Complement Gene Variants and Shiga Toxin-Producing
Age Factors
Atypical Hemolytic Uremic Syndrome
/ genetics
Child, Preschool
Complement Activation
/ genetics
Complement System Proteins
/ genetics
Disease Progression
Escherichia coli Infections
/ genetics
Female
France
Gene Frequency
Genetic Predisposition to Disease
Genetic Variation
Host-Pathogen Interactions
Humans
Infant
Kidney Failure, Chronic
/ genetics
Male
Phenotype
Prognosis
Retrospective Studies
Risk Assessment
Risk Factors
Shiga-Toxigenic Escherichia coli
/ immunology
Time Factors
Atypical Hemolytic Uremic Syndrome
Biomarkers
CD46 protein
Complement
Complement Activation
Complement Factor H
Complement System Proteins
Escherichia coli
Gene Frequency
Genetic Background
Genotype
High-Throughput Nucleotide Sequencing
Kidney Failure, Chronic
Membrane Cofactor Protein
Shiga Toxin
complement factor H
hemolytic uremic syndrome
human
pathogenic variants
Journal
Clinical journal of the American Society of Nephrology : CJASN
ISSN: 1555-905X
Titre abrégé: Clin J Am Soc Nephrol
Pays: United States
ID NLM: 101271570
Informations de publication
Date de publication:
07 03 2019
07 03 2019
Historique:
received:
08
05
2018
accepted:
04
12
2018
pmc-release:
07
03
2020
pubmed:
25
1
2019
medline:
1
4
2020
entrez:
25
1
2019
Statut:
ppublish
Résumé
Inherited complement hyperactivation is critical for the pathogenesis of atypical hemolytic uremic syndrome (HUS) but undetermined in postdiarrheal HUS. Our aim was to investigate complement activation and variants of complement genes, and their association with disease severity in children with Shiga toxin-associated HUS. Determination of complement biomarkers levels and next-generation sequencing for the six susceptibility genes for atypical HUS were performed in 108 children with a clinical diagnosis of post-diarrheal HUS (75 Shiga toxin-positive, and 33 Shiga toxin-negative) and 80 French controls. As an independent control cohort, we analyzed the genotypes in 503 European individuals from the 1000 Genomes Project. During the acute phase of HUS, plasma levels of C3 and sC5b-9 were increased, and half of patients had decreased membrane cofactor protein expression, which normalized after 2 weeks. Variants with minor allele frequency <1% were identified in 12 Shiga toxin-positive patients with HUS (12 out of 75, 16%), including pathogenic variants in four (four out of 75, 5%), with no significant differences compared with Shiga toxin-negative patients with HUS and controls. Pathogenic variants with minor allele frequency <0.1% were found in three Shiga toxin-positive patients with HUS (three out of 75, 4%) versus only four European controls (four out of 503, 0.8%) (odds ratio, 5.2; 95% confidence interval, 1.1 to 24; Rare variants and complement activation biomarkers were not associated with severity of Shiga toxin-associated HUS. Only pathogenic variants with minor allele frequency <0.1% are more frequent in Shiga toxin-positive patients with HUS than in controls.
Sections du résumé
BACKGROUND AND OBJECTIVES
Inherited complement hyperactivation is critical for the pathogenesis of atypical hemolytic uremic syndrome (HUS) but undetermined in postdiarrheal HUS. Our aim was to investigate complement activation and variants of complement genes, and their association with disease severity in children with Shiga toxin-associated HUS.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS
Determination of complement biomarkers levels and next-generation sequencing for the six susceptibility genes for atypical HUS were performed in 108 children with a clinical diagnosis of post-diarrheal HUS (75 Shiga toxin-positive, and 33 Shiga toxin-negative) and 80 French controls. As an independent control cohort, we analyzed the genotypes in 503 European individuals from the 1000 Genomes Project.
RESULTS
During the acute phase of HUS, plasma levels of C3 and sC5b-9 were increased, and half of patients had decreased membrane cofactor protein expression, which normalized after 2 weeks. Variants with minor allele frequency <1% were identified in 12 Shiga toxin-positive patients with HUS (12 out of 75, 16%), including pathogenic variants in four (four out of 75, 5%), with no significant differences compared with Shiga toxin-negative patients with HUS and controls. Pathogenic variants with minor allele frequency <0.1% were found in three Shiga toxin-positive patients with HUS (three out of 75, 4%) versus only four European controls (four out of 503, 0.8%) (odds ratio, 5.2; 95% confidence interval, 1.1 to 24;
CONCLUSIONS
Rare variants and complement activation biomarkers were not associated with severity of Shiga toxin-associated HUS. Only pathogenic variants with minor allele frequency <0.1% are more frequent in Shiga toxin-positive patients with HUS than in controls.
Identifiants
pubmed: 30674459
pii: 01277230-201903000-00009
doi: 10.2215/CJN.05830518
pmc: PMC6419292
doi:
Substances chimiques
Complement System Proteins
9007-36-7
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
364-377Informations de copyright
Copyright © 2019 by the American Society of Nephrology.
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