Genetic Risk factors for Multi-system Inflammatory Syndrome in Children and Pediatric Long COVID (GRIP)

Project description

In zeldzame gevallen kunnen kinderen na een corona-infectie een levensbedreigende ontstekingsziekte krijgen. Dit heet MIS-C (multi-system inflammatory syndrome in children). Ook zijn er kinderen die na een corona-infectie langdurig gezondheidsklachten houden. Dit wordt ‘post-COVID klachten’ of ‘long COVID’ genoemd. Het is op dit moment niet helemaal duidelijk waarom sommige kinderen ernstige of langdurige klachten krijgen na een corona-infectie, terwijl de meeste kinderen weinig tot geen klachten krijgen.

Doel

In dit onderzoek wordt onderzocht of kinderen die MIS-C of post-COVID klachten hebben gehad erfelijke afwijkingen hebben in de afweer. Hierdoor hopen de onderzoekers beter te begrijpen waardoor sommige kinderen zo ziek worden na een corona-infectie. En als we dit beter begrijpen kan dit uiteindelijk tot nieuwe en betere behandelingen leiden.

Onderzoeksopzet

De onderzoekers gaan genetisch onderzoek doen bij kinderen met MIS-C hebben gehad en kinderen die post-COVID klachten hebben. Hierbij kijken ze naar genen die belangrijk zijn voor de afweer. Dit zullen ze vergelijken met kinderen die wel een corona-infectie kregen, maar hier niet of weinig last van hadden.

Uitvoerende partijen

Leids Universitair Medisch Centrum (LUMC), Amsterdam Universitair Medisch Centrum (Amsterdam UMC), Universitair Medisch Centrum Groningen (UMCG), Spaarne Gasthuis, Universitair Medisch Centrum Utrecht (UMC Utrecht), ErasmusMC, COPP-consortium (www.covidkids.nl).

Meer informatie

Hoofdaanvrager, projectleider en penvoerder: E. Buddingh (LUMC

Reports


Summary of the application

RESEARCH QUESTION About 1:2000 to 1:5000 children develop the potentially life-threatening disease multi-system inflammatory syndrome in children (MIS-C) about 1 month after infection with SARS-CoV-2 and some children develop post-COVID condition. It is unknown why some children develop severe or prolonged symptoms after SARS-CoV-2 infection, while most children have asymptomatic or mild disease. HYPOTHESIS Rare variants in genes associated with the immune system predispose children to develop MIS-C or post-COVID condition after infection with SARS-CoV-2. STUDY DESIGN WP 1: WES to detect rare, high impact immunological genetic variants in MIS-C and post-COVID condition. We will perform Whole Exome Sequencing (WES) using Next Generation Sequencing (NGS) on DNA from blood or saliva. In this workpackage we have two objectives: WP1.1. To diagnose previously unsuspected inborn error of immunity in cases of MIS-C or post-COVID condition. This approach enables the detection of potentially deleterious variants in genes known to be associated with IEI with high sensitivity. WP1.2. To determine if the proportion of children with MIS-C or post-COVID condition (cases) with deleterious variants in immunological genes is larger than in SARS-CoV-2 exposed controls. This approach will shed further light on the pathogenesis of MIS-C and post-COVID condition. WP 2: Clinical characteristics and long-term effects of pediatric COVID-19 and MIS-C: In WP2 our objective is to describe the clinical characteristics of children hospitalized with COVID-19 or MIS-C. Also, we will evaluate the long-term effects of pediatric COVID-19 and MIS-C. WP 3: integrated analysis and identification of therapeutic targets In WP 3 our objectives are: 1. To validate the results from the individual genetic study (WP 1.1) 2. To validate the results from the case-control study (WP1.2) 3. To evaluate if genetic risk factors (as identified in WP1) aggregate in specific subgroups of patients (as identified in WP2). 4. To identify therapeutic targets STUDY POPULATION (1) MIS-C cases: Children with a history of MIS-C (n=100); (2) post-COVID condition cases: Children with post-COVID condition (n=100); and (3) Controls: SARS-CoV-2 exposed age-matched control group (n=200): children who were infected with SARS-CoV-2 but did not develop moderate to severe COVID-19, MIS-C or post-COVID condition. SAMPLE SIZE In a previous study in MIS-C, 17% of patients (3/18) had deleterious variants in immunological genes. In controls, the prevalence of (predicted) loss of function variants in our geneset is about 3.7% (according to gnomAD v. 2.1.1 data, using a minor allele frequency of <0.00001). Therefore, for the power analysis, we conservatively assume that cases have more qualifying variants than healthy controls, with an odds ratio of 4. We hypothesize that causative genetic variants that are more prevalent in cases are functionally related. They underly a pathogenic mechanism and should cluster together. Using these assumptions, we have done Monte Carlo simulations (100x, with 100 cases and 200 controls). Assuming an odds ratio of 4 the power for an overall positive result is above 80%. The power to detect the responsible cluster is around 80%. The false positive rate is below a= 0.05. DATA ANALYSIS In WP 1.1 we will use existing diagnostic algorithms to diagnose monogenic inborn errors of immunity in MIS-C or post-COVID condition cases. This means that in WP1.1 we will restrict our analysis to pathogenic (class 5) or likely pathogenic (class 4) variants in genes known to be associated with monogenic inborn errors of immunity (IUIS IEI gene set) In WP 1.2 we will do a hierarchical analysis to test the following hypotheses: 1. Cases have more deleterious variants in immunological genes than controls: Overall collapsing analysis of qualifying variants in the IUIS IEI gene set 2. We can identify the cluster(s) of functionally related genes in which these deleterious variants are present: Collapsing analysis of variants in the five clusters of functionally related genes 3. We can identify the immunological pathway(s) responsible for the excess of variants in cases: KEGG-pathways within an affected cluster with qualifying variants in cases and/or controls will be selected. Qualifying variants will be collapsed in these pathways. If the pathway includes genes not yet included in our original geneset, we will assess these genes for qualifying variants in cases and controls as well. 4. The identified immunological pathways can be validated using functional immunological tests in WP3. Depending on which cluster or pathway(s) we identify as having an excess of deleterious variants in cases as compared to controls, specific immunological functional tests will be done. The study is powered to address hypothesis 1 and 2. WP 2: Analyses in this workpackage are descriptive. The exact analyses in WP3 depend on the results of WP1.

Features

Project number:
10430102110009
Duration: 68%
Duration: 68 %
2022
2025
Part of program:
Project lead and secretary:
E.P. Buddingh
Responsible organisation:
Leids Universitair Medisch Centrum