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Variabilité Génétique et Maladies Humaines

Tutelles >

Université Paris Diderot

UFR de rattachement >

Institut Universitaire Hématologie (IUH)

Label unité >

UMRS

Partenaires >

INSERM

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

[pasteur-02075958] Asthma and atopic dermatitis are associated with increased risk of clinical Plasmodium falciparum malaria

Date: 5 aoû 2022 - 15:54

Desc: To assess the impact of atopy and allergy on the risk of clinical malaria.

[hal-00719536] A SUMOylation-defective MITF germline mutation predisposes to melanoma and renal carcinoma.

Date: 5 aoû 2022 - 15:54

Desc: So far, no common environmental and/or phenotypic factor has been associated with melanoma and renal cell carcinoma (RCC). The known risk factors for melanoma include sun exposure, pigmentation and nevus phenotypes; risk factors associated with RCC include smoking, obesity and hypertension. A recent study of coexisting melanoma and RCC in the same patients supports a genetic predisposition underlying the association between these two cancers. The microphthalmia-associated transcription factor (MITF) has been proposed to act as a melanoma oncogene; it also stimulates the transcription of hypoxia inducible factor (HIF1A), the pathway of which is targeted by kidney cancer susceptibility genes. We therefore proposed that MITF might have a role in conferring a genetic predisposition to co-occurring melanoma and RCC. Here we identify a germline missense substitution in MITF (Mi-E318K) that occurred at a significantly higher frequency in genetically enriched patients affected with melanoma, RCC or both cancers, when compared with controls. Overall, Mi-E318K carriers had a higher than fivefold increased risk of developing melanoma, RCC or both cancers. Codon 318 is located in a small-ubiquitin-like modifier (SUMO) consensus site (ΨKXE) and Mi-E318K severely impaired SUMOylation of MITF. Mi-E318K enhanced MITF protein binding to the HIF1A promoter and increased its transcriptional activity compared to wild-type MITF. Further, we observed a global increase in Mi-E318K-occupied loci. In an RCC cell line, gene expression profiling identified a Mi-E318K signature related to cell growth, proliferation and inflammation. Lastly, the mutant protein enhanced melanocytic and renal cell clonogenicity, migration and invasion, consistent with a gain-of-function role in tumorigenesis. Our data provide insights into the link between SUMOylation, transcription and cancer.

[hal-02650683] A Genome-Wide Association Study of Upper Aerodigestive Tract Cancers Conducted within the INHANCE Consortium

Date: 5 aoû 2022 - 15:54

Desc: Genome-wide association studies (GWAS) have been successful in identifying common genetic variation involved in susceptibility to etiologically complex disease. We conducted a GWAS to identify common genetic variation involved in susceptibility to upper aero-digestive tract (UADT) cancers. Genome-wide genotyping was carried out using the Illumina HumanHap300 beadchips in 2,091 UADT cancer cases and 3,513 controls from two large European multi-centre UADT cancer studies, as well as 4,821 generic controls. The 19 top-ranked variants were investigated further in an additional 6,514 UADT cancer cases and 7,892 controls of European descent from an additional 13 UADT cancer studies participating in the INHANCE consortium. Five common variants presented evidence for significant association in the combined analysis (p <= 5 x 10(-7)). Two novel variants were identified, a 4q21 variant (rs1494961, p = 1 x 10(-8)) located near DNA repair related genes HEL308 and FAM175A (or Abraxas) and a 12q24 variant (rs4767364, p = 2 x 10(-8)) located in an extended linkage disequilibrium region that contains multiple genes including the aldehyde dehydrogenase 2 (ALDH2) gene. Three remaining variants are located in the ADH gene cluster and were identified previously in a candidate gene study involving some of these samples. The association between these three variants and UADT cancers was independently replicated in 5,092 UADT cancer cases and 6,794 controls non-overlapping samples presented here (rs1573496-ADH7, p = 5 x 10(-8); rs1229984-ADH1B, p = 7 x 10(-9); and rs698-ADH1C, p = 0.02). These results implicate two variants at 4q21 and 12q24 and further highlight three ADH variants in UADT cancer susceptibility.

[hal-01670197] BRCA Share: A Collection of Clinical BRCA Gene Variants

Date: 5 aoû 2022 - 15:34

Desc: As next-generation sequencing increases access to human genetic variation, the challenge of determining clinical significance of variants becomes ever more acute. Germline variants in the BRCA1 and BRCA2 genes can confer substantial lifetime risk of breast and ovar-ian cancer. Assessment of variant pathogenicity is a vital part of clinical genetic testing for these genes. A database Additional Supporting Information may be found in the online version of this article. † These authors contributed equally to this work. ‡ This author is deceased. of clinical observations of BRCA variants is a critical resource in that process. This article describes BRCA Share TM , a database created by a unique international alliance of academic centers and commercial testing laboratories. By integrating the content of the Universal Mutation Database generated by the French Unicancer Genetic Group with the testing results of two large commercial laboratories, Quest Diagnostics and Laboratory Corporation of America (LabCorp), BRCA Share TM has assembled one of the largest publicly accessible collections of BRCA variants currently available. Although access is available to academic researchers without charge, commercial participants in the project are required to pay a support fee and contribute their data. The fees fund the ongoing cu-ration effort, as well as planned experiments to functionally characterize variants of uncertain significance. BRCA Share TM databases can therefore be considered as models of successful data sharing between private companies and the academic world.