Allelic Variants of Complement Genes Associated with Dense Deposit Disease

Abstract

The alternative pathway of the complement cascade plays a role in the pathogenesis of dense deposit disease (DDD). Deficiency of complement factor H and mutations in CFH associate with the development of DDD, but it is unknown whether allelic variants in other complement genes also associate with this disease. We studied patients with DDD and identified previously unreported sequence alterations in several genes in addition to allelic variants and haplotypes common to patients with DDD. We found that the likelihood of developing DDD increases with the presence of two or more risk alleles in CFH and C3. To determine the functional consequence of this finding, we measured the activity of the alternative pathway in serum samples from phenotypically normal controls genotyped for variants in CFH and C3. Alternative pathway activity was higher in the presence of variants associated with DDD. Taken together, these data confirm that DDD is a complex genetic disease and may provide targets for the development of disease-specific therapies.

The role of the alternative pathway of complement activation in glomerular diseases

“…1), the 3D model of C3 places the MG1 (C3S/F; rs2230199) and C3d region (CFH binding site) in a close proximity [14,47]. This implicates the possibility that the presence of many different risks variants of C3 and CFH [50] + (DDD) --c.C1775T/p.R592Q (rs121909583) [101] + --V619 M (rs146613648) [64] + --R1303H [64] + --R13200Q [64] + --C1518R [64] + --D1625H [64] + --ΔDG3923 [64] + (DDD) + -c.131_146del; p.Leu44Argfs*19 [73] - [12,34,62,65,68] + (DDD, C3GN) + (SLE) -V62I (rs800292) [34,[63][64][65] + (DDD) [75] + − − Duplication in CFHR1 gene [39] + − − CFHR3-1 hybrid gene [76] + --CFHR2-CFHR5 hybrid gene [40] + --CFHR5-CFHR2 hybrid gene [77] + − − CFHR1-5 hybrid gene [80] + − − rs16840639 [69] - [34] + (DDD) --−20T/C (rs9427662) [34] + (DDD) --IVS1 + 75T/A [34] + (DDD) --IVS2 + 58C/T [34] + (DDD) --in a single individual may have a more potent effect on AP regulation and may increase the risk of GN development.…”

“…As rs1047286 is located in the MG3 domain of C3 (binding site of CFB), polymorphic variant HAV4-1+ has stronger ability to bind to CFB (Fig. 1) [46,50].…”

“…In case of V62I (rs800292), guanine (G) is changed to adenine (A), causing single amino acid change (valine to isoleucine transition) [34,63]. Both SNPs are reported to be associated with various diseases including C3G, SLE and AMD [50,[63][64][65][66][67][68]. The genome-wide association studies (GWAS) suggest that cumulative, synergistic effect of some SNPs, mainly in C3 and CFH genes, rather than a single mutation, contribute to the glomerular disease [50,65].…”

“…Both SNPs are reported to be associated with various diseases including C3G, SLE and AMD [50,[63][64][65][66][67][68]. The genome-wide association studies (GWAS) suggest that cumulative, synergistic effect of some SNPs, mainly in C3 and CFH genes, rather than a single mutation, contribute to the glomerular disease [50,65]. Although the CFH binding sites and the common C3 SNPs are situated in two different chains (α and β, respectively) of the C3 molecule ( Fig.…”

“…Aberera-Abeleda et al described the additive cumulative risk of C3F/S (R102G; rs2230199) and HAV4-1+/− (P314L; rs1047286) SNPs of the C3 gene together with the CFH SNP Y402H (rs1061170) for the development of DDD. The presence of at least one copy of the both C3 G102 (C3 F) and C3 L314 (HAV4-1+) causes stronger affinity of C3 binding to CFB, while the CFH H402 allele shows an impaired C3b binding that finally results in enhancing the C3 convertase activity and an uncontrolled consumption of the AP components [50]. Habbig et al presented two female siblings (12 and 7 years old) with the deletion of 224 lysine in rs796052138, located in the N-terminal end of CFH (SCR-domain 4), affected by a renal disease compatible with C3G.…”