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.

Figure 1.

Interaction graph showing the synergistic interaction between CFH and C3. Red or orange lines indicate strong synergistic interaction; blue or green lines indicate redundant interaction or no interaction. Values inside boxes or nodes indicate information gain (IG) of individual attribute or main effects, whereas values between nodes exemplify IG of pairwise combination of attributes or interaction effects. C3 p.P314L has the highest IG, whereas CFH p.V62I has the lowest. However, the IG for the interaction of these two SNPs is the highest among pairwise combinations.

Figure 2.

(A) Box plot shows that controls with the DDD risk allele C3 G102 have lower APH50 values (n = 38; mean = 82.67) than controls who are homozygous for the protective allele C3 R102 (n = 64; mean = 96.17) (P-value = 0.0450). (B) Controls with the risk allele C3 L314 (n = 38; mean = 80.67) have lower APH50 values than controls who are homozygous for the protective allele C3 P314 (n = 64; mean = 97.35) (P-value = 0.0176). (C) Controls with both C3 G102 and L314 (n = 41; mean = 82.49) have lower APH50 values than controls homozygous for both C3 R102 and P314 (n = 61; mean = 96.95). (D) Controls with the risk allele CFH H402 (n = 59; mean = 79.44) have lower %AP values than controls homozygous for the protective allele CFH Y402 (n = 43; mean = 85.95) (P-value = 0.0345). Legends: (+), mean; line in box, median or 50th percentile; lower whisker, lowest data still within 1.5 interquartile range (IQR) of the lower quartile; upper whisker, highest data still within 1.5 IQR of the upper quartile; circles, outliers. (A–C, APH50 values; D, %AP values).