Abstract: SA-PO602
CARD9 Risk Allele and IgA Nephropathy
Session Information
- Glomerular Diseases: Immunology, Inflammation - II
November 09, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1202 Glomerular Diseases: Immunology and Inflammation
Authors
- Kadhim, Fateh Oudah, University of Leicester, Leicester, United Kingdom
- Molyneux, Karen, Leicester University, Leicester, United Kingdom
- Pawluczyk, Izabella Z a, University of Leicester, Leicester, United Kingdom
- Zhang, Hong, Peking University First Hospital, Beijing, China
- Yanna, Wang, Peking University First Hospital, Beijing, China
- Zhou, Xujie, Peking University First Hospital, Beijing, China
- Barratt, Jonathan, University of Leicester, Leicester, United Kingdom
Background
IgA nephropathy (IgAN) is a common cause of primary glomerulonephritis and is most prevalent in East Asian populations. The pathogenesis of IgAN is not well understood. IgAN GWAS studies have revealed an association with rs4077515, a SNP within the coding sequence of CARD9, an essential mediator of the innate immune system. However the place of CARD9 in the pathogenesis of IgAN has yet to be defined. The aim of this study was to investigate the expression of CARD9 in the kidney and determine whether it has an intrarenal role in IgAN.
Methods
Screening kidney cell lines for synthesis of CARD9 by western blotting revealed greatest CARD9 synthesis in human mesangial cells (hMC). To test the significance of the risk allele we incubated hMC that were heterozygous or homozygous negative or positive for the risk allele rs4077515-T with IgA1 isolated from 5 individuals (3 IgAN, 2 healthy subjects) and measured IL-6 synthesis using ELIZA.
Results
We observed increased expression of CARD9 mRNA in whole kidney biopsies in IgAN compared to kidney disease controls (p<0.005). Immunohistochemistry demonstrated CARD9 protein in both the glomerular and tubulointerstitial compartments in IgAN. The presence of rs4077515-T resulted in significantly increased production of the pro-inflammatory cytokine IL-6 following exposure to IgA1 (p<0.0001: TT:CC and p<0.001: CT:CC). In parallel, similar increases were seen in mRNA coding for IL-6 IgA1 (p<0.001: TT:CC and p=0.0109: CT:CC), the signal transducer, IL-6ST (p<0.0001: TT:CC and p<0.0023: CT:CC) and monocyte chemoattractant protein 1 (p<0.0001: TT:CC and p=0.0004: CT:CC).This in vitro data suggests that the presence of rs4077515-T could result in a greater inflammatory response to mesangial IgA deposition in IgAN and therefore rs4077515-T may play a role in determining the rate of renal function decline in IgAN. To test this hypothesis we analysed the association of rs4077515-T with renal function outcome in 1,279 Chinese IgAN patients. There was a significant association between rs4077515-T and the likelihood of renal function decline in this population (HR values of 1.85 (95% CI 1.17-2.93) TT:CC and 1.33 (95% CI 0.98-1.82) CT:CC).
Conclusion
This data suggests intrarenal CARD9 may play a significant role in determining mesangial response to IgA deposition in IgAN and ultimately influence the likelihood of renal function decline.