Yan-Li Li, Ruo-Peng Yang, Wei Liu, Ping Xia, Jing Feng?

Department of Orthopaedics, First Hospital of Wuhan, Wuhan 430022, China

Keywords:Spinal tuberculosis Susceptibility Gene polymorphisms

ABSTRACT Spinal tuberculosis, as one of the most serious forms of extrapulmonary tuberculosis, is one of the primary causes of spinal deformity and paralysis in developing countries. It immensely affects people's quality of life with high incidences of deformity and disability. The onset of spinal tuberculosis is related to many factors such as gender, age, environment, habits and hereditary factor. As a genetic factor, gene polymorphism plays an important role in the occurrence and development of tuberculosis. This article reviews the research progress of the susceptibility of spinal tuberculosis and its related gene polymorphisms, in order to provide reference for early prevention and treatment of spinal tuberculosis.

1. Introduction

Tuberculosis is a common chronic infectious disease caused by Mycobacterium tuberculosis infection in developing countries,80% of which occur in the lungs, and the remaining 20% of secondary infections occur in other parts such as meninges, cervical lymph, muscles, bones, etc.[1]. These tuberculosis that occurs in all parts of the lungs except the lungs are collectively referred to as extrapulmonary tuberculosis. Spinal tuberculosis is one of the most serious forms of extrapulmonary tuberculosis. Its incidence accounts for 15% of the world's extrapulmonary tuberculosis and 50% of bone and joint tuberculosis. It is one of the main causes of spinal deformity and paralysis in developing countries, Has a high disability rate and case fatality rate [2-4]. It is estimated that people infected with Mycobacterium tuberculosis account for 1/3 of the global population, but only 1/10 of them show clinical symptoms[5,6]. This shows that there are certain predisposing factors for spinal tuberculosis, which have not yet been Clarify. Generally speaking, the incidence of spinal tuberculosis is related to many factors, including gender, age, living environment, habits, genetics,etc. In recent years, the genetic susceptibility of spinal tuberculosis has gradually become a research hotspot in the industry. Domestic and foreign studies are mostly based on case-control. Through the detection of genetic polymorphisms of spinal tuberculosis, it is found that genetic factors play an important role in the susceptibility of spinal tuberculosis. The genetic susceptibility genes of spinal tuberculosis can be roughly divided into human leucocyte antigen(HLA) genes and non-HLA genes[7]. This article reviews the recent research progress on susceptibility and genetic polymorphism of spinal tuberculosis.

2. HLA gene

HLA is the expression product of human major histocompatibility complex (MHC). Its essence is a polygenic allogeneic antigen,which can be divided into type I antigen and type II antigen according to its distribution and function. Class I antigens are encoded by the three sites of HLA A, B, and C. Class II antigens are controlled by the HLA-D region, which contains 5 subregions of DP,DM, DO, DQ and DR [8]. HLA has a high degree of polymorphism,so it has become the most representative marker of individual genetic specificity. Studies have shown that compared with healthy people, the frequency of HLA genes in pulmonary tuberculosis patients is significantly higher [9], which shows that HLA genes have an important impact on susceptibility to tuberculosis. Using wholeexome sequencing to screen and analyze the susceptibility genes of spinal tuberculosis, Shen et al. used the Han population in southern China as the research object, and found that the HLA-DQA1 gene C>G mutation is related to the occurrence of spinal tuberculosis.This mutation leads to a decrease in HLA-DQA1 mRNA levels, and an increase in serum inflammatory factors IL-6 and TNF-a levels,which may eventually lead to the onset of spinal tuberculosis [10],which further supports the hypothesis that HLA-DQA1 is a STB susceptibility gene. Other studies have shown that some genes of different gene loci of HLA are often inherited in linkage, so there is an imbalance [11]. Therefore, it is difficult to clarify the relationship between genes and diseases, and further research is needed.

