Brief Report: identification of MTMR3 as a novel susceptibility gene for lupus nephritis in northern Han Chinese by shared-gene analysis with IgA nephropathy

Abstract

Objective: Several novel susceptibility genes for systemic lupus erythematosus (SLE) and IgA nephropathy have been identified in recent genome-wide association studies. Since both lupus nephritis and IgA nephropathy are autoimmune diseases of the kidney, they may share common disease mechanisms that overlap with genetic susceptibility. To test this hypothesis, we sought to identify genetic variants associated with IgA nephropathy in lupus nephritis.

Methods: In the first stage, 500 patients with lupus nephritis, 240 SLE patients without nephritis, and 500 healthy controls were enrolled. Fifteen single-nucleotide polymorphisms (SNPs) that had the topmost association signals with IgA nephropathy were selected for further testing in patients with lupus nephritis. Three independent cohorts from Beijing, Shanghai, and Hong Kong were included as replicates. We also analyzed the functional significance of identified noncoding variants on regulatory motifs and gene expression. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated.

Results: In addition to associations with HLA gene polymorphisms, genetic variants of MTMR3 in 22q12 showed associations with lupus nephritis (for rs9983A, OR 1.61 [95% CI 1.19-2.19], P = 2.07 × 10(-3) ) compared to healthy controls in the first stage. Associations were replicated and reinforced among northern Han Chinese (for lupus nephritis patients versus SLE patients without nephritis, P = 0.01) but not southern Han Chinese, although significant genetic heterogeneity was observed. Conservative and regulatory features of rs9983 were predicted in in silico analyses. In expression analysis, we observed lower MTMR3 transcription levels in samples of blood with rs9983A and in renal biopsy samples from lupus nephritis and IgA nephropathy patients.

Conclusion: Our results suggest that the MTMR3 gene is shared between IgA nephropathy and lupus nephritis in the northern Chinese population, further highlighting the role of autophagy in SLE. However, widespread replication of these experiments, fine mapping, and functional assays are required to establish this connection.

Figure 1. The overall and pooled ORs with a 95% CI for overall and subgroup analysis testing of the association between rs9983 and lupus nephritis

In a subgroup of northern Han Chinese, 878 SLE patients with lupus nephritis, and 556 SLE patients without lupus nephritis as a control were enrolled. I² = 0 and P = 0.83 in test for heterogeneity, and Z = 2.56 and P = 0.01 in a test for overall effect. In a subgroup of southern Han Chinese, 535 SLE patients with lupus nephritis and 688 SLE patients without lupus nephritis as a control were enrolled. I² = 0, P = 0.83 in a test for heterogeneity, and Z = −0.62 and P = 0.53 in a test for overall effect. Of the total Chinese Han individuals enrolled, 1413 were SLE patients with lupus nephritis and 1244 were SLE patients without lupus nephritis as a control. I² = 44.7% and P = 0.02 in a test for heterogeneity, and Z = 0.62 and P = 0.54 in a test for overall effect. A random effects model was used to pool the results because heterogeneity was present.