表皮生长因子受体超级通路内吞运输中的基因变异与非综合征性唇裂伴或不伴腭裂风险的关联。
Associations of genetic variants in endocytic trafficking of epidermal growth factor receptor super pathway with risk of nonsyndromic cleft lip with or without cleft palate.
作者信息
Li Bing, Ma Lan, Zhang Chi, Zhou Zhixuan, Yuan Hua, Jiang Hongbing, Pan Yongchu, Tan Qian
机构信息
Department of Burns and Plastic Surgery, The Drum Tower Clinical Medical College, Nanjing Medical University, Nanjing, China.
Department of Oral and Maxillofacial Surgery, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, China.
出版信息
Mol Genet Genomic Med. 2018 Nov;6(6):1157-1167. doi: 10.1002/mgg3.497. Epub 2018 Nov 8.
BACKGROUND
The genetic etiology of nonsyndromic cleft lip with or without cleft palate (NSCL/P) has not been fully clarified to date. Epidermal growth factor receptor (EGFR) was reportedly involved in its biological establishment and regulation of cell migration during the embryonic stage.
METHODS
We selected a super pathway of endocytic trafficking of EGFR and investigated the associations of single-nucleotide polymorphisms (SNPs) in the super pathway with the risk of NSCL/P by analyzing our published genome-wide association study (GWAS) data from 504 NSCL/P individuals and 455 controls. After the false discovery rate (FDR) control, we conducted linkage disequilibrium (LD) analyses and conditional regression analyses to obtain independent lead SNPs. We performed LD analyses between the lead SNPs and the reported SNPs to find novel ones from our study. We annotated the lead SNPs and investigated their mapped genes in silico.
RESULTS
A total of 82 SNPs showed a statistical association with the risk of NSCL/P after FDR control. They contained three reported SNPs which were g.117068049G>A (rs7078160), g.117086783C>G (rs10886040), and g.117101266G>T (rs17095681). Four independent lead SNPs were obtained, including g.116979803 T>C (rs1905539) and g.117037960A>G (rs7902502) at 10q25.3, g.35720163G>C (rs75656820) at 17q12, and g.156864512G>A (rs1800877) at 1q23.1. Three of them were in low LD (r < 0.5) with the reported SNPs except g.117037960A>G (rs7902502), so these three were newly identified. Lead SNPs were mapped to three genes: SHTN1, AP2B1, and NTRK1. The three genes were relatively more highly expressed in the human craniofacial region and in the proximal maxillary location during the craniofacial development stage of the embryonic mouse.
CONCLUSION
Our results suggested that SHTN1, AP2B1, and NTRK1 might be associated with the development of NSCL/P.
背景
目前，非综合征性唇裂伴或不伴腭裂（NSCL/P）的遗传病因尚未完全阐明。据报道，表皮生长因子受体（EGFR）参与了其生物学形成过程以及胚胎期细胞迁移的调控。
方法
我们选择了一条EGFR内吞转运的超级通路，通过分析我们发表的来自504例NSCL/P患者和455例对照的全基因组关联研究（GWAS）数据，研究该超级通路中的单核苷酸多态性（SNP）与NSCL/P风险的关联。在控制错误发现率（FDR）后，我们进行了连锁不平衡（LD）分析和条件回归分析，以获得独立的主效SNP。我们在主效SNP与已报道的SNP之间进行LD分析，以从我们的研究中发现新的SNP。我们对主效SNP进行注释，并在计算机上研究它们所映射的基因。
结果
在控制FDR后，共有８２个SNP显示出与NSCL/P风险存在统计学关联。它们包含三个已报道的SNP，分别为g.117068049G>A（rs7078160）、g.117086783C>G（rs10886040）和g.117101266G>T（rs17095681）。获得了四个独立的主效SNP，包括位于10q25.3的g.116979803 T>C（rs1905539）和g.117037960A>G（rs7902502）、位于17q12的g.35720163G>C（rs75656820）以及位于1q23.1的g.156864512G>A（rs1800877）。除g.117037960A>G（rs7902502）外，其中三个与已报道的SNP处于低LD（r < 0.5）状态，因此这三个是新发现的。主效SNP映射到三个基因：SHTN1、AP2B1和NTRK1。在胚胎小鼠颅面发育阶段，这三个基因在人类颅面部区域和上颌近端位置相对表达较高。
结论
我们的结果表明，SHTN1、AP2B1和NTRK1可能与NSCL/P的发生有关。
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