3. Non-HLA genes

3.1 Monocyte chemotactic protein-1 (MCP-1) gene

Monocyte chemoatracttant protein-1 (MCP-1) is a representative of the β subfamily of chemotactic cytokines, which can be divided into two types: MCP-1α and MCP-1β according to the molecular mass [12]. MCP-1 can activate and chemoattract a variety of cells such as monocytes and macrophages, enhance its lethality against Mycobacterium tuberculosis by increasing the concentration of intracellular free oxygen, and regulate the immune response related to tuberculosis. Studies have found that MCP-1 gene polymorphism is closely related to susceptibility to tuberculosis; MCP-1 plays an important role in the early immune response process of tuberculosis infection [13]. Zhang Rubing and others found that the serum MCP-1 concentration of patients with spinal tuberculosis was significantly higher than that of tuberculosis patients and healthy patients [14], which proved that the expression of MCP-1 is related to the incidence of spinal tuberculosis. Gao Qile et al. found that the distribution frequency of MCP-1-2518GG genotype in fasting venous blood in patients with spinal tuberculosis in the early morning was significantly higher than that of healthy people. It is speculated that both the GG genotype and G allele may be related to the onset of spinal tuberculosis [15]. Zhang Hongqi and others studied the polymorphisms at MCP-1-362 in patients with confirmed spinal tuberculosis in Hunan Han nationality and healthy people and found that the three genotypes of MCP-1-CC, GG and GC were distributed in the case group and the control group. There is a significant difference between the two, in which the distribution frequency of the CC genotype in the case group is significantly increased [16].Similar to the results of Guo et al.'s research, it was found that the high frequency distribution of MCP-1-362-CC genotype is closely related to the susceptibility to spinal tuberculosis [17].

3.2 Vitamin D receptor (VDR) gene

Vitamin D receptor (VDR) is a nucleophilic protein that can mediate 1,25(OH), D3 (the main active form of vitamin D) to achieve multiple biological functions. Vitamin D can maintain the body's calcium and phosphorus metabolism, regulate cell proliferation and differentiation, and mainly depends on its combination with VDR. The human VDR gene is located on the long arm of chromosome 12 and has a variety of single nucleotide polymorphisms, including ApaI, BsmI, FokI, TaqI and other sites[18]. VDR gene polymorphism can cause changes in amino acid sequence and slow down gene transcription, so that vitamin D cannot be fully and effectively combined with VDR, and gradually reduce the activity and autophagy ability of monocytes and macrophages,which affects the human body against Mycobacterium tuberculosis The immune defense [19,20]. A number of studies have shown that [21,22], VDR gene polymorphism is associated with the susceptibility of bone and joint tuberculosis and tuberculosis. When Wang et al. used PCR-RFLP technology to analyze the VDR-Fok I polymorphism,they found that compared with the control group, the frequency of the VDR-Fok I-FF genotype and F allele in spinal tuberculosis patients was significantly higher, and increased to a certain extent.The risk of spinal tuberculosis is basically the same as the findings of Zhang et al., suggesting that the VDR-Fok I gene polymorphism,especially the FF genotype, contributes to the susceptibility of spinal tuberculosis [23, 24]. In addition, the study by Panwar A et al. also found that vitamin D deficiency is particularly prominent in patients with spinal tuberculosis, and the VDR-Apa I gene polymorphism alone or in combination with other genes may lead to the susceptibility of spinal tuberculosis [25].

3.3 Interferon-γ (IFN-γ) gene and its receptor gene

Interferon (IFN) can be divided into type I, type II and type III, and is a class of proteins with high species specificity. Type I IFN mainly includes α,β,ω, δ and other subtypes; and interferon-γ (IFN-γ)is the only type II interferon, also called immune interferon, which participates in the regulation of human immunity Response; Type III interferons include IFN-λ1, IFN-λ2, IFN-λ3 [26]. IFN-γ is usually produced by T lymphocytes stimulated by mitogens,which can induce the activation of macrophages and help the body defend against Mycobacterium tuberculosis. Wu Taifeng and others found that the expression of serum INF-γ in patients with spinal tuberculosis was significantly increased [27], suggesting that INF-γ may be involved in the immune regulation of spinal tuberculosis.Studies have reported that if the mouse's IFN-γ gene is disrupted, it will not be able to produce reactive nitrogen intermediates that can restrict the growth of Mycobacterium tuberculosis when infected with Mycobacterium tuberculosis [28]; similarly, genetic factors cause partial or partial IFN-γ receptors People with complete deficiency are more susceptible to tuberculosis infection. The above studies all suggest that IFN-γ and IFN-γ receptors play an important role in the process of tuberculosis infection and pathogenesis. Li et al. studied the three SNPs of IFN-γ-rs2069718 gene, IRGMrs10065172 gene and MBL2-rs11003125 gene in 183 cases of pulmonary tuberculosis, 177 cases of spinal tuberculosis and 360 cases of healthy Han people. The results of the test found that the genetic distribution of IFN-γ-rs2069718 genotype in pulmonary tuberculosis and spinal tuberculosis patients was different,and the correlation between IFN-γ-rs2069718 genotype and tuberculosis susceptibility was confirmed [29]. Wei et al. found that the IFN-γ+874t/A (rs2430561) polymorphism may be related to tuberculosis susceptibility through a meta-analysis, and can be used as a predictive biomarker of combined onset [30]. The IFN-γ gene is located on chromosome 12 and has 6 polymorphic sites. At present,the research on IFN-γ and its receptor genes at home and abroad mainly focuses on tuberculosis, and its genetic polymorphism is in the susceptibility to spinal tuberculosis. The specific role needs to be further explored.

