Deletion of CFHR3 and CFHR1 genes in age-related macular degeneration

Age-related macular degeneration (AMD) impairs vision for approximately 7.5 million Americans. Both susceptibility variants and protective haplotypes in the complement factor H (CFH) gene modulate risk for AMD. Recently, deletion of the 'CFH-related' genes CFHR1 and CFHR3 was found to be segregating with a particular CFH haplotype, which reduced the risk of AMD. We tested the deletion for association in a Caucasian population of 780 cases and 265 controls and examined its effect in the context of known AMD risk factors. The deletion did not segregate perfectly with any one SNP, as previously suggested. CFH haplotype P2 was the most frequent haplotype in deletion homozygotes (47%), and the majority (14/16) of these individuals were homozygous for the non-risk allele of Y402H. Overall, deletion homozygosity was significantly more frequent in controls than cases (2.6% controls, 0.8% cases, P = 0.025, OR = 0.29, 95% CI = 0.10-0.86). After controlling for age, Y402H, smoking and LOC387715 A69S, the protective effect of the deletion was no longer statistically significant (P = 0.27). However, using a CFH haplotype that all deletion homozygotes share as a surrogate for the deletion, this marker remained modestly associated with AMD after adjustment for known risk factors (OR = 0.63, 95% CI 0.39-1.04, P = 0.07). Therefore, deletion of CFHR1 and CFHR3 may account for a small portion of the protection from AMD associated with particular haplotypes in CFH. The presence of protective haplotypes in CFH that do not carry the deletion, suggests that other protective variants in this region have yet to be discovered.     

Factor H and CFHR1 polymorphisms associated with atypical Haemolytic Uraemic Syndrome (aHUS) are differently expressed in Tunisian and in Caucasian populations

Several polymorphisms in the complement components factor H and CFHR1 are associated with higher risk to develop atypical Haemolytic Uraemic Syndrome (aHUS) in Caucasians. We have determined the prevalence of these polymorphisms in Tunisian controls by using genetic and immunological techniques. No differences in the frequency of the factor H risk alleles c.-331C>T, c.2089A>G or c.2881G>T between Tunisian and Caucasians were found. On the contrary, the analysis of CFHR1 polymorphism revealed a higher frequency of Tunisian individuals homozygous for the CFHR1*Del (deleted) allele, and of individuals presenting the CFHR1*A phenotype. These results suggest distinct contributions of factor H and CFHR1 polymorphisms to aHUS in Tunisian and Caucasian populations.     

Variations in the complement regulatory genes factor H (CFH) and factor H related 5 (CFHR5) are associated with membranoproliferative glomerulonephritis type II (dense deposit disease)

Introduction

Membranoproliferative glomerulonephritis type II or dense deposit disease (MPGN II/DDD) causes chronic renal dysfunction that progresses to end stage renal disease in about half of patients within 10 years of diagnosis. Deficiency of and mutations in the complement factor H (CFH) gene are associated with the development of MPGN II/DDD, suggesting that dysregulation of the alternative pathway of the complement cascade is important in disease pathophysiology.

Subjects

Patients with MPGN II/DDD were studied to determine whether specific allele variants of CFH and CFHR5 segregate preferentially with the MPGN II/DDD disease phenotype. The control group was compromised of 131 people in whom age related macular degeneration had been excluded.

Results

Allele frequencies of four single nucleotide polymorphisms in CFH and three in CFHR5 were significantly different between MPGN II/DDD patients and controls.

Conclusion

We have identified specific allele variants of CFH and CFHR5 associated with the MPGN II/DDD disease phenotype. While our data can be interpreted to further implicate complement in the pathogenesis of MPGN II/DDD, these associations could also be unrelated to disease pathophysiology. Functional studies are required to resolve this question.