Complement Gene Variants Determine the Risk of Immunoglobulin-Associated MPGN and C3 Glomerulopathy and Predict Long-Term Renal Outcome

Mol Immunol. 2016 Mar;71:131-142. doi: 10.1016/j.molimm.2016.01.010. Epub 2016 Feb 16.

Abstract

Background: Membranoproliferative glomerulonephritis (MPGN) is an uncommon cause of chronic nephropathy recently reclassified into immunoglobulin-associated MPGN (Ig-MPGN) and C3 glomerulopathy (C3G). In this study we aimed: (1) to evaluate the complement genetic and biochemical profile in patients with Ig-MPGN/C3G; (2) to investigate whether genetic variants and different patterns of complement activation (i.e., fluid versus solid phase) correlate with disease manifestations and outcomes.

Methods: In 140 patients with idiopathic Ig-MPGN or C3G we performed complement biochemical and genetic screening and correlated genetic, biochemical and histology data with clinical features.

Results: Mutations in genes encoding alternative pathway complement proteins were found in both Ig-MPGN and C3G, and mutations in the two components of the C3 convertase are the most prevalent. We also report a mutation in THBD encoding thrombomodulin in a C3G patient. The presence of mutations alone does not significantly increase the risk of Ig-MPGN or C3G, but it does so when combined with common susceptibility variants (CD46 c.-366A in Ig-MPGN; CFH V62 and THBD A473 in C3G). Finally, patients without complement gene mutations or C3NeFs--autoantibodies that stabilize the alternative pathway C3 convertase--have a higher risk of progressing to end-stage renal disease than patients with identified mutations and/or C3NeFs, suggesting the existence of different pathogenetic mechanisms that lead to renal disease.

Conclusions: We provide new insights into the pathogenesis of Ig-MPGN/C3G that underscore the complex nature of these diseases and suggest that the current C3G classification may miss many cases associated with abnormalities of the complement alternative pathway.

Keywords: C3 glomerulonephritis; C3 glomerulopathy; Dense-Deposit Disease; Membranoproliferative glomerulonephritis; Rare diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Complement C3 Nephritic Factor / genetics
  • Complement Pathway, Alternative / genetics*
  • Female
  • Fluorescent Antibody Technique
  • Genetic Predisposition to Disease
  • Genetic Variation*
  • Glomerulonephritis, Membranoproliferative / classification*
  • Glomerulonephritis, Membranoproliferative / genetics*
  • Glomerulonephritis, Membranoproliferative / pathology
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Immunoglobulins
  • Kidney Failure, Chronic / etiology
  • Male
  • Multiplex Polymerase Chain Reaction
  • Polymorphism, Single Nucleotide
  • Risk Factors
  • Thrombomodulin / genetics*
  • Young Adult

Substances

  • Complement C3 Nephritic Factor
  • Immunoglobulins
  • THBD protein, human
  • Thrombomodulin