Abstract
IgA nephropathy is the most prevalent primary glomerulonephritis worldwide, with identical immunopathological characteristics caused by multiple etiologies as well as influenced by geographical and ethnical factors. To elucidate the role of immunologic and inflammatory mechanisms in the susceptibility to IgA nephropathy, we explored single nucleotide polymorphisms of related molecules in the immune pathways. We searched the PubMed database for studies that involved all gene variants of molecules in the 20 immunologic and inflammatory pathways selected from the Kyoto Encyclopedia of Genes and Genomes database. The odds ratios with their corresponding 95% confidence intervals in six genetic models (allele model, dominant model, homozygote model, heterozygote model, overdominant model, and recessive model) were summarized using fixed or random effect models. Subgroup analysis was conducted based on different ethnicities with generalized odds ratios. Heterogeneity was evaluated using the Q and I2 tests. Begg’s funnel plot and Egger’s linear regression test were used to evaluating possible publication bias among the included studies, and sensitivity analysis was used to test the stability of the overall results. A total of 45 studies met our selection criteria and eight related genetic association studies were retrieved, including 320 single-nucleotide polymorphisms from 20 candidate pathways, ranging from 2000 to 2021. A total of 28,994 healthy people versus 20,600 IgA nephropathy patients were enrolled. Upon meta-analyzed results that TGFB1 (rs1800469, rs1982073, rs1800471), IL-1B (rs1143627), IL-18 (rs1946518), and TLR1 (rs5743557) showed effect with or without ethnicity difference. And 10 variants presented stable and robust related to IgA nephropathy. This research showed that genetic variants are related to the immunologic and inflammatory effects of IgA nephropathy pathogenesis. The meta-analysis results supported the previous researches, and may help deepen the understanding of pathogenesis and explore new targets for IgA nephropathy-specific immunotherapy.
Highlights
IgA nephropathy (IgAN) is the most prevalent primary glomerulonephritis in the world, and 30–40% of patients progress to the end-stage renal disease within 20–30 years after diagnosis, requiring kidney transplantation or renal replacement therapy [1]
Our meta-analysis found that rs4833095 and rs5743557 in Toll Like Receptor 1 (TLR1) increases the risk of IgAN both in Chinese and Korean pediatric patients group; upon haplotype analysis, we found that Trs4833095 and Trs5743557 haplotype were associated with IgAN
The IL-18 level hinted at development of glomerulonephritis and genotype of IL18 rs1946518CC was related with a higher level of IL-18 mRNA, the current study revealed that rs1946518 may not be associated with clinical symptoms and pathology grade in IgAN [26, 55]
Summary
IgA nephropathy (IgAN) is the most prevalent primary glomerulonephritis in the world, and 30–40% of patients progress to the end-stage renal disease within 20–30 years after diagnosis, requiring kidney transplantation or renal replacement therapy [1]. The disease appears to be sporadic, there is an increasing number of reports showing familial clusters of IgAN These familial cases have poorer renal outcomes and have fewer gender differences than sporadic cases [5]. The characteristics of IgAN includes an IgA deposition in the glomerular mesangium area with complexes which activate mesangial cells to overproduce cytokines, chemokines, and complements [8]. These mesangial-released inflammatory mediators cause local glomerular damage and may aggravate podocytes and the renal tubular interstitium through humoral crosstalk [9]. The generalized linear odds ratio (ORG) analyzes the account of cases/healthy control pairs in the study to indicate the mutational load of disease susceptibility [11]
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