Rs2262251 in lncRNA RP11‐462G12.2 is associated with nonsyndromic cleft lip with/without cleft palate
Rs2262251 in lncRNA RP11‐462G12.2 is associated with nonsyndromic cleft lip with/without cleft palate
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DOI：
10.1002/humu.23859
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发表时间：
2019-11
期刊：
影响因子：
3.9
通讯作者：
Yun Lu;Lan Ma;Meilin Wang;Fan Yang;Shiyi Kan;Chi Zhang;Min Xu;Dandan Li;Yifei Du;
中科院分区：
文献类型：
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作者：
Yun Lu;Lan Ma;Meilin Wang;Fan Yang;Shiyi Kan;Chi Zhang;Min Xu;Dandan Li;Yifei Du;
非综合征性唇裂伴/不伴腭裂（NSCL/P）是最常见的人类先天性缺陷之一。长非编码RNA（lncRNA）RP11-462G12.2中的Rs2262251（G>C）与rs8049367处于高度连锁不平衡，这在我们之前的NSCL/P全基因组关联研究中被鉴定出来，并且是NSCL/P的潜在致病单核苷酸多态性（SNP）。为了检验这些假设，在另一组 1,314 例病例和 1,259 例对照中对 rs2262251 进行了评估。 Rs2262251 与 NSCL/P 风险相关 (p = .003)。然而，没有检测到仅与腭裂相关。 SNP rs2262251 影响 NSCL/P 患者 HEK293 和 HEPM 细胞以及唇组织中 lncRNA RP11-462G12.2 的结构和表达。 rs2262251 G等位基因的过度表达有助于减少处于G0/G1期的细胞数量，抑制细胞凋亡，并促进体外细胞增殖。 rs2262251 C 等位基因调节 miR-744-5p 及其靶基因 IQSEC2 的表达，两者均在人类唇部组织中表达，并在小鼠唇部发育过程中表现出反向相关性。综上所述，这些发现表明 rs2262251 与 NSCL/P 的风险相关，并参与 lncRNA-miRNA-mRNA 调控轴，其中 miR-744-5p 和 IQSEC2 结合控制 NSCL/P 的发展。
Nonsyndromic cleft lip with/without cleft palate (NSCL/P) is one of the most common human congenital defects. Rs2262251 (G>C) in long noncoding RNA (lncRNA) RP11‐462G12.2 is in high linkage disequilibrium with rs8049367, which was identified in our previous genome‐wide association study on NSCL/P, and is a potential causative single‐nucleotide polymorphism (SNP) for NSCL/P. To test these hypotheses, rs2262251 was evaluated in another cohort of 1,314 cases and 1,259 controls. Rs2262251 was associated with NSCL/P risk (p = .003). However, no association was detected for cleft palate only. SNP rs2262251 affected the structure and expression of lncRNA RP11‐462G12.2 in HEK293 and HEPM cells and in lip tissues from patients with NSCL/P. Overexpression of the rs2262251 G allele contributed to reducing the number of cells in the G0/G1 phase, inhibiting cell apoptosis, and promoting cell proliferation in vitro. The rs2262251 C allele regulated the expression of miR‐744‐5p and its target gene IQSEC2, both of which were expressed in human lip tissues, and showed reverse correlation during mouse lip development. Taken together, these findings suggest that rs2262251 is associated with the risk of NSCL/P and participates in a lncRNA–miRNA–mRNA regulatory axis in which miR‐744‐5p and IQSEC2 combine to control NSCL/P development.