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Analysis of complement C4 loci in Caucasoids and Japanese with idiopathic membranous nephropathy
S H Sacks1, S Nomura, C Warner
1Renal Laboratory, United Medical School, Guy's Hospital, London, England, United Kingdom.
Insights
C4A gene deletion is strongly associated with idiopathic membranous nephropathy (IMN) in European Caucasoids, but not in Japanese populations. This suggests C4A deletion may be a specific risk factor for IMN in certain ethnicities.
Area of Science:
- Immunogenetics
- Nephrology
- Autoimmune Diseases
Background:
- Deletion of the complement gene C4A is linked to autoimmune disease susceptibility.
- Idiopathic membranous nephropathy (IMN) is a significant cause of nephrotic syndrome.
Purpose of the Study:
- To investigate the association between C4A gene deletion and IMN risk in European Caucasoids and Japanese populations.
- To determine if C4A deletion is an independent risk factor for IMN or linked to specific HLA haplotypes.
Main Methods:
- Case-control study comparing C4A gene deletion frequencies in IMN patients and healthy controls.
- Analysis of C4A deletion in European Caucasoid and Japanese cohorts.
- Examination of C4B locus polymorphism in Japanese IMN patients.
Main Results:
- A strong positive association was found between C4A gene deletion and IMN in European Caucasoids (63% vs. 20%).
- C4A deletion was rare in Japanese IMN patients (3%) and controls (2%).
- No significant association was observed between C4B polymorphism and IMN in the Japanese population.
Conclusions:
- C4A gene deletion confers a significant risk for IMN in Caucasoids.
- The association between C4A deletion and IMN is not observed in Japanese individuals, suggesting ethnic-specific genetic factors.
- This indicates C4A deletion may not be universally involved in IMN pathogenesis or that multiple genetic mechanisms contribute to the disease.
Abstract:
Deletion of the HLA class III complement gene, C4A, has been linked with susceptibility to a number of autoimmune diseases. In this study, we show a strong positive association between C4A gene deletion and development of idiopathic membranous nephropathy (IMN) in European Caucasoids [patients, 17/27 (63%); healthy controls, 13/65 (20%); RR 6.8; P = 0.003]. To clarify whether C4A deletion is an independent risk factor for IMN or is increased secondarily to the Caucasoid HLA A1, B8, DR3 extended haplotype, we examined the frequency of C4A deletion in Japanese patients, in whom the disease is associated with another HLA haplotype (DR2-DQw1). Analysis of 31 Japanese patients and 46 healthy controls showed that C4A deletion was present in only one patient (3%) and one control (2%). In addition, examination of the C4B locus in Japanese patients showed that there was no significant increase in the estimated frequency of C4B deletion in patients against controls (31 vs. 27%) and no difference in the frequency of the C4B long gene (73 vs. 87%) or C4B short gene (77 vs. 78%). We conclude that although C4A deletion confers significant risk of IMN in Caucasoids, there is no significant association between C4 polymorphism, as detected here, and risk of IMN in Japanese. This suggests that either C4A deletion is irrelevant to the pathogenesis of IMN or that more than one genetic mechanism is involved.