Complement C3 polymorphisms associated with Dense Deposit Disease.

Complement C3 polymorphisms associated with Dense Deposit Disease. M.A. Abrera-Abeleda^1,2, C. Nishimura¹, S. Sethi³, P. Zipfel⁴, S. Ramaswamy⁵, G. Silvestri⁶, G. Hageman⁷, R.J.H. Smith^1,2,8 1) Dept Otolaryngology, Univ of Iowa, Iowa City, IA; 2) Genetics PhD Program, Univ of Iowa, Iowa City, IA; 3) Dept Lab Med and Pathology, The Mayo Clinic, Rochester MN; 4) Leibniz-Institute for Natural Products Research and Infection Biology,Jena, Germany; 5) Dept of Biochemistry, Univ of Iowa, Iowa City, IA; 6) Department of Ophthalmology, Queens University, Belfast, UK; 7) Dept of Ophthalmology , Univ of Iowa, Iowa City IA; 8) Dept of Internal Medicine, Univ of Iowa, Iowa City IA.

Dense Deposit Disease (or Membranoprofilerative Glomerulonephritis type II, DDD/MPGNII) is a rare cause of chronic renal dysfunction. Deficiency of Factor H (FH) in pigs and mice is associated with the development of DDD/MPGNII, suggesting that dysregulation of the alternative pathway of the complement cascade is important in its pathophysiology. Consistent with this hypothesis, we have shown that DDD/MPGNII is associated with specific polymorphisms of FH and Factor H-related 5. Because alternative pathway control is dependent on the interaction of complement proteins, we screened the coding regions and splice sites of C3, Factor B (FB), Factor I (FI) and Factor D (FD) for allele variants in 38 DDD/MPGNII patients and 103 controls. Our results showed a significant association of the R102G (p<0.0007) and L314P (p<0.05) polymorphisms of C3 with DDD/MPGNII. Both of these SNPs are located in the beta-chain of C3 and may affect the conformational structure of C3, which could change binding affinities for FH and FB, and expose novel epitopes of C3b, which may potentiate the formation of the DDD/MPGNII-specific autoantibody, C3NeF. In addition we identified an unreported missense mutation in one MPGNII/DDD patient. This K1203R change is located in the alpha-chain of C3 near to a FH and complement receptor 2 binding site, suggesting that it may affect the binding of the two proteins to C3. Several SNPs were identified in FB, FI and FD, but none was associated with the DDD/MPGNII. Our results suggest that DDD/MPGNII is a complex genetic disease and provide further evidence to implicate the alternative complement pathway in its pathogenesis. (Supported in part by NIH grant R01DK074409).