Li Mu-Jia, Shi Jia-Yu, Zhang Bi-He, Chen Qian-Ming, Shi Bing, Jia Zhong-Lin
State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
Department of Cleft Lip and Palate, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
Front Genet. 2022 Aug 17;13:947126. doi: 10.3389/fgene.2022.947126. eCollection 2022.
Rs560426 at 1p22 was proved to be associated with NSCL/P (non-syndromic cleft lip with or without the palate) in several populations, including Han Chinese population. Here, we conducted a deep sequencing around rs560426 to locate more susceptibility variants in this region. In total, 2,293 NSCL/P cases and 3,235 normal controls were recruited. After sequencing, association analysis was performed. Western blot, RT-qPCR, HE, immunofluorescence staining, and RNA sequencing were conducted for functional analyses of the selected variants. Association analysis indicated that rs77179923 was the only SNP associated with NSCLP specifically ( = 4.70E-04, OR = 1.84), and rs12071152 was uniquely associated with LCLO ( = 4.00E-04, OR = 1.30, 95%CI: 1.12-1.51). Moreover, harmful rare variant NM_004815.3, NP_004806.3; c.1652G>C, p.R551T in resulted in a decreased expression level of , which in turn affected NSCL/P-related biological processes; however, no overt cleft palate (CP) phenotype was observed. In conclusion, rs12071152 was a new susceptible variant, which is specifically associated with LCLO among the Han Chinese population. Allele A of it could increase the risk of having a cleft baby. Rs77179923 and rare variant NM_004815.3, NP_004806.3; c.1652G>C, p.R551T at 1p22 were both associated with NSCLP among the Han Chinese population. However, this missense variation contributes to no overt CP phenotype due to dosage insufficiency or compensation from other genes.
1p22处的Rs560426已被证明在包括汉族人群在内的多个群体中与非综合征性唇腭裂(NSCL/P)相关。在此,我们在rs560426周围进行了深度测序,以定位该区域更多的易感变异。总共招募了2293例NSCL/P病例和3235例正常对照。测序后进行了关联分析。对所选变异进行了蛋白质免疫印迹、逆转录定量聚合酶链反应、苏木精-伊红染色、免疫荧光染色和RNA测序等功能分析。关联分析表明,rs77179923是唯一与NSCLP特异性相关的单核苷酸多态性(P = 4.70E - 04,优势比[OR]=1.84),而rs12071152与单纯唇裂(LCLO)独特相关(P = 4.00E - 04,OR = 1.30,95%置信区间[CI]:1.12 - 1.51)。此外,有害的罕见变异NM_004815.3,NP_004806.3;c.1652G>C,p.R551T导致该基因表达水平降低,进而影响与NSCL/P相关的生物学过程;然而,未观察到明显的腭裂(CP)表型。总之,rs12071152是一个新的易感变异,在汉族人群中它与单纯唇裂特异性相关。其等位基因A会增加生出唇裂婴儿的风险。rs77179923以及1p22处的罕见变异NM_004815.3,NP_004806.3;c.1652G>C,p.R551T在汉族人群中均与NSCLP相关。然而,由于剂量不足或其他基因的补偿作用,这种错义变异并未导致明显的CP表型。