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The interplay between human genetic variation, persistent infections and chronic inflammation: relevance for cardiovascular and neuropsychiatric morbidity

English title The interplay between human genetic variation, persistent infections and chronic inflammation: relevance for cardiovascular and neuropsychiatric morbidity
Applicant Fellay Jacques
Number 175603
Funding scheme Project funding (Div. I-III)
Research institution Global Health Institute EPFL SV-DO
Institution of higher education EPF Lausanne - EPFL
Main discipline Genetics
Start/End 01.02.2018 - 31.07.2022
Approved amount 696'032.00
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All Disciplines (2)

Discipline
Genetics
Immunology, Immunopathology

Keywords (7)

Persistent pathogens; Human genomics; Humoral immunity; Genome-wide association study; Cardiovascular diseases; Chronic inflammation; Neuropsychiatric diseases

Lay Summary (French)

Lead
Les maladies cardiovasculaires et certains troubles neuro-psychologiques sont en partie dus à une activation chronique du système immunitaire, à laquelle contribuent les infections persistantes ou récurrentes. Notre étude a pour objectif de mieux comprendre les interactions complexes entre variations du génome humain, infections fréquentes et maladies chroniques.
Lay summary
Les études d'association à l'échelle du génome (GWAS) permettent d'identifier les variations génétiques humaines associées à des maladies. Nous proposons ici d'exploiter les outils les plus modernes de la génomique et de la bioinformatique pour mieux comprendre les interactions entre infections persistantes, inflammation chronique et maladies cardiovasculaires et neuropsychiatriques complexes.
Pour ce faire, nous utiliserons des échantillons et des données collectées dans le cadre de l'étude CoLaus, une grande cohorte populationnelle basée à Lausanne, qui suit près de 6000 personnes depuis plus de 10 ans. Nous chercherons en premier lieu à identifier les variations du génome humain qui ont un impact sur notre capacité à nous défendre contre les infections, estimée au travers de tests sérologiques (mesure des taux d'anticorps). Nous étudierons ensuite l'influence du génome sur l'inflammation, avant de construire des scores génétiques qui permettront une analyse globale des paramètres génétiques, infectieux et inflammatoires, et de leur effet combiné sur les troubles cardiovasculaires et neuropsychiatriques, deux domaines avec un importance majeure en santé publique.
Ces analyses ont le potentiel d'élucider certains mécanismes à l'origine de ces maladies. Les résultats de ce projet pourraient ainsi inclure de nouveaux tests diagnosiques, de meilleures stratégies de prédiction et de prévention, ou des cibles innovantes pour le développement de médicaments.
Direct link to Lay Summary Last update: 11.12.2017

Responsible applicant and co-applicants

Employees

Collaboration

Group / person Country
Types of collaboration
Adrian Hill's group / Oxford University Great Britain and Northern Ireland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
German Cancer Research Center, Heidelberg Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure
CoLaus, CHUV, Lausanne Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
European Human Genetics Virtual Conference - ESHG 2020 Poster An indel in the promoter region of NFKB1 confers protection against infection but increases risk of allergy 06.06.2020 virtual, Switzerland Fellay Jacques; Hodel Flavia;
European Human Genetics Conference - ESHG 2019 Poster Human genetic determinants of chronic low-grade inflammation in the general population 15.06.2019 Gothenburg, Sweden Hodel Flavia; Naret Olivier;
Summer School SFM 2019 - Shaping the Future of (Bio-)Medicine Individual talk Human genomics of humoral immunity 12.05.2019 Bellinzona, Switzerland Fellay Jacques; Hodel Flavia;


Associated projects

Number Title Start Funding scheme
197721 Multi-omic analysis of anti-viral immunity: From relevant biological pathways to inborn errors of immunity in patients with severe viral diseases 01.08.2021 Project funding (Div. I-III)

Abstract

Contemporary genomic approaches make it possible to seek answers to biological questions that were previously out of reach. Genome-wide association studies (GWAS) have identified many genetic polymorphisms associated with human diseases, shedding new light on genes and pathways involved in pathogenesis. We here propose to harness the power of large-scale genomics and bioinformatics to understand the interactions between persistent infections, chronic low-grade inflammation and complex cardiovascular and neuropsychiatric diseases. Using samples and data collected in the context of the CoLaus study, a large population-based cohort from Lausanne, we will identify the major genomic determinants of specific immune responses against multiple persistent human pathogens by GWAS and fine-mapping of associated loci. The magnitude of specific antibody responses, which varies strongly between individuals, will be measured by multiplex serological assays in 5000 participants. A GWAS strategy will also be used to describe the influence of human genetic factors on the plasma levels of inflammatory biomarkers, which are correlated with certain persistent infections. Genetic risk scores will be built to summarize the combined effect of associated variants on infectious and inflammatory phenotypes. Finally, we will develop statistical models to explore the respective and combined influences of genetic variation, persistent infections and low-grade inflammation on cardiovascular and neuropsychiatric disorders, two major elements of the global burden of disease. These analyses have the potential to elucidate important pathogenic mechanisms. From a translational perspective, outcomes of this project could thus include novel disease biomarkers, better prediction models, or innovative targets for diagnostic or therapeutic development.
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