Genetic variants in Mammalian STE20-like protein kinase 2 were associated with risk of NSCL/P.

AIM: Mammalian STE20-like protein kinase 2 (MST2) plays an important role in apoptosis and the development of many disorders. Here, we aim to explore if genetic variants in MST2 are associated with the risk of non-syndromic cleft lip with or without palate (NSCL/P). MATERIALS AND METHODS: The association study was performed in a two-stage study of 1,069 cases and 1,724 controls to evaluate the association between genetic variants in the MST2 and NSCL/P risk. The potential function of the candidate single nucleotide polymorphism (SNP) was predicted using HaploReg, RegulomeDB, and public craniofacial histone chromatin immunoprecipitation sequencing (ChIP-seq) data. Haploview was used to perform the haplotype of risk alleles. The expression quantitative trait loci (eQTL) effect was assessed using the Genotype-Tissue Expression (GTEx) project. Gene expression in mouse embryo tissue was performed using data downloaded from GSE67985. The potential role of candidate gene in the development of NSCL/P was assessed by correlation and enrichment analysis. RESULTS: Among SNPs in MST2, rs2922070 C allele (P(meta) = 2.93E-04) and rs6988087 T allele (P(meta) = 1.57E-03) were linked with significantly increased risk of NSCL/P. Rs2922070, rs6988087 and their high linkage disequilibrium (LD) SNPs constituted a risk haplotype of NSCL/P. Individuals carrying 3-4 risk alleles had an elevated risk of NSCL/P compared to those who carried less risk alleles (P = 2.00E-04). The eQTL analysis revealed a significant association between these two variants and MST2 in muscle tissue of the body. The MST2 expressed during mouse craniofacial development and over-expressed in the human orbicularis oris muscle (OOM) of NSCL/P patients compared to controls. MST2 was involved in the development of NSCL/P by regulating the mRNA surveillance pathway, the MAPK signaling pathway, the neurotrophin signaling pathway, the FoxO signaling pathway and the VEGF signaling pathway. CONCLUSION: MST2 was associated with the development of NSCL/P.