Variabilité Génétique et Maladies Humaines
Présentation
Les objectifs généraux du programme de recherche de l’UMR-946 sont :
- d'identifier les facteurs génétiques impliqués dans les maladies humaines
- de comprendre les mécanismes d'action de ces gènes
- de caractériser les autres facteurs (environnementaux, mode de vie...) qui peuvent moduler l’effet des gènes sur la maladie.
Ce programme s'articule autour de 2 thématiques principales et complémentaires :
- Méthodologie Statistique en Génétique Epidémiologique
- Etudes de Génétique Epidémiologique de Maladies Multifactorielles
Au total, le programme de recherche de l' UMR-946 est conçu pour répondre aux nouveaux défis posés par les avancées sans cesse croissantes dans les technologies de génotypage et de séquençage et de la biologie à grande échelle afin de progresser vers une approche de biologie des systèmes des maladies.
Thèmes de recherche
1. Méthodologie Statistique en Génétique Epidémiologique
Les objectifs de nos développements méthodologiques sont :
- de prendre en compte les mécanismes complexes impliqués dans les maladies multifactorielles :
interactions GènexGène, GènexEnvironnement, pléiotropie, hétérogénéité génétique…
- d’étendre les méthodes basées sur la consanguinité pour faciliter l’identification des gènes
- de permettre l’étude d'un large spectre de variabilité génétique
- d’intégrer les données de la biologie à grande échelle (génomique, transcriptomique, épigenomique,…)
2. Etudes de Génétique Epidémiologique de Maladies Multifactorielles
Nos études de génétique épidémiologique sont principalement ciblées sur l'asthme, les maladies allergiques et les cancers. Ces études reposent sur de grandes collections de données que nous avons recueillies pour divers cancers (mélanome, cancer du poumon, cancer des voies aérodigestives supérieures, cancer de la vessie) ou auxquelles notre unité est étroitement associée (comme l’Etude épidémiologique des facteurs Génétiques et Environnementaux de l’asthme (EGEA). Ces études intègrent des études d'association pangénomique et des approches de biologie à grande échelle appliquées à de nombreux phénotypes associés aux maladies. Ces études sont menées dans un cadre pluridisciplinaire et dans un contexte de nombreuses collaborations nationales, européennes et internationales.
Les principaux objectifs de ces études sont :
- d’identifier de nouveaux gènes et des interactions gène-environnement impliqués dans ces maladies
- de mieux comprendre les mécanismes moléculaires qui sous-tendent le processus pathologique
- de traduire les résultats de la recherche en applications médicales
[hal-02866706] Respirable Crystalline Silica Exposure, Smoking, and Lung Cancer Subtype Risks: A Pooled Analysis of Case–control Studies
Date: 19 jan 2021 - 16:51
Desc: Respirable crystalline silica is a lung carcinogen with millions of exposed workers globally. We aimed to address current knowledge gaps in lung cancer risks associated with low levels of occupational silica exposure and the joint effects of smoking and silica exposure on lung cancer risks.
[hal-02866675] Diesel Engine Exhaust Exposure, Smoking, and Lung Cancer Subtype Risks: A Pooled Exposure-response Analysis of 14 Case–control Studies
Date: 19 jan 2021 - 16:50
Desc: We expanded upon a previous pooled case-control analysis on diesel engine exhaust and lung cancer by including 3 additional studies and quantitative exposure assessment to evaluate lung cancer and subtype risks associated with occupational exposure to diesel exhaust, characterized by elemental carbon (EC) concentrations.
[hal-02151167] Detecting the dominance component of heritability in isolated and outbred human populations
Date: 19 jan 2021 - 11:08
Desc: [...]
[inserm-00748654] Meta-analysis of 20 genome-wide linkage studies evidenced new regions linked to asthma and atopy.
Date: 19 jan 2021 - 11:08
Desc: Asthma is caused by a heterogeneous combination of environmental and genetic factors. In the context of GA2LEN (Global Allergy and Asthma European Network), we carried out meta-analyses of almost all genome-wide linkage screens conducted to date in 20 independent populations from different ethnic origins (>or=3024 families with >or=10 027 subjects) for asthma, atopic asthma, bronchial hyper-responsiveness and five atopy-related traits (total immunoglobulin E level, positive skin test response (SPT) to at least one allergen or to House Dust Mite, quantitative score of SPT (SPTQ) and eosinophils (EOS)). We used the genome scan meta-analysis method to assess evidence for linkage within bins of traditionally 30-cM width, and explored the manner in which these results were affected by bin definition. Meta-analyses were conducted in all studies and repeated in families of European ancestry. Genome-wide evidence for linkage was detected for asthma in two regions (2p21-p14 and 6p21) in European families ascertained through two asthmatic sibs. With regard to atopy phenotypes, four regions reached genome-wide significance: 3p25.3-q24 in all families for SPT and three other regions in European families (2q32-q34 for EOS, 5q23-q33 for SPTQ and 17q12-q24 for SPT). Tests of heterogeneity showed consistent evidence of linkage of SPTQ to 3p11-3q21, whereas between-study heterogeneity was detected for asthma in 2p22-p13 and 6p21, and for atopic asthma in 1q23-q25. This large-scale meta-analysis provides an important resource of information that can be used to prioritize further fine-mapping studies and also be integrated with genome-wide association studies to increase power and better interpret the outcomes of these studies.
[hal-00595804] Evidence for a locus in 1p31 region specifically linked to the co-morbidity of asthma and allergic rhinitis in the EGEA study.
Date: 19 jan 2021 - 11:08
Desc: OBJECTIVE: A recent genome scan conducted in French EGEA families led to detect linkage of 1p31 to either asthma or allergic rhinitis (AR) and more significantly to asthma associated with AR. The goal of the present study was to assess formally whether 1p31 is a linkage region shared by two different diseases, asthma and AR, or whether it is specific to the co-morbidity asthma plus AR. METHODS: We used two different statistical approaches: the Triangle Test Statistic (TTS) and the Predivided Sample Test (PST), to search for heterogeneity of linkage to 1p31 according to the affection status being defined by either the presence of the two diseases (asthma plus AR) or the presence of only one disease ('asthma only' or 'AR only' or 'asthma only or AR only'). RESULTS: While no heterogeneity between the 'two diseases' phenotype and the 'one disease' phenotype was detected by the TTS, there was significant evidence for heterogeneity (p = 0.00007/0.002 after correction for multiple testing) using the PST. There was no indication of linkage in sib-pairs with 'one disease' only, while there was significant evidence for linkage in sib-pairs displaying asthma plus AR (p = 0.0002/0.0016 after correction). CONCLUSION: The present analysis shows that the co-morbidity, asthma plus AR, represents a phenotypic entity, distinct from asthma only or AR only, controlled by a genetic factor located on 1p31.
Autres contacts
Hôpital St Louis - Centre Hayem
1, avenue Claude Vellefaux
75475 PARIS CEDEX 10
