COMPLEMENT GENE VARIANTS DETERMINE THE RISK OF IMMUNOGLOBULIN-ASSOCIATED MPGN AND C3 GLOMERULOPATHY AND PREDICT LONG-TERM RENAL OUTCOME
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.
Mutations in complement genes are found both in Ig-MPGN and C3G
- We found mutations in genes encoding alternative pathway complement proteins in 18% of patients (C3 n=12, CFH n=5, CFI n=2, CFB n=3, CD46 n=1 and THBD n=1). C3 was the most frequently affected gene and mutations were found both in IC-MPGN and C3G.
- Mutation prevalence was similar among histology groups (17% in Ig-MPGN and 18% in C3G) (Table 1).
- The THBD D486Y and P495S rare pathogenic variants, characterized by lower C3b inactivation, were identified in two C3G patient.
Common SNPs are risk factors for Ig-MPGN and C3G
- We observed a higher frequency of the CD46 c.-366A (OR=1.7, 95%CI 1.1-2.6, p=0.015) and the c.*783T (OR=1.6, 95%CI 1.02-4.4, p=0.041) alleles in Ig-MPGN patients compared to 286 ethnically matched controls from the 1000 Genomes database.
- Homozygous CFH V62 (OR=1.9, 95%CI 1.1-3.2, p=0.030) and homozygous THBD A473 (OR=2.0, 95%CI 1.1-3.8, p=0.02) were overrepresented in C3G patients compared to controls.
Combination of mutations with common SNPs synergistically increases disease risk
We combined the presence of mutations with the homozygous or heterozygous CD46 c.-366A allele for Ig-MPGN and with the homozygous CFH V62 and THBD A473 (susceptibility variants) for C3G (Fig.2).
For Ig-MPGN presence of mutations combined with the CD46 c.-366A allele significantly increased disease risk (OR=19.2, 95%CI 4.6-80.8).
For C3G disease risk was highest in subjects carrying mutations and 2 susceptibility variants (OR=23.9, 95%CI 4.0-143.2 ) and intermediate (OR=8.2, 95%CI 1.9-35.4) for subjects with mutations and 1 susceptibility variant.
The presence of mutations in the absence of risk SNP alleles did not affect risk of C3G or Ig-MPGN.
Differences in Serum Complement Profile
- DDD patients had a higher prevalence of C3NeF and lower serum C3 levels (Table 1).
- Patients carrying mutations and/or C3NeF had lower serum C3 levels and higher plasma SC5b-9 compared with patients carrying neither, both in Ig-MPGN and in C3G (Fig.3).
- Cumulative incidence of ESRD during follow-up did not differed between Ig-MPGN and C3G (Fig.4A).
- Patients carrying mutations and/or C3NeF had a lower risk of developing ESRD (p=0.018, Fig.4B).
- The prevalence of complement gene mutations is comparable between Ig-MPGN and C3G.
- Mutations of C3 and CFB that encode for the two components of complement alternative pathway C3 convertase account for two thirds of the mutations.
- CFH and THBD common variants are involved in the risk of C3G, while CD46 variants influence the risk of Ig-MPGN.
- IF-based classification does not correlate with ESRD during follow-up.
- Patients carrying complement gene mutations or C3NeF are characterized by lower serum C3 levels, higher plasma SC5b-9 levels and by lower risk of developing ESRD.