title: A miRNA-binding-site SNP of MSX1 is Associated with NSOC Susceptibility.
abstract: MSX1 is a favorable candidate gene for susceptibility to non-syndromic orofacial clefts (NSOCs). However, the roles of MSX1 genetic variants in the development of NSOC are controversial and vary among human populations. In the present study, the roles of 4 potentially functional single-nucleotide polymorphisms (SNPs) of MSX1 (rs12532 in 3'-untranslated region [UTR], and rs3821947, rs3821949, and rs4464513 in 5' upstream) were investigated in a case-control study of 602 NSOC cases and 605 healthy controls. The findings showed that rs12532 located within 3'-UTR of MSX1 could influence the risk of developing NSOC. Individuals who carried the variant genotype (rs12532AA genotype) showed a decreased possibility of developing NSOC (AA vs. GG: OR = 0.69, 95% CI = [0.49, 0.98]). Interestingly, similar effects were also observed on cleft lip with palate (CLP), in a stratified analysis (allelic comparison-12532A allele vs. 12532G allele, OR = 0.80, 95% CI = [0.66, 0.99]; genotypic comparison-AA vs. GG, OR = 0.58 95% CI = [0.37, 0.91]). Sequence analysis indicated that this SNP might alter the binding ability of miR-3649, confirmed by luciferase activity assay showing a lower expression level of rs12532 A allele compared with that of the G allele (p < .001 for 293A and COS7 cell lines). Furthermore, an in vivo study showed that MSX1 expression among individuals carrying the AA genotype of rs12532 was markedly lower than that in those with the GG genotype, while the inverse correlation was observed for miR-3649, thus providing a possible interaction between MSX1 and miR-3649 in the etiology of NSOC. Taken together, these findings indicate that SNPs in the miRNA-binding sites might play an important role in the development of NSOCs. Furthermore, if confirmed in subsequent studies, the polymorphisms may be considered as additional markers for the evaluation of infants' risk of NSOCs.
authors.affiliation: Institute of Stomatology, Nanjing Medical University, Nanjing, China.
authors.forename: L
authors.initials: L
authors.lastname: Ma
authors.affiliation: Institute of Stomatology, Nanjing Medical University, Nanjing, China.
authors.forename: M
authors.initials: M
authors.lastname: Xu
authors.affiliation: Institute of Stomatology, Nanjing Medical University, Nanjing, China.
authors.forename: D
authors.initials: D
authors.lastname: Li
authors.affiliation: Institute of Stomatology, Nanjing Medical University, Nanjing, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Han
authors.affiliation: Institute of Stomatology, Nanjing Medical University, Nanjing, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Institute of Stomatology, Nanjing Medical University, Nanjing, China.
authors.forename: H
authors.initials: H
authors.lastname: Yuan
authors.affiliation: Institute of Stomatology, Nanjing Medical University, Nanjing, China.
authors.forename: J
authors.initials: J
authors.lastname: Ma
authors.affiliation: Institute of Stomatology, Nanjing Medical University, Nanjing, China.
authors.forename: W
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Institute of Stomatology, Nanjing Medical University, Nanjing, China.
authors.forename: H
authors.initials: H
authors.lastname: Jiang
authors.affiliation: Institute of Stomatology, Nanjing Medical University, Nanjing, China State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China nydwlktz@gmail.com 393774987@qq.com.
authors.forename: Y
authors.initials: Y
authors.lastname: Pan
authors.affiliation: Institute of Stomatology, Nanjing Medical University, Nanjing, China State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China nydwlktz@gmail.com 393774987@qq.com.
authors.forename: L
authors.initials: L
authors.lastname: Wang
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D024506:5' Flanking Region / Q000235:genetics; D000225:Adenine; D016022:Case-Control Studies; D002971:Cleft Lip / Q000235:genetics*; D002972:Cleft Palate / Q000235:genetics*; D005787:Gene Frequency / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics; D005838:Genotype; D006147:Guanine; D006801:Humans; D051957:MSX1 Transcription Factor / Q000235:genetics*; D035683:MicroRNAs / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012307:Risk Factors
chemical_list: D020413:3' Untranslated Regions; D051957:MSX1 Transcription Factor; C484083:MSX1 protein, human; D035683:MicroRNAs; D006147:Guanine; D000225:Adenine
keywords: case-control study; genetics; microRNA; non-syndromic orofacial clefts; risk factors; single-nucleotide polymorphism