Association of tyrosine kinase 2 polymorphisms with susceptibility to microscopic polyangiitis in a Guangxi population

Introduction

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a heterogeneous group of small vasculitis of unknown etiology, characterized by the presence of proteinase 3 (PR3) and myeloperoxidase (MPO) in the serum (Kitching et al., 2020). This condition frequently involves inflammation and necrosis of the vessel wall. There are several types of this systemic vasculitis, including granulomatosis with polyangiitis (GPA) (Puechal, 2020), microscopic polyangiitis (MPA) (Aiyegbusi et al., 2021; Hunter et al., 2020), and eosinophilic granulomatosis with polyangiitis (EGPA) (Treccani et al., 2024). The distribution of AAV subtypes varies by region. GPA is prevalent in Northern Europe (Berti et al., 2017), while MPA is more common in China and Japan (Fujimoto et al., 2011; Watts & Scott, 2012).

The incidence of MPA ranges from 0.5 to 24.0 cases per million person-years, and its prevalence ranges from 9.0 to 94.0 cases per million person-years, with onset ages ranging from 55 to 75 years (Kitching et al., 2020). In Asia, the reported prevalence of AAV is between 46 and 421 per million population (Kawasaki & Tsuchiya, 2021). Kidney damage occurs in nearly all patients with MPA, characterized by necrotizing and crescentic pauci-immune glomerulonephritis. The deterioration of renal function can lead to end-stage renal disease and increased mortality (Binda, Moroni & Messa, 2018).

The human leukocyte antigen (HLA) region is a significant genetic risk factor for AAV (Trivioli et al., 2022). Genome-wide studies have identified a unique association between MPA and HLA-DQ (Li et al., 2021). In Chinese populations, the alleles HLA DQA1*03:02 and DQB1*03:03 are associated with MPO-AAV susceptibility (Wang et al., 2019). Similarly, in Japanese populations, these alleles are associated with both MPO-AAV susceptibility and recurrence risk (Kawasaki et al., 2023). The genetic studies enhance our understanding of the genetic susceptibility factors contributing to AVV, thereby improving patient management and treatment strategies.

Tyrosine kinase 2 (TYK2) is a vital signal transduction kinase in Janus kinase (JAK)/signal transducer and activator of transcription signaling pathway (Gonciarz et al., 2021), which is crucial in differentiating T helper 1 (Th1) and T helper type 17 (Th17) cells. Dysfunction of TYK2 can contribute to the development of autoimmune and inflammatory diseases (Muromoto et al., 2021). The necessity of TYK2 activity for interleukin (IL)-12, IL-23, and type I interferon (IFN1) signaling has been demonstrated experimentally in mice with TYK2 deficiency (Gorman et al., 2019). Moreover, inhibiting TYK2 activity has been reported to block the downstream signal transduction of IL-12 and other cytokines (Elyoussfi et al., 2023).

TYK2 gene mutations are genetically linked to ankylosing spondylitis, psoriasis, Crohn’s disease, ulcerative colitis, type 1 diabetes, multiple sclerosis (MS), lupus erythematosus (SLE), and rheumatoid arthritis (RA) (Parkes et al., 2013). Currently, research indicates that multiple selective inhibitors of TYK2 have been approved for treating autoimmune diseases, such as plaque psoriasis (Rusinol & Puig, 2023; Yuan et al., 2023). Novel TYK2 inhibitors are expected to have significant clinical impacts (Muromoto et al., 2021). Previous research has reported a close association between TYK2 variants rs34536443 and AAV in European individuals (Ortiz-Fernandez et al., 2020); however, no reports currently exist on the association between TYK2 gene rs2304256, rs280519, rs1272027 variants and patients with MPA.

Materials and Methods

Results

Discussion

Current research indicates that MPA is closely associated with genetic factors, environmental influences, and patient age (Hunter et al., 2020). In this case-control study, we examined the relationships between three potential effect SNPs of the TYK2 gene and MPA risk in a Guangxi population in China. TYK2 is the first member of the JAK family, a 27.9-kb gene with 25 exons located on chromosome 19p13.2 (Lindqvist et al., 2000). This gene moderates immune responses to IL-12, IL-23, IFNα, and Th17 (Gonzalez Lopez de Turiso & Guckian, 2022). Research has shown that IL-12, IL-23, IFNα, Th1, and Th17 are closely associated with MPA (Ortiz-Fernandez et al., 2020; Yuan et al., 2023). For example, in an ANCA-mediated mouse model of experimental vasculitis, Hoshino et al. (2008) found that activated neutrophils produced IL-17A and IL-23 via the classical complement pathway in response to MPO-ANCA. This pathway provides a local environment that promotes IL-17 production and Th17-mediated autoimmunity, becoming the first step in initiating chronic autoimmune inflammation (Hoshino et al., 2008).

