A haplotype in CFH family genes confers high risk of rare glomerular nephropathies

Yin Ding,Jianping Lu,Feng Xu,Caihong Zeng,Haitao Zhang,Tao Zhang,Zhihong Liu,Weiwei Zhao,Shuzhen Wen,Xin Su,Mingchao Zhang,Huimei Chen,Hao Qiang

doi:10.1038/s41598-017-05173-8

Abstract

Despite distinct renal lesions, a series of rare glomerular nephropathies are reportedly mediated by complement overactivation. Genetic variations in complement genes contribute to disease risk, but the relationship of genotype to phenotype has not been straightforward. Here, we screened 11 complement genes from 91 patients with atypical hemolytic uremic syndrome (aHUS), C3 glomerulopathy (C3G) and membranoproliferative glomerulonephritis type I (MPGN I), and identified the concomitant presence of three missense variations located within the human complement Factor H (CFH) gene cluster. The three variations, rs55807605, rs61737525 and rs57960694, have strong linkage disequilibrium; subsequent haplotype analysis indicated that ATA increased the susceptibility of these renal diseases. In silico analysis, the CFHR3 rs61737525-T risk allele altered the physical and structural properties and generated a reduction in binding affinity of the CFHR3/C3b complex. Surface plasmon resonance (SPR) binding analysis further demonstrated the substitution induced a decrease of two orders of magnitude in C3b-binding properties, with a declined cofactor activity in fluid phase. These data suggest that the haplotype carrying the causative allele behaves as a partial C3 convertase deficiency, predisposing individuals to diverse pathologic lesions underlying complement overactivation. Such genotype-phenotype discrepancies allow better understanding about these nephropathies mediated by genetic complement disorders.

Highlights

The complement cascade is part of the innate immune system and provides an important line of defense against invasive pathogens
We focused on three rare single nucleotide polymorphisms (SNPs), rs55807605
The patients with atypical hemolytic uremic syndrome (aHUS) and C3 glomerulonephritis (C3GN) presented a low level of C3, while the other two patients were in the normal range during the disease period

Summary

Introduction

The complement cascade is part of the innate immune system and provides an important line of defense against invasive pathogens. Increasing association of genetic variations in complement and complement control proteins was observed in patients with these rare renal diseases. Mutations in the CFH gene are associated with a number of infectious and inflammatory conditions, which include an increased tendency for MPGN I and aHUS, as well as C3G6–11. We reported three rare single nucleotide polymorphisms (SNPs) located within the CFH gene cluster by high-throughput sequencing for 11 complement genes. They were identified to be causative variations, which have been associated with renal patients with aHUS, DDD, C3GN or MPGN I. The pathologic significance was systematically evaluated in the present study

Methods

Results

Conclusion