Complement Gene Variants and Shiga Toxin-Producing Escherichia coli-Associated Hemolytic Uremic Syndrome: Retrospective Genetic and Clinical Study.
Clin J Am Soc Nephrol
; 14(3): 364-377, 2019 03 07.
Article
em En
| MEDLINE
| ID: mdl-30674459
ABSTRACT
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; P=0.03). The genetic background did not significantly affect dialysis requirement, neurologic manifestations, and sC5b-9 level during the acute phase, and incident CKD during follow-up. However, the only patient who progressed to ESKD within 3 years carried a factor H pathogenic variant.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.Palavras-chave
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
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Variação Genética
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Proteínas do Sistema Complemento
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Ativação do Complemento
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Infecções por Escherichia coli
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Escherichia coli Shiga Toxigênica
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Síndrome Hemolítico-Urêmica Atípica
Tipo de estudo:
Etiology_studies
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Observational_studies
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Prognostic_studies
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Risk_factors_studies
Limite:
Child, preschool
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Female
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Humans
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Infant
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Male
País como assunto:
Europa
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article