse1,3,4, Elise Jeannesson1,3,4, Pierre Rouyer1, Justine Flayac1, Philippe Gerard1, Anne Le Touze6, Béatrice Bonin-Goga7, Dominique Goga7, Etienne Simon8,9, François Feillet1, Miikka Vikkula5, Jean-Louis Guéant1,3,4. 1. Faculty of Medicine of Nancy, INSERM U954, NGERE-Nutrition, Genetics, and Environmental Risk Exposure, University of Lorraine, Vandoeuvre-lès-Nancy, France. 2. Department of Pediatric Surgery, University Hospital of Nancy, Vandoeuvre-lès-Nancy, France. 3. Department of Molecular Medicine and Personalized Therapeutics, University Hospital of Nancy, Vandoeuvre-lès-Nancy, France. 4. Division of Biochemistry, Molecular Biology, Nutrition, and Metabolism, University Hospital of Nancy, Vandoeuvre-lès-Nancy, France. 5. Human Molecular Genetics (GEHU), de Duve Institute-Université catholique de Louvain, Brussels, Belgium. 6. Department of Pediatric Visceral Surgery, Francois Rabelais University, and University Hospital of Tours, Tours, France. 7. Department of Maxillofacial Surgery, Hospital Trousseau, CHRU Tours, Tours, France. 8. Department of Maxillofacial, Plastic, Reconstructive and Cosmetic Surgery, University Hospital of Nancy, Nancy, France. 9. University of Lorraine, Vandoeuvre-lès-Nancy, Lorraine, France.
Abstract
BACKGROUND: Orofacial cleft (OFC) is the most prevalent craniofacial birth defect. Genes involved in one-carbon, folate and vitamin B12 metabolisms have been associated with OFC but no study performed a concomitant assessment on genes involved in these three pathways. OBJECTIVE: We looked for potential genetic variants associated with OFC using an exhaustive gene panel of one-carbon metabolism. METHODS: 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). RESULTS: 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). CONCLUSIONS: 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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.
BACKGROUND: Orofacial cleft (OFC) is the most prevalent craniofacial birth defect. Genes involved in one-carbon, folate and vitamin B12 metabolisms have been associated with OFC but no study performed a concomitant assessment on genes involved in these three pathways. OBJECTIVE: We looked for potential genetic variants associated with OFC using an exhaustive gene panel of one-carbon metabolism. METHODS: 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). RESULTS: 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). CONCLUSIONS: 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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.