3.4 Tumor Necrosis Factor-α (TNF-α) Gene

Tumor necrosis factor (TNF) is the earliest cytokine found to induce hemorrhagic necrosis in tumor tissue cells. It is mainly produced by macrophages, NK cells and T lymphocytes. It can be divided into TNF-α and TNF- Two types of β. Among them,TNF produced by monocyte-macrophages is called TNF-α, and its biological activity accounts for 70-90% of TNF. It participates in the body's immune response and induces macrophages to resist the invasion of Mycobacterium tuberculosis. Zheng et al. studied the relationship between TNF-α polymorphism and spinal tuberculosis and found that compared with the control group, patients with spinal tuberculosis showed a significantly higher T allele on the TNF-α-857 gene polymorphism And CT genotype frequency [31], suggesting that TNF-α-857 gene polymorphism may be a risk factor for spinal tuberculosis. Zhou et al. used a similar method to study the relationship between the TNF-α gene and the susceptibility of spinal tuberculosis in the southern Chinese population. The results showed that the TNF-α-238A allele has a protective effect on spinal tuberculosis, and TNF-α-308G>A (rs1800629 ) Has nothing to do with the susceptibility of pulmonary tuberculosis and spinal tuberculosis in southern China [32]. On the contrary, Zhang Yukun and others used spinal tuberculosis patients in Xinjiang as the research population. After testing and statistics, they found that TNFα-308A alleles and GA gene polymorphisms at -238 are associated with spinal tuberculosis susceptibility [33]. Huang et al. conducted a meta-analysis on the association between TNF-α-308 and -238 gene polymorphisms and susceptibility to spinal tuberculosis, but the results suggested that TNF-α gene polymorphisms did not significantly lead to spinal tuberculosis [34]. Different researchers tested the same indicators, but the results were different. Based on this phenomenon, Cao Taijian and others conducted studies on TNF-α gene polymorphisms in patients with spinal tuberculosis of different ethnic groups in Qinghai. The results showed that TNF-α gene polymorphisms are related to the incidence of Tibetan spinal tuberculosis in Qinghai and are related to Han people. There is no obvious association between the incidence of spinal tuberculosis in Hui nationality [35]. It can be speculated that whether TNF-α gene polymorphism can be used as an indicator of susceptibility to spinal tuberculosis may be related to geography and ethnicity.

3.5 Interleukin (IL) gene and its receptor gene

Interleukin (IL) refers to aLymphokines that act in white blood cells or immune cells have complex functions such as transmitting information, activating and regulating immune cells. When Mycobacterium tuberculosis invades the body, interleukins regulate the body's immunity by binding to their receptors, and play an important role in the pathogenesis of tuberculosis. The IL receptor gene is mainly related to the pathogenesis of tuberculosis. Chen Yue et al. found that the IL-10 gene rs1800896 site may be a susceptibility site for tuberculosis, and it is more likely to carry the G allele [36]. The research results of Li Yang et al. showed that in Chinese Han pulmonary tuberculosis patients, IL-6, IL-4, IL-10 genes have significant polymorphisms and are associated with pulmonary tuberculosis infection [37]. In addition, Lu Lu et al. found that the genetic polymorphisms of the rs568408G/A locus in the IL-12A gene and the rs3212227A/C locus in the IL-12B gene may be related to the pathogenesis of bone and joint tuberculosis in the study of the Guangxi Zhuang population No obvious correlation[38]. Conducting research in the same way in the same area, Wu Zhaoyuan and others found that the gene polymorphisms of IL-23 receptor rs10489629T/C and rs10889675C/A are related to the susceptibility of bone and joint tuberculosis [39]. At present, there are few studies on IL gene and receptor gene polymorphisms and the susceptibility of spinal tuberculosis. There is only one report showing that the rs1800871(A/G) polymorphism of IL-10 gene is related to the susceptibility of spinal tuberculosis. Carrying the G allele may increase the risk of spinal tuberculosis [40]. It can be seen that there is a correlation between IL gene polymorphism and the incidence of spinal tuberculosis. As for whether there are regional or ethnic differences in TNF-α gene, it is worth continuing to study.

