Purpose Lupus nephritis (LN) is a major cause of morbidity in Systemic Lupus Erythematosus (SLE) and a subset of patients still develop end stage renal disease (ESRD). Genetics is important in SLE pathogenesis and today >180 SLE risk loci have been identified at Genome-wide significance (GWS). Here we investigate how gene-gene interactions influence the risk of WHO class III or IV LN in patients with SLE.
Methods Patients with SLE from Sweden and Norway (n=1455) were genotyped with Illumina’s Global Screening Array. Clinical information was retrieved from medical charts, including kidney biopsy data classified according to the WHO. Eleven SLE GWS risk single nucleotide polymorphisms (SNPs) were analyzed regarding gene-gene interaction for LN; ITGAM, IRF5, STAT4, IL12A, TYK2, PTPN22, TNFSF4, BANK1, BLK, and two tag SNPs for HLA-DRB1*03:01 and HLA-DRB1*15:01. Data was analyzed using cox regression and logistic regression including the individual SNPs, sex and SLE duration as covariates (SPSS version 184.108.40.206 (142)). P-value < 0.05 was considered significant.
Results In total, 33% (476/1455) of patients had a history of LN, according to the ACR-82 criteria, with an average age at onset of 33 years. Kidney biopsy data was available for 301 patients and 65% (197/301) of the biopsies showed WHO class III or IV LN. Comparing patients with class III/IV LN with non-nephritis patients, we identified a significant interaction between the HLA-DRB1*03:01 and STAT4 risk alleles (OR 3.4 (1.4–8.3), p= 0.009 for 3 risk variants and OR 9.1 (1.1–73), p= 0.037 for 4 risk variants), Table 1. An interaction was also observed when including patients with 3 or 4 risk variants as one group in a model (OR 3.3 (1.4–8.0), p= 0.008). The prevalence of class III/IV LN in patients with 3–4 risk variants was 30% (24/81) compared with 16% (166/1059) in patients with 0–2 risk variants, p = 0.001. Furthermore, patients with 3–4 risk alleles displayed a decreased time from SLE diagnosis to the onset of class III/IV LN (HR 2.6 (1.1–5.8), p= 0.022) compared with patients with 0–2 risk alleles. Finally, when analyzing the 2 SNPs separately for association with class III/IV LN, no association was observed for STAT4, but patients homozygous for the HLA-DRB1*03:01 tag risk allele had an increased risk (OR 1.9 (1.0–3.5), p= 0.036).
Conclusions An interaction between HLA-DRB1*03:01 and STAT4 risk gene variants increase the risk of WHO class III and IV LN in SLE. The results indicate an importance of gene-gene interaction for LN development and a potential role of interactions between genes in SLE pathogenesis.
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