engleski

The role of single nucleotide polymorphisms of genes HMGB1 and AGER in the susceptibility and clinical features of patients with IgA vasculitis

Introduction: The pathogenesis of IgA vasculitis (IgAV) is complex and still insufficiently elucidated. It is a multifactorial disease in the development of which, in addition to numerous environmental factors, the genetic background also plays an important role. Previous genome-wide association study studies have established an association between IgAV susceptibility and the HLA class II genes, although many small studies have indicated the importance of variants in various non-HLA genes in the manifestation of different disease phenotypes. Objectives: The aim of this research was to investigate single nucleotide polymorphisms (SNPs) of genes HMGB1 and AGER encoding for high mobility group box-1 (HMGB1) and receptor for advanced glycation endproducts (RAGE), both acting as mediators of inflammation, in the susceptibility and clinical features of patients with IgAV. Methods: Genomic DNA was extracted from whole blood samples after which the HMGB1 and RAGE gene polymorphisms were genotyped using a real-time polymerase chain reaction. The presence and frequency of polymorphisms in HMGB1 (rs2249825, rs1045411, rs1060348, rs1412125 and rs41369348) and RAGE (rs1800625, rs1800624, rs2070600 and rs3134940) were determined. Clinical data were collected from database with systematic analysis of patients with IgAV in Croatian population from two Croatian University Centers for pediatric rheumatology and nephrology care. Results: The research included 81 pediatric IgAV patients, of whom 45 were boys and 36 girls, as well as 150 age- and sex-matched healthy controls without any history of autoimmune disease. The median (range) age of IgAV patients was 6.25 (4.60-8.20) years, and among them 71.6% had joint involvement, 29.62% had gastrointestinal manifestations, while 27.16% patients developed nephritis. The purpuric rash which extended from lower extremities to the trunk, upper extremities and face (generalized rash) was present in 43.20% of patients and 27.16% had at least one relapse. Among the analyzed polymorphisms, only in the rs1412125 there was a deviation from the Hardy Weinberger equilibrium. There was no statistically significant association of the analyzed polymorphisms with the IgAV susceptibility, compared to healthy controls. However, the two polymorphisms proved to be linked with a well- defined clinical phenotype. Polymorphism rs2070600 was significantly related with the development of nephritis in IgAV, while rs1412125 was associated with gastrointestinal involvement. The IgAV patients carrying the T allele (rs2070600) of the AGER had significantly increased risk of nephritis development compared with the IgAV patients with homozygous CC genotype in dominant (OR 4.05, CI 1.09-15.03, p = 0.037) and additive genetic models (OR 3.95, CI 1.16-13.47, p = 0.049). The minor C allele (rs1412125) of the HMGB1 was found to significantly increase the risk of gastrointestinal involvement in overdominant model with an allelic odd ratio of 2.78 (CI 1.04-7.43, p = 0.04). Conclusion: Although neither of analyzed HMGB1 and RAGE polymorphisms was not associated with IgAV susceptibility, our results indicated that these polymorphisms may be involved in the pathogenesis of IgAV with possible effect on different disease phenotypes. SUPPORT: Croatian Science Foundation project IP- 2019-04-8822

IgA vasculitis ; HMGB1 ; AGER ; polymorphism

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