Lupus nephritis susceptibility loci in women with systemic lupus erythematosus

Abstract

Lupus nephritis is a manifestation of SLE resulting from glomerular immune complex deposition and inflammation. Lupus nephritis demonstrates familial aggregation and accounts for significant morbidity and mortality. We completed a meta-analysis of three genome-wide association studies of SLE to identify lupus nephritis-predisposing loci. Through genotyping and imputation, >1.6 million markers were assessed in 2000 unrelated women of European descent with SLE (588 patients with lupus nephritis and 1412 patients with lupus without nephritis). Tests of association were computed using logistic regression adjusting for population substructure. The strongest evidence for association was observed outside the MHC and included markers localized to 4q11-q13 (PDGFRA, GSX2; P=4.5×10(-7)), 16p12 (SLC5A11; P=5.1×10(-7)), 6p22 (ID4; P=7.4×10(-7)), and 8q24.12 (HAS2, SNTB1; P=1.1×10(-6)). Both HLA-DR2 and HLA-DR3, two well established lupus susceptibility loci, showed evidence of association with lupus nephritis (P=0.06 and P=3.7×10(-5), respectively). Within the class I region, rs9263871 (C6orf15-HCG22) had the strongest evidence of association with lupus nephritis independent of HLA-DR2 and HLA-DR3 (P=8.5×10(-6)). Consistent with a functional role in lupus nephritis, intra-renal mRNA levels of PDGFRA and associated pathway members showed significant enrichment in patients with lupus nephritis (n=32) compared with controls (n=15). Results from this large-scale genome-wide investigation of lupus nephritis provide evidence of multiple biologically relevant lupus nephritis susceptibility loci.

Keywords: SLE; epidemiology; genetic renal disease; lupus nephritis; outcomes.

Figure 1.

Manhattan plot showing patients with LN in contrast with patients with lupus without LN.

Figure 2.

HLA region associations with patients with LN in contrast with patients with SLE without LN. (A) Associations adjusting for principal components. (B) Associations adjusting for principal components and HLA SLE risk tagging SNPs rs9271366 (HLA-DR2) and rs2187668 (HLA-DR3).

Figure 3.

Regional plots of LN loci. Genotyped and imputed SNPs are plotted with their meta-analysis P values (as -log₁₀ values) as a function of genomic position (Human Genome Build 18) within a 500-kb region surrounding the most significant SNP. Recombination rates from the HapMap phase II CEU (Utah residents with ancestry from northern and western Europe) are plotted in blue to reflect the regional LD structure. In each region, the index SNP is represented by a purple diamond, and the color of all other SNPs (circles) indicates LD with the index SNP based on pairwise r² values from HapMap CEU (red, r²>0.80; orange, r²=0.60–0.80; green, r²=0.40–0.60; light blue, r²=0.20–0.40; dark blue, r²<0.20). Known human genes in the UCSC Genome Browser (University of California, Santa Cruz, CA) are below each plot.