Interferon-λ3/4 genetic variants and interferon-λ3 serum levels are biomarkers of lupus nephritis and disease activity in Taiwanese

Background: Type III interferons (IFNs) or IFN-lambda s are the newly discovered cytokines that primarily target the cells of epithelial and myeloid lineages, which are major components of kidneys. The current study aimed to investigate whether IFN-lambda s are involved in the pathogenesis of systemic lupus erythematosus (SLE) and lupus nephritis. Methods: TaqMan allele discrimination assays were used to determine IFNL3/4 SNP genotypes of 1620 healthy controls and 1013 SLE patients (two independent cohorts consisting of 831 and 182 subjects, respectively) from Taiwan. The distributions of IFNL3/4 SNP genotypes and allele frequencies were compared between SLE patients and healthy controls and among SLE patients stratified by clinical phenotypes. ELISA was used to determine the serum IFN-lambda 3 concentrations of SLE patients. Results: All major IFN3/4 SNP alleles were significantly associated with the risk for lupus nephritis (rs8099917T, P-FDR = 0.0021, OR 1.75, 95% CI 1.24-2.47; rs12979860C, P-FDR = 0.0034, OR 1.65, 95% CI 1.18-2.30; rs4803217C, P-FDR = 0.0021, OR 1.76, 95% CI 1.25-2.48; and ss469415590TT, P-FDR = 0.0021, OR 1.73, 95% CI 1.23-2.42) among SLE patients. Similarly, the major IFNL3/4 SNP haplotype rs8099917T-ss469415590TT-rs12979860C-rs4803217C (or T-TT-C-C) was a significant risk factor for lupus nephritis (P= 0.0015, OR 1.68, 95% CI 122-232). Additionally, all minor IFN3/4 SNP alleles were significantly associated with SLE susceptibility in nephritis-negative SLE patients as compared to normal healthy controls (rs8099917G, P-FDR = 0.00177, OR 1.68, 95% CI 124-2.28; rs12979860T, P-FDR = 0.00299, OR 1.58, 95% CI 1.18-2.32; rs4803217A, P-FDR = 0.00176, OR 1.65, 95% CI 1.22-223; and ss469415590 Delta G, P-FDR = 0.00176, OR 1.70, 95% CI 126-229). Furthermore, the elevated serum levels of IFN-lambda 3 were significantly correlated with the complement depression and the high SLE disease activities in SLE patients. Conclusions: IFN-lambda 3/4 genetic variants play a unique role in the development of lupus nephritis and SLE.