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

Xinze Xu; Junyan Lin; Xiaofeng Li; Qinghua Shao; Xing Cui; Guirong Zhu; Shu Lou; Weijie Zhong; Luwei Liu; Yongchu Pan

doi:10.1016/j.gene.2023.147459

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

Gene. 2023 Jul 15:873:147459. doi: 10.1016/j.gene.2023.147459. Epub 2023 May 3.

Authors

Xinze Xu¹, Junyan Lin¹, Xiaofeng Li¹, Qinghua Shao¹, Xing Cui¹, Guirong Zhu¹, Shu Lou¹, Weijie Zhong², Luwei Liu³, Yongchu Pan⁴

Affiliations

¹ Jiangsu Province Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, 210000, China; Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, 210000, China; Department of Orthodontics, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, 210000, China.
² Department of Stomatology, Dushu Lake Hospital Affiliated to Soochow University, Suzhou, China Suzhou, 215127, China; Department of Stomatology, Medical Center of Soochow University, Suzhou, 215127, China. Electronic address: [email protected].
³ Jiangsu Province Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, 210000, China; Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, 210000, China; Department of Orthodontics, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, 210000, China. Electronic address: [email protected].
⁴ Jiangsu Province Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, 210000, China; Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, 210000, China; Department of Orthodontics, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, 210000, China. Electronic address: [email protected].

PMID: 37141954
DOI: 10.1016/j.gene.2023.147459

Abstract

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.

Keywords: Genetic variants; MST2; NSCL/P.

MeSH terms

Animals
Case-Control Studies
Cleft Lip* / genetics
Cleft Palate* / genetics
Genetic Predisposition to Disease
Genotype
Haplotypes
Humans
Mammals
Mice
Polymorphism, Single Nucleotide
Protein Kinases / genetics

Substances

Protein Kinases