A miRNA-binding-site SNP of MSX1 is Associated with NSOC Susceptibility
A miRNA-binding-site SNP of MSX1 is Associated with NSOC Susceptibility
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DOI：
10.1177/0022034514527617
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发表时间：
2014-03
影响因子：
7.6
通讯作者：
L. Ma;M. Xu;D. Li;Y. Han;Z. Wang;H. Yuan;J. Ma;W. Zhang;H. Jiang;Y. Pan;L. Wang
中科院分区：
文献类型：
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作者：
L. Ma;M. Xu;D. Li;Y. Han;Z. Wang;H. Yuan;J. Ma;W. Zhang;H. Jiang;Y. Pan;L. Wang
MSX1是非综合征性口面裂（nsoc）易感性的有利候选基因。然而，MSX1基因变异在NSOC发展中的作用是有争议的，并且在人群中存在差异。本研究通过602例NSOC患者和605名健康对照者的病例对照研究，探讨了MSX1的4个潜在功能单核苷酸多态性（rs12532位于3 ‘ -非翻译区[UTR]， rs3821947、rs3821949和rs4464513位于5 ’上游）的作用。结果表明，位于MSX1 3 ' -UTR内的rs12532可能影响NSOC的发生风险。携带变异基因型（rs12532AA基因型）的个体发生NSOC的可能性降低（AA与GG: OR = 0.69, 95% CI =[0.49, 0.98]）。有趣的是，在分层分析中，在唇腭裂（CLP）中也观察到类似的效果（等位基因比较- 12532a等位基因vs 12532G等位基因，OR = 0.80, 95% CI =[0.66, 0.99]；基因型比较- aa vs GG， OR = 0.58, 95% CI =[0.37, 0.91]）。序列分析表明，该SNP可能改变miR-3649的结合能力，荧光素酶活性测定证实，rs12532 a等位基因的表达水平低于G等位基因的表达水平（在293A和COS7细胞系中p < 0.001）。此外，一项体内研究表明，MSX1在携带rs12532的AA基因型个体中的表达明显低于GG基因型个体，而miR-3649的表达则呈负相关，这可能表明MSX1与miR-3649在NSOC的病因学中存在相互作用。综上所述，这些发现表明mirna结合位点的snp可能在nsoc的发展中起重要作用。此外，如果在随后的研究中得到证实，这些多态性可能被认为是评估婴儿nsoc风险的额外标记。
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.