3.6 Osteopontin (OPN) gene

Osteopontin (Osteopontin, OPN) is a glycosylation-based protein that mainly exists in the extracellular matrix. OPN is an important factor that induces cellular immunity, and it also plays an important role in the mineralization and absorption of bone matrix [41]. OPN can promote the secretion of IFN-γ and IL-12, induce T cells to differentiate into Th1 cells, and play a key role in the body damage caused by Mycobacterium tuberculosis infection [42]. A number of studies have shown that the serum OPN expression level of tuberculosis patients is significantly higher than that of healthy people, suggesting that OPN may be involved in the immune regulation of tuberculosis [43,44]. When Wu Taifeng and others studied the significance of serum OPN expression in patients with spinal tuberculosis, they found that OPN levels in patients with spinal tuberculosis were significantly increased, which shows that OPN may be related to the incidence of spinal tuberculosis[45]. Through a case-control study, Wang et al. found that the GG genotype and G allele in the OPN-66T>G gene polymorphism in patients with spinal tuberculosis had a higher frequency, suggesting that the OPN-66T>G gene polymorphism and the susceptibility of spinal tuberculosis Related [23]. At present, there are few research reports on OPN gene polymorphism and susceptibility to spinal tuberculosis. Whether the incidence of spinal tuberculosis is related to gene polymorphisms at other sites of OPN needs further research.

3.7 Other genes

P2X7 receptor (P2X7 peceptor, P2X7R) is an important regulator in the purinergic receptor family, involved in important physiological processes such as apoptosis, immune defense and bone turnover.Zhou et al. studied the relationship between 179 patients with confirmed spinal tuberculosis and the genetic polymorphisms of P2X7R-762T and -489T, and the results suggest that the P2X7R-762CC genotype and -762C allele increased the incidence of spinal tuberculosis to a certain extent. Risk [46].

The 2',5'-oligoadenylate synthetase 1 (2',5'-oligoadenylate synthetase, OAS1) gene is one of the effector genes induced by INF-γ, which participates in the body's specific immunity and nonspecific immunity. The body plays an important role in resisting the virus. Zhang Ting et al. studied the relationship between OAS1 gene polymorphism and susceptibility to spinal tuberculosis and found that OAS1-rs1131454AG, AA genotype and spinal tuberculosis are related [47].

In addition to the above two genes, there are related studies on genes such as TLR4, Fat-1, MIF, etc. [48-50] confirmed that their polymorphisms are related to the onset of spinal tuberculosis, but the scale needs to be expanded. Further verification.

4. Summary

At present, there are more and more studies on the susceptibility and genetic polymorphism of spinal tuberculosis, but the results of the studies are quite different. Differences in individuals, environments,regions, races, and gene interactions may cause different degrees of research results. Impact. Existing studies mostly focus on the relationship between single gene or single locus polymorphism and susceptibility to spinal tuberculosis in a certain area, and there are certain limitations in the research methods. Researchers need to increase the sample size, adopt multi-center, multi-ethnic, and multi-gene research at the same time, and also need to consider the combined effect of genes. In-depth study of the relationship between susceptibility to spinal tuberculosis and genetic polymorphisms is helpful to the early prevention of spinal tuberculosis and can lead the treatment of spinal tuberculosis into a new stage of individualization and precision.

Author’s Contribution Li Yanli is the main author of the review, completing the collection and analysis of relevant literature and the writing of the first draft of the paper; Yang Ruopeng and Liu Wei participated in the analysis and sorting of the literature; Xia Ping is the creator of the project;Feng Jing is the project The person in charge and instructor in charge of the essay writing. All authors have read and agreed to the final text.