Functional Effects of SNPs in MYH9 and Risks of Nonsyndromic Orofacial Clefts
Functional Effects of SNPs in MYH9 and Risks of Nonsyndromic Orofacial Clefts
复制标题
MYH9 中 SNP 的功能影响和非综合征性口颌面裂的风险
DOI：
10.1177/0022034517743930
复制
发表时间：
2018-04
期刊：
影响因子：
--
通讯作者：
Pan Yongchu
中科院分区：
文献类型：
--
作者：
Wang Yuting;Li D;an;Xu Yan;Ma Lan;Lu Yun;Wang Zhendong;Wang Lin;Zhang Weibing;Pan Yongchu
非综合征性口面裂 (NSOC) 是先天性新生儿畸形。肌球蛋白重链9（MYH9）是NSOCs的候选基因。为了研究 MYH9 的单核苷酸多态性 (SNP) 与 NSOC 易感性之间的关联，设计了一项 2 阶段病例对照研究，并选择 MYH9 的 4 个潜在功能性 SNP（rs12107、rs2269529、rs9619601、rs5756130），并通过 iPLEX Sequenom MassARRAY 和 TaqMan 测定进行基因分型。第一阶段（599 个 NSOC 病例和 590 个对照）。第一阶段中的显着 SNP 通过 TaqMan 测定在第二阶段（676 个 NSOC 病例和 705 个对照）中得到复制。相应地进行逆转录聚合酶链反应、细胞转染和荧光素酶测定以探索其功能。在第一阶段，rs12107 名义上与 NSOC 相关，而 rs2269529 显示出显着相关性（rs12107：Phet = 0.028；rs2269529：Phet = 0.001）。在 II 期，rs12107 名义上与 NSOC 相关，而 rs2269529 显示出显着相关性（rs12107：Phom = 0.014；rs2269529：Phet = 0.006）。在组合阶段，这 2 个 SNP 获得了显着的关联（rs12107：Pdom = 0.004；rs2269529：Pdom = 4.4 × 10–5）。在亚表型分析中，这2个SNP与仅唇裂(CLO)和唇腭裂(CLP)相关，并且rs2269529也与仅腭裂(CPO)相关。单倍型分析揭示了 rs12107-G/rs2269529-T 与 NSOC 易感性之间的关联 (P = 0.011)。 rs12107 和 rs2269529 的联合分析表明，NSOC 的风险随着风险等位基因数量的增加而增加（rs12107-G 和 rs2269529-T，趋势 P = 0.008）。与相应的野生型纯合子相比，MYH9 SNP rs12107 AG + GG 和 rs2269529 CT + TT 与唇组织中较高的 MYH9 表达相关。对于rs12107，在荧光素酶测定中观察到G等位基因的荧光素酶活性高于A等位基因。当将 MYH9 的假定结合靶标 miR-196b-3p 转染至人胚胎板间充质 (HEPM) 和 C2C12 细胞系时，MYH9 被下调。对于 rs2269529，C > T 导致 MYH9 信使 RNA 增加。总之，rs12107 和 rs2269529 与 MYH9 的表达相关，并有助于 NSOC 的易感性。
Nonsyndromic orofacial clefts (NSOCs) are congenital newborn malformations. Myosin heavy chain 9 (MYH9) is a candidate gene of NSOCs. To investigate the associations between single-nucleotide polymorphisms (SNPs) of MYH9 and NSOC susceptibility, a 2-stage case-control study was designed and 4 potentially functional SNPs of MYH9 (rs12107, rs2269529, rs9619601, rs5756130) were selected and genotyped by iPLEX Sequenom MassARRAY and TaqMan assay in the first stage (599 NSOC cases and 590 controls). The significant SNPs in the first stage were replicated in the second stage (676 NSOC cases and 705 controls) by TaqMan assay. Reverse transcription polymerase chain reaction, cell transfection, and luciferase assay were performed accordingly to explore their functionality. In stage I, rs12107 was nominally associated with NSOCs, whereas rs2269529 showed a significant association (rs12107: Phet = 0.028; rs2269529: Phet = 0.001). In stage II, rs12107 was nominally associated with NSOCs, and rs2269529 showed a significant association (rs12107: Phom = 0.014; rs2269529: Phet = 0.006). In combined stages, these 2 SNPs gained significant associations (rs12107: Pdom = 0.004; rs2269529: Pdom = 4.4 × 10–5). In subphenotype analysis, these 2 SNPs were associated with cleft lip only (CLO) and cleft lip with palate (CLP), and rs2269529 was also associated with cleft palate only (CPO). Haplotype analysis revealed associations between rs12107-G/rs2269529-T and NSOC susceptibility (P = 0.011). Combined analysis of rs12107 and rs2269529 indicated the risk of NSOCs increased with the number of risk alleles (rs12107-G and rs2269529-T, P for trend = 0.008). MYH9 SNP rs12107 AG + GG and rs2269529 CT + TT were associated with higher MYH9 expression in lip tissues compared with their corresponding wild-type homozygote. For rs12107, higher luciferase activities of G allele than A allele were observed in the luciferase assay. MYH9 was downregulated when transfecting its putative binding target miR-196b-3p into human embryo plate mesenchyme (HEPM) and C2C12 cell lines. For rs2269529, C > T contributed to increased MYH9 messenger RNA. In conclusion, rs12107 and rs2269529 were associated with the expression of MYH9 and contributed to the susceptibility of NSOCs.
登录
查看更多内容
影响因子：
2.9
作者：
M. Chung;T. Lao;Y. Ting;T. Leung;T. Lau;Tze-Wai Wong
通讯作者：
M. Chung;T. Lao;Y. Ting;T. Leung;T. Lau;Tze-Wai Wong
影响因子：
30.8
作者：
Westra, Harm-Jan;Peters, Marjolein J.;Esko, Tonu;Yaghootkar, Hanieh;Schurmann, Claudia;Kettunen, Johannes;Christiansen, Mark W.;Fairfax, Benjamin P.;Schramm, Katharina;Powell, Joseph E.;Zhernakova, Alexandra;Zhernakova, Daria V.;Veldink, Jan H.;Van den Berg, Leonard H.;Karjalainen, Juha;Withoff, Sebo;Uitterlinden, Andre G.;Hofman, Albert;Rivadeneira, Fernando;'t Hoen, Peter A. C.;Reinmaa, Eva;Fischer, Krista;Nelis, Mari;Milani, Lili;Melzer, David;Ferrucci, Luigi;Singleton, Andrew B.;Hernandez, Dena G.;Nalls, Michael A.;Homuth, Georg;Nauck, Matthias;Radke, Doerte;Voelker, Uwe;Perola, Markus;Salomaa, Veikko;Brody, Jennifer;Suchy-Dicey, Astrid;Gharib, Sina A.;Enquobahrie, Daniel A.;Lumley, Thomas;Montgomery, Grant W.;Makino, Seiko;Prokisch, Holger;Herder, Christian;Roden, Michael;Grallert, Harald;Meitinger, Thomas;Strauch, Konstantin;Li, Yang;Jansen, Ritsert C.;Visscher, Peter M.;Knight, Julian C.;Psaty, Bruce M.;Ripatti, Samuli;Teumer, Alexander;Frayling, Timothy M.;Metspalu, Andres;van Meurs, Joyce B. J.;Franke, Lude
通讯作者：
Franke, Lude
DOI：
10.1007/3-540-30020-1
发表时间：
2006
期刊：
--
影响因子：
--
作者：
通讯作者：
--
影响因子：
2
作者：
Saposnik, Beatrice;Binard, Sylvie;Fenneteau, Odile;Nurden, Alan;Nurden, Paquita;Hurtaud-Roux, Marie-Francoise;Schlegel, Nicole
通讯作者：
Schlegel, Nicole
影响因子：
--
作者：
Sung SR;Song SH;Kang KM;Park JE;Nam YJ;Shin YJ;Cha DH;Seo JT;Yoon TK;Shim SH
通讯作者：
Shim SH