To date, several lines of evidence have shown that genetic factors may play a part in DLSS. We performed a WES study design on 50 patients and 25 controls to detect genes contributing to DLSS. In our study, we discover several novel candidate genes that have not been previously identified in relation to DLSS.
Prior studies have identified several candidate genes in association with lumbar disc degeneration. Jason et al. carried out a genome-wide association study, and multiple SNPs identified suggested a multi-factorial origin of DLSS (11). HLA-DRB1 genotyping was reported to increase the risk of developing pain after surgery or lumbar disc herniation (12). A variant in the PARK2 gene associated with Lumbar disc degeneration by influencing methylation of the PARK2 (13). In this study, HLA-DRB1 and PARK2 are identified as susceptibility genes associated with a predisposition to DLSS. Lumbar disc degeneration causes intervertebral collapse, which may accelerate the development of DLSS. Obviously, there could be some overlapped D:\æœç‹—émechanism between the two degenerative processes. To some extent, our results are in accordance with the previous studies. The specific mechanism of the two genes contributing to DLSS needs further investigation.
In this study, ACTR8, AOAH, BCORL1, MKRN2, NRG4, NUP205 were novel genes reported in correlation with DLSS. ACTR8 is located on chromosome 3p21.1 and has 14 exons. Mutation in the ACTR8 was associated with lineage-specific expression in primates (14). AOAH is on chromosome 7p14.2, encoding both the light and heavy subunits of acyloxyacyl hydrolaseregion. AOAH polymorphisms have been reported to associate with asthma, chronic rhinosinusitis, and bronchial hyperreactivity (15, 16). Located on chromosome Xq26.1, BCORL1 encoding a transcriptional corepressor that is found tethered to promoter regions by DNA-binding proteins. Pathogenic variants in BCORL1 underlie a newly identified X-linked epigenetic syndrome (17). MKRN2, on chromosome 3p25.2, encodes a probable E3 ubiquitin ligase containing several zinc finger domains. MKRN2 is involved in the regulation of inflammatory response, non-small-cell lung cancer (18, 19). NRG4 is located on chromosome 15q24.2. NRG4 is a member of the epidermal growth factor (EGF) family of extracellular ligands, highly expressed in adipose tissues, enriched in brown fat, and markedly increased during brown adipocyte differentiation (20). NUP205 on chromosome ch7q33 encoding a nucleoporin, which is a subunit of the nuclear pore complex that functions in the active transport of proteins, RNAs, and ribonucleoprotein particles between the nucleus and cytoplasm. Mutations in NUP205 are associated with steroid-resistant nephrotic syndrome (21).
Several other candidate genes associated with DLSS were identified including GPRIN2, MYOT, PDE4DIP, etc. Some pathways were enriched through analysis of the differentially expressed genes between the patient and control groups. These genes had never been reported to be associated with DLSS,
We recognize several limitations of this study. First, the number (50) is still inadequate for genetic study. Concerning the inadequate number, we enroll three family cases in this study. Numerous candidate genes identified in this study warrant further investigation. Functional study should be conducted to determine the mechanism and pathways in which the genes involved affect the development of the disease. As a next step, we will continue increasing the sample size to reveal more susceptible genes.
In conclusion, in this study, we identifed mutations with DLSS in Chinese patients for the first time using WES. From our analysis, we found two potential pathogenic loci for DLSS on HLA-DRB1 and PARK2, which have previously been reported to be associated with lumbar disc degeneration, and SNPS on several novel genes including ACTR8, AOAH, BCORL1, MKRN2, NRG4, NUP205, etc, which had not previously been reported to be DLSS. Further replication and functional studies are required to confirm these positive findings, helping to detect early and to provide novel therapeutic approaches of DLSS.