title: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Peking University First Hospital, Peking University Institute of Nephrology, Key Laboratory of Renal Disease, Ministry of Health of China, and Key Laboratory of Chronic Kidney Disease Prevention and Treatment at Peking University, Ministry of Education of China, Beijing, China.
authors.forename: Xu-Jie
authors.initials: XJ
authors.lastname: Zhou
authors.forename: Swapan K
authors.initials: SK
authors.lastname: Nath
authors.forename: Yuan-Yuan
authors.initials: YY
authors.lastname: Qi
authors.forename: Fa-Juan
authors.initials: FJ
authors.lastname: Cheng
authors.forename: Hai-Zhen
authors.initials: HZ
authors.lastname: Yang
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Wanling
authors.initials: W
authors.lastname: Yang
authors.forename: Jian-Yang
authors.initials: JY
authors.lastname: Ma
authors.forename: Ming-Hui
authors.initials: MH
authors.lastname: Zhao
authors.forename: Nan
authors.initials: N
authors.lastname: Shen
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
mesh_terms: D000328:Adult; D044466:Asian People / Q000235:genetics; D002681:China; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D005922:Glomerulonephritis, IGA / Q000235:genetics*; D006723:Hong Kong; D006801:Humans; D008181:Lupus Nephritis / Q000235:genetics*; D008297:Male; D020641:Polymorphism, Single Nucleotide; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000235:genetics*
chemical_list: C444436:MTMR3 protein, human; D054558:Protein Tyrosine Phosphatases, Non-Receptor