Single nucleotide polymorphisms (SNPs) are a class of human genetic polymorphisms that are polymorphisms in DNA sequences caused by conversions, reversals, deletions and insertions of individual nucleotides at the genomic level [20]. It occurs in more than 1% of the population, and there is roughly one SNP for every 1000 bases in the human genome. SNPs are also considered to be a major source of human variation, especially when their position in the DNA sequence affects gene expression or function. SNPs have become an important tool for the study of the human genome. At present, the most studied genes of tuberculosis include human leukocyte differentiation antigen genes involved in antigen presentation [21], cytokines or chemokines and their receptor genes involved in inflammation and regulation of immune response [22], nucleosome protein genes involved in macrophage apoptosis or T-cell downregulation [23], and identified pathogen toll-like receptor genes [24], which encode proteins related to the immune response between the body and tuberculosis or participate in some links of the immune response between the body and tuberculosis, and their gene single nucleotide polymorphisms may affect the susceptibility or severity of the host to tuberculosis.
RNA splicing removes pre-mRNA in introns and exon connections and is thus a process of mature RNA. Pre-mRNA splicing is a key step in eukaryotic gene expression[25]. RNA splicing is catalyzed by the giant ribonucleic acid protein complex spliceosome. The major human spliceosome contains five intranuclear small ribonucleoprotein complexes, U1, U2, U4/U6 and U5 snRNP, and more than 100 protein components[26]. Mammalian SF3A is composed of SF3A60 (SF3A3, SAP61), SF3A66 (SF3A2, SAP62), and SF3A120 (SF3A1, SAP114). The SF3A complex is an important component for the formation of active 17S U2 snRNP in mammals. SF3A120 is a constitutive splicing factor and is involved in alternative splicing. Depletion of SF3A120 significantly reduced SF1 mRNA and protein expression levels[27]. SF3A1 is a component of SF3A120 and is involved in the entire alternative splicing process. RNA splicing regulation plays an important role in regulating basic biological processes such as cell proliferation and differentiation, organism development, and maintenance of intracellular homeostasis[28].
SF3A1, as an important member of SF3a, plays an important role in selective splicing. Sha et al. found that stem‒loop 4 of U1 snRNA is essential for splicing and interacts with the U2 snRNP-specific SF3A1 protein during spliceosome assembly[29]. In vivo experiments showed that SF3A1 interacted with the P2X6 subunit, ultimately leading to a decrease in the splicing activity of mRNA[30]. Since the SF3A1 gene plays an important role in splicing, its importance has been gradually recognized with the deepening of whole-gene association studies. The SF3A1 gene is associated with susceptibility to lung cancer[31], breast cancer[32], and inflammatory bowel disease[33] according to a gene-wide association study. Yoshida et al [34] recently found that the mutation rate of SF3A1 is low in most patients with myelodysplastic syndrome (MDS). Jing et al[35] found that the TT or TC genotype at rs2074733 in SF3A1 had a lower risk of pancreatic cancer than the CC genotype in unrelated Han Chinese individuals (OR: 0.59, 95% confidence interval: 0.48–0.73, P < 0.05).
The innate immune system is the first line of defense of the body against pathogens. Mycobacterium tuberculosis is a typical intracellular parasite whose primary target cells in the body are macrophages, and the clearance of intracellular bacteria depends on the natural immune system. The SF3a mRNA splicing complex is required for the innate immune response. SF3A promotes inflammation by inhibiting the production of negative splicing forms of Toll-like receptor (TLR) signaling adaptor myeloid differentiation factor 88 (MyD88). By using RNAi to inhibit SF3a1, subsequent RNA-seq studies showed that when SF3A1 was inhibited, the expression of many TLR signaling pathway genes or mRNA splicing were changed[36]. This study revealed the important role of SF3A1 in innate immunity, but it was based on animal experiments in mice. To date, SF3A1 has not been reported in tuberculosis and infectious diseases. Therefore, the purpose of our study was to further explore the relationship between SF3A1 gene polymorphisms and susceptibility to tuberculosis and to further explore whether SF3A1 gene polymorphisms have any influence on the severity of tuberculosis. We found that allele C of rs2074733 reduced the risk of susceptibility to tuberculosis infection after adjusting for age and sex in 558 cases of severe TB, 579 cases of mild TB and 581 healthy controls. The rs2074733 CC genotype showed a significantly reduced risk of susceptibility to tuberculosis infection compared with genotype TT. In the genetic model analysis, the SNP rs2074733 also showed a significantly reduced risk of susceptibility to tuberculosis infection in additive models. The minor alleles A of rs10376 increased the risk of susceptibility to tuberculosis infection. In addition, the SNP rs10376 also showed a significantly increased risk of susceptibility to tuberculosis infection in additive models. However, the distribution frequencies of alleles, genotypes and gene models of the four tag SNPs showed no significant differences between mild and severe tuberculosis. It is suggested that SF3A1 gene polymorphism is associated with TB susceptibility but not with TB severity. However, this study is based on the Chinese Han population aged 15–45 years old and needs to be further confirmed by other populations.
There are some limitations to our study. First, we compared mild and severe tuberculosis in the subgroup analysis. The definition of severe tuberculosis was based on relevant literature at home and abroad. However, due to the lack of definition standards for severe tuberculosis at present, the results may be affected by our different definitions of the severe tuberculosis population. Second, we only studied the Chinese Han population aged between 15 and 45 years old, which needs to be further verified in other populations. The conclusion of these data is only for the Chinese Han population, and caution should be taken in explaining this finding in other ethnic groups.
In this study, rs2074733 and rs10673 in the SF3A1 gene were associated with TB susceptibility but not with TB severity. This is the first study to investigate the relationship between the SF3A1 gene and TB susceptibility and severity.