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Genetic study on HLA class II and class III region in the disease associated with IgA nephropathy
1Department of Immunology, National Children's Hospital Medical Research Center, Tokyo, Japan.
Insights
Complement 4 (C4) gene deletions are more common in patients with IgA nephropathy (IgAN) and Henoch-Schönlein purpura nephritis (HSPN). Lower C4 levels in these patients suggest a role in disease development.
Area of Science:
- Immunogenetics
- Nephrology
Background:
- IgA nephropathy (IgAN) and Henoch-Schönlein purpura nephritis (HSPN) are kidney diseases with complex etiologies.
- The complement system, particularly complement 4 (C4), plays a role in immune regulation and inflammation.
Purpose of the Study:
- To investigate the frequency of C4 gene deletions in patients with IgAN and HSPN.
- To explore the association between C4 gene deletions, serum C4 levels, and specific HLA gene polymorphisms in these kidney diseases.
Main Methods:
- Genomic DNA analysis using Southern blotting and restriction fragment length polymorphism (RFLP) typing.
- Analysis of C4, factor B protein allotypes, and HLA DQ beta and DR beta chain genes.
- Comparison of gene frequencies and serum C4 concentrations between patient cohorts and controls.
Main Results:
- Significantly increased frequency of C4 gene deletions observed in IgAN and HSPN patients (16.1%) compared to controls (2.8%).
- Patients with C4 gene deletions exhibited significantly lower serum C4 concentrations.
- Increased frequency of specific HLA DQw4/8/9 and DR4 alleles noted in patients, but not directly responsible for C4 deletions.
Conclusions:
- C4 gene deletions are associated with an increased risk of developing IgA nephropathy and Henoch-Schönlein purpura nephritis.
- Reduced serum C4 levels due to gene deletions may contribute to the pathogenesis of these kidney diseases.
Abstract:
Increased frequency of C4 gene deletions in IgA nephropathy and Henoch-Schönlein purpura nephritis. To determine the frequency of complement 4 (C4) deficiency among the patients with IgA nephropathy (IgAN) and Henoch-Schönlein purpura nephritis (HSPN), C4 and factor B protein allotypes and the DNA restriction fragment length polymorphism (RFLP) of C4, steroid 21-hydroxylase (21OHase), HLA DQ beta and DR beta chain genes were studied. Genomic DNA from 32 patients with IgAN, 24 patients with HSPN and 143 controls was digested with restriction enzyme TaqI or BamHI and subjected to Southern analysis. The frequency of C4 gene deletions was significantly increased in the patients (16.1 vs. 2.8%, p = 0.002). The serum C4 concentration in patients with C4 gene deletion was significantly lower than in patients without gene deletion (11.4 +/- 2.4 vs. 19.7 +/- 5.2 mg/dl, p = 0.001). DNA-RFLP typing of DQB/BamHI and DRB/TaqI showed increased frequency of 10.26 kb of D-DQw4/8/9 (87.5 vs. 64.5%, p = 0.004) and 5.22 kb of D-DR4 (66.1 vs. 41.7%, p = 0.03) among the patients. Segregation analysis showed that the association of the D-DQw4/8/9 and D-DR4 with the diseases was not responsible for the increased frequency of C4 gene deletion in the patients. The decreased concentration of C4 in sera in C4 gene-deleted patients might be directly involved in the pathogenesis of IgAN and HSPN.