Comprehensive Analysis of Complement Genes in Patients with Atypical Hemolytic Uremic Syndrome

Abstract

Background: Genetic defects in complement proteins reportedly contribute to the atypical hemolytic uremic syndrome (aHUS). Numerous genetic studies have been published in recent years, but limited data have been gathered from Asian countries. Methods: Genetic variants of 11 complement genes were analyzed in 23 Chinese patients with aHUS by high-throughput sequencing. The genotype-phenotype relationship in the Han population was evaluated and compared with the relationship that existed in other ethnicities. Results: We identified 20 causative mutations in complement genes, including 19 missense mutations and 1 splicing mutation. Six previously reported mutations, 6 mutations detected for the first time, and 8 rare polymorphisms were noted. Twelve out of 23 patients harbored complement mutations. Among the patients, one was a homozygote (Arg142Cys in CFHR3), and 4 carried combined mutations. Chinese patients have a similar prevalence of complement mutations as European, Japanese, and American patients. Complement factor H (CFH) mutations were common in aHUS in different ethnicities, but Chinese patients exhibited a higher percentage of complement factor B mutations than were found in European patients and a lower percentage of component 3 (C3) mutations than in Japanese patients. Compared with non-carriers, the aHUS patients carrying mutations had reduced C3 levels. In particular, patients with CFH mutations had a worse renal function than those with membrane cofactor protein mutations, a higher level of serum creatinine at the disease onset and a higher percentage of renal insufficiency during follow-up. Conclusions: Because complement genetic dysfunction has clinical significance in aHUS, a comprehensive assessment of variants is necessary for the proper management of aHUS patients in China.

Complement component C3 – The “Swiss Army Knife” of innate immunity and host defense

“…Although the molecular consequences of this polymorphism are still being explored, the C3F variant appears to be associated with an unfavorable outcome in several diseases, including IgA nephropathy, partial lipodystrophy, and systemic vasculitis . Meanwhile, numerous distinct C3 variants have been correlated with certain pathologic conditions, particularly with age‐related macular degeneration (AMD), aHUS, and C3G . Complement dysregulation is a common feature in these diseases, producing a situation featuring chronic inflammation and tissue damage .…”

“…164 Meanwhile, numerous distinct C3 variants have been correlated with certain pathologic conditions, particularly with age-related macular degeneration (AMD), aHUS, and C3G. [165][166][167][168][169][170][171][172][173] Complement dysregulation is a common feature in these diseases, producing a situation featuring chronic inflammation and tissue damage. 4 Notably, the exact involvement of complement can differ between diseases and even between patients.…”

Cadmium Induces Glomerular Endothelial Cell–Specific Expression of Complement Factor H via the −1635 AP-1 Binding Site

“…Defects in CFH result in uncontrolled C3 activation and excessive complement activation, leading to the development of C3 glomerulopathy, which is characterized by low serum C3 levels and C3 deposition in glomeruli (18,19). CFH gene variants are associated with several diseases, including various renal diseases such as atypical hemolytic uremic syndrome (20), membranoproliferative glomerulonephritis type I, and dense deposit disease (21,22). In addition, a decrease in CFH activity also leads to tubulointerstitial injury, as it binds to tubular epithelial cells and inhibits complement activation in ischemic renal injury (23).…”

Genetic Analysis of 400 Patients Refines Understanding and Implicates a New Gene in Atypical Hemolytic Uremic Syndrome

“…In addition, only a few genes were considered. Because the genetic landscape of aHUS is changing and other complement genes like C4BPA, 19 C7, 20 and CFHR2, 21 and noncomplement genes like CBL, INF2, 22-24 MMACHC, [25][26][27] CLU, 28 PLG, 29 and F12, 30 have been implicated in pathogenesis, we sought to analyze rare coding variant burden in a large aHUS cohort in which we control for population stratification, integrate two control cohorts, and study a large number of genes.…”