Rs2304256 is one of the most common SNPs of TYK2, located in exon 8, and its genetic association has been widely investigated (Gonciarz et al., 2021; Morand et al., 2024). Although rs2304256 is associated with SLE in Finnish, Swedish, British (Cunninghame Graham et al., 2007; Hellquist et al., 2009; Sigurdsson et al., 2005; Suarez-Gestal et al., 2009), and Chinese Han (Tang et al., 2015) populations, it shows reversed association in Hong Kong (Li et al., 2011) and Japanese (Kyogoku et al., 2009) populations. TYK2 rs2304256 was verified to be closely related to systemic sclerosis susceptibility (SSc) in the European population (Lopez-Isac et al., 2016), while the results were negative in the Chinese Han SSc population (Liu et al., 2021). These inconsistencies appear to arise from differences in geography and ethnicity (Liu et al., 2021). Pellenz et al. (2021) pooled data from 34 articles for a meta-analysis assessing the impact of multiple TYK2 variants on susceptibility to autoimmune diseases. Their data suggested that rs2304256 is a susceptibility factor for several autoimmune diseases, including SLE, MS, and rheumatoid RA, with the A allele acting as a protective factor (Pellenz et al., 2021). Our study illustrated that the rs2304256 (C > A) variant in the overdominant model potentially decreases susceptibility to MPA in males. This effect is because the A allele contributes to the substitution of valine 362 with phenylalanine in the JAK homologous four region. This domain is crucial for the interaction between TYK2 and IFNAR1, which is essential for maintaining IFNAR1 expression on the cell membrane. The amino acid substitution affects the processing of precursor mRNA (Li et al., 2020), leading to the downregulation of IFN-α signaling and subsequent reduction in proinflammatory cytokines and inflammation (Marroqui et al., 2015). Additionally, both the PolyPhen-2 and sorting intolerant from tolerant tools indicate that rs2304256 is a benign variant (Adzhubei et al., 2010; Kumar, Henikoff & Ng, 2009), aligning with our research findings.

The rs280519 and rs12720270 variants are located in the TYK2 intron region. An earlier meta-analysis, including 16,335 patients with SLE and 30,065 controls, revealed that the rs280519 polymorphism was significantly associated with SLE risk in Caucasians and Asians (Lee & Bae, 2016). A Turkish study involving 60 patients with Crohn’s disease and 151 patients with ulcerative colitis found that the rs280519 AA genotype was a risk factor for ulcerative colitis, while the AG genotype was a protective factor for ulcerative colitis and Crohn’s disease (Can et al., 2015). Affected by the IFN signaling pathway, the rs280519 (A > G) G allele may influence the severe National Institute on Aging classification in patients with chronic hepatitis C (Lopez-Rodriguez et al., 2017). Moreover, both the rs280519 and rs12720270 variants reduced the risk of juvenile idiopathic arthritis in the Chinese Han population (Qian et al., 2022). Additionally, rs12720270 may downregulate coronavirus disease 2019 severity by decreasing TYK2 expression (Zabihi Rizi et al., 2023). Our study results showed that rs280519A > G might be related to autoimmune and chronic inflammatory diseases, which is consistent with previous research findings. Similarly, in the codominant and overdominant models, the AG genotype of rs280519 can reduce male susceptibility to MPA. In the overdominant model, the GA genotype of rs12720270 can also reduce male susceptibility to MPA. We hypothesize that the intronic variants rs280519 and rs12720270 may cause splicing abnormalities, intronic mutations, protein-coding disruption, altering of residue positions, and loss or insertion of the internal coding frame (Bryen et al., 2019). This may lead to abnormal expression of TYK2, thereby affecting the cytokine signaling pathway (Zabihi Rizi et al., 2023) and ultimately reducing susceptibility to MPA. However, no significant effects were found in females across the three loci (Table 4). Overall, this study explored the relationship between TYK2 gene polymorphisms in the Guangxi population and susceptibility to MPA. It revealed that TYK2 gene polymorphisms rs2304256, rs280519, and rs12720270 in the male population of Guangxi may be associated with susceptibility to MPA. The strength of this study include the subgroup analysis across various genetic models and multiple SNP interactions. However, as a single-center retrospective study with limited cases, these conclusions require validation through larger, multi-center, prospective clinical studies.

Conclusions

This study found that mutations in the TYK2 gene—rs2304256, rs280519, and rs12720270—may be associated with a reduced risk of MPA in the male Chinese population in Guangxi. The A allele of SNP rs2304256 may be a protective factor against MPA, while the G alleles of SNPs rs280519 and rs12720270 are protective factors against MPA. However, the potential molecular mechanisms require further investigation. For example, we can use gene editing technology to study the effect of TYK2 gene mutations on cell function and animal phenotypes to better understand their role in the pathogenesis of MPA and provide a valuable theoretical basis for its treatment.

Supplemental Information