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
[inserm-02874534] Multiancestry association study identifies new asthma risk loci that colocalize with immune-cell enhancer marks
Date: 18 juin 2020 - 21:31
Desc: [...]
[inserm-00681614] Common variants at 12p11, 12q24, 9p21, 9q31.2 and in ZNF365 are associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers.
Date: 22 Mar 2012 - 01:08
Desc: ABSTRACT: INTRODUCTION: Several common alleles have been shown to be associated with breast and/or ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Recent genome-wide association studies of breast cancer have identified eight additional breast cancer susceptibility loci: rs1011970 (9p21, CDKN2A/B), rs10995190 (ZNF365), rs704010 (ZMIZ1), rs2380205 (10p15), rs614367 (11q13), rs1292011 (12q24), rs10771399 (12p11 near PTHLH) and rs865686 (9q31.2). METHODS: To evaluate whether these single nucleotide polymorphisms (SNPs) are associated with breast cancer risk for BRCA1 and BRCA2 carriers, we genotyped these SNPs in 12599 BRCA1 and 7132 BRCA2 mutation carriers and analysed the associations with breast cancer risk within a retrospective likelihood framework. RESULTS: Only SNP rs10771399 near PTHLH was associated with breast cancer risk for BRCA1 mutation carriers (per-allele Hazard Ratio (HR)= 0.87, 95%CI:0.81-0.94, P-trend=3x10^-4). The association was restricted to mutations proven or predicted to lead to absence of protein expression (HR=0.82, 95%CI:0.74-0.90, P-trend=3.1x10^-5, P-difference=0.03). Four SNPs were associated with the risk of breast cancer for BRCA2 mutation carriers: rs10995190, P-trend=0.015; rs1011970, P-trend=0.048; rs865686, 2df-P=0.007; rs1292011 2df-P=0.03. rs10771399 (PTHLH) was predominantly associated with estrogen receptor (ER)-negative breast cancer for BRCA1 mutation carriers (HR=0.81, 95%CI: 0.74-0.90, P-trend=4x10^-5) and there was marginal evidence of association with ER-negative breast cancer for BRCA2 mutation carriers (HR=0.78, 95%CI:0.62-1.00, P-trend=0.049). CONCLUSIONS: The present findings, in combination with previously identified modifiers of risk, will ultimately lead to more accurate risk prediction and an improved understanding of the disease etiology in BRCA1 and BRCA2 mutation carriers.
[inserm-01321840] Identification of a new locus at 16q12 associated with time-to-asthma onset
Date: 26 mai 2016 - 13:36
Desc: Background: Asthma is a heterogeneous disease in which age-of-onset plays an important role. Objective: We sought to identify the genetic variants associated with time-to-asthma onset. Methods: We conducted a large-scale meta-analysis of nine genome-wide association studies of time-to-asthma onset (total of 5,462 asthmatics with a broad range of age-of-asthma onset and 8,424 controls of European ancestry) performed using survival analysis techniques. Results: We detected five regions associated with time-to-asthma onset at genome-wide significant level (P<5x10-8). We evidenced a new locus in 16q12 region (near cylindromatosis turban tumor syndrome gene (CYLD)) and confirmed four asthma risk regions: 2q12 (IL1RL1), 6p21 (HLA-DQA1), 9p24 (IL33) and 17q12-q21 (ZPBP2-GSDMA). Conditional analyses identified two distinct signals at 9p24 (both upstream of IL33) and at 17q12-q21 (near ZPBP2 and within GSDMA). These seven distinct loci explained together 6.0% of the variance in time-to-asthma onset. In addition, we showed that genetic variants at 9p24 and 17q12-q21 were strongly associated with an earlier onset of childhood asthma (P≤0.002) whereas 16q12 SNP was associated with a later asthma onset (P=0.04). A high burden of disease risk alleles at these loci was associated with earlier age-of-asthma onset (4 years versus 9-12 years, P=10-4). Conclusion: The new susceptibility region for time-to-asthma onset at 16q12 harbors variants that correlate with the expression of CYLD and NOD2 (nucleotide-binding oligomerization domain 2), two strong candidates for asthma. This study demonstrates that incorporating the variability of age-of-asthma onset in asthma modeling is a helpful approach in the search for disease susceptibility genes.
[hal-02042301] Highlighting the impact of cascade carrier testing in cystic fibrosis families
Date: 20 fév 2019 - 12:18
Desc: [...]
[inserm-00663706] DNA methylation in glioblastoma: impact on gene expression and clinical outcome.
Date: 27 jan 2012 - 14:12
Desc: BACKGROUND: Changes in promoter DNA methylation pattern of genes involved in key biological pathways have been reported in glioblastoma. Genome-wide assessments of DNA methylation levels are now required to decipher the epigenetic events involved in the aggressive phenotype of glioblastoma, and to guide new treatment strategies. RESULTS: We performed a whole-genome integrative analysis of methylation and gene expression profiles in 40 newly diagnosed glioblastoma patients. We also screened for associations between the level of methylation of CpG sites and overall survival in a cohort of 50 patients uniformly treated by surgery, radiotherapy and chemotherapy with concomitant and adjuvant temozolomide (STUPP protocol). The methylation analysis identified 616 CpG sites differentially methylated between glioblastoma and control brain, a quarter of which was differentially expressed in a concordant way. Thirteen of the genes with concordant CpG sites displayed an inverse correlation between promoter methylation and expression level in glioblastomas: B3GNT5, FABP7, ZNF217, BST2, OAS1, SLC13A5, GSTM5, ME1, UBXD3, TSPYL5, FAAH, C7orf13, and C3orf14. Survival analysis identified six CpG sites associated with overall survival. SOX10 promoter methylation status (two CpG sites) stratified patients similarly to MGMT status, but with a higher Area Under the Curve (0.78 vs. 0.71, p-value < 5e-04). The methylation status of the FNDC3B, TBX3, DGKI, and FSD1 promoters identified patients with MGMT-methylated tumors that did not respond to STUPP treatment (p-value < 1e-04). CONCLUSIONS: This study provides the first genome-wide integrative analysis of DNA methylation and gene expression profiles obtained from the same GBM cohort. We also present a methylome-based survival analysis for one of the largest uniformly treated GBM cohort ever studied, for more than 27,000 CpG sites. We have identified genes whose expression may be tightly regulated by epigenetic mechanisms and markers that may guide treatment decisions.
Autres contacts
Hôpital St Louis - Centre Hayem
1, avenue Claude Vellefaux
75475 PARIS CEDEX 10
