Cystathionine β-synthase genetic variant rs2124459 is associated with a reduced risk of cleft palate in French and Belgian populations. Issue 12 (17th August 2016)

• Record Type: Journal Article
• Authors: Goffinet, Laetitia; Oussalah, Abderrahim; Guéant-Rodriguez, Rosa-Maria; Chery, Céline; Basha, Mirta; Avogbe, Patrice Hodonou; Josse, Thomas; Jeannesson, Elise; Rouyer, Pierre; Flayac, Justine; Gerard, Philippe; Le Touze, Anne; Bonin-Goga, Béatrice; Goga, Dominique; Simon, Etienne; Feillet, François; Vikkula, Miikka; Guéant, Jean-Louis
• Is Part Of: Journal of medical genetics. Volume 53:Issue 12(2016)
• Page Start: 828
• Page End: 834
• Publication Date: 2016-08-17
• Subjects: one-carbon metabolism -- orofacial cleft -- cleft palate -- cystathionine beta-synthase -- homocysteine transsulfuration pathway; Medical genetics -- Periodicals; 616.042
• DOI: 10.1136/jmedgenet-2016-104111
• Languages: English
• ISSNs: 1468-6244

Abstract

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.