STAT4 gene polymorphism may be associated with microscopic polyangiitis susceptibility in a Chinese Guangxi population: A case-control analysis based on propensity score matching

Background: Microscopic polyangiitis (MPA) is a severe multisystem autoimmune disease featured by small-vessel vasculitis with few or no immune complex, also has a significant genetic predisposition. Growing evidence has confirmed that STAT4 gene is tightly associated with multiple autoimmune diseases, but its contribution to MPA onset is still elusive.

Objective: The aim was to investigated the association between STAT4 gene polymorphisms (rs7572482, rs7574865 and rs12991409) and MPA susceptibility in a Guangxi population of China.

Methods: 260 MPA patients and 295 healthy adult volunteers were selected, 1:1 propensity score matching (PSM) was performed to control potential confounding variables, then 199 MPA patients and 199 healthy adult volunteers matched in gender, ethnicity and age were included in this study. High-throughput sequencing and multiplex PCR were applied to detect the target STAT4 SNPs. SHEsis and SNPstats were used to evaluated the allele frequency, genotype frequency, linkage disequilibrium (LD), haplotype, and the association between SNPs and the MPA susceptibility in multiple genetic models. SNP-SNP interactions were explored based on generalized multifactor dimensionality reduction (GMDR) algorithm. Some clinical indicators, such as renal pathology and therapeutic effects, were collected and compared.

Results: The allele and genotype frequencies of rs7574865 displayed significant diversities between case group and control group (p < 0.05). Strong LD was found between rs7572482 and rs12991409 (D'=0.9). The haplotype GGT was related to a reduced risk of MPA (OR = 0.661, 95 %CI: 0.469-0.931, p = 0.017), and haplotype GTT might perform an increased risk of MPA (OR = 1.922, 95 %CI: 1.225-3.015, p = 0.004). Rs7574865 polymorphism was associated with an increased risk of MPA in codominant model (OR:2.03; p = 0.0093), dominant model (OR: 1.88p = 0.0023), and overdominant model (OR:1.57; p = 0.027). In Han and male subgroups, rs7574865 polymorphism dramatically increased the MPA risk. GMDR suggested that STAT4 rs7574865 and PTPN22 rs3811021 composed the most risk combinations (p = 0.0010). Moreover, renal pathology, Birmingham vasculitis activity score (BVAS), and alanine aminotransferase (ALT) might be linked with STAT4 gene polymorphisms (p < 0.05).

Conclusions: The genetic polymorphism of STAT4 may be associated with MPA susceptibility and renal pathological classification in Chinese Guangxi population; the T allele of rs7574865 may be an important risk factor for MPA.