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-03156815] Novel genes and insights in complete asthma remission: A genome-wide association study on clinical and complete asthma remission
Date: 4 Mar 2021 - 03:25
Desc: Background: Asthma is a chronic respiratory disease without a cure, although there exists spontaneous remission. Genome-wide association (GWA) studies have pinpointed genes associated with asthma development, but did not investigate asthma remission. Objective: We performed a GWA study to develop insights in asthma remission. Methods: Clinical remission (ClinR) was defined by the absence of asthma treatment and wheezing in the last year and asthma attacks in the last 3 years and complete remission (ComR) similarly but additionally with normal lung function and absence of bronchial hyperresponsiveness (BHR). A GWA study on both ClinR and ComR was performed in 790 asthmatics with initial doctor diagnosis of asthma and BHR and long-term follow-up. We assessed replication of the 25 top single nucleotide polymorphisms (SNPs) in 2 independent cohorts (total n = 456), followed by expression quantitative loci (eQTL) analyses of the 4 replicated SNPs in lung tissue and epithelium. Results: Of the 790 asthmatics, 178 (23%) had ClinR and 55 ComR (7%) after median follow-up of 15.5 (range 3.3-47.8) years. In ClinR, 1 of the 25 SNPs, rs2740102, replicated in a meta-analysis of the replication cohorts, which was an eQTL for POLI in lung tissue. In ComR, 3 SNPs replicated in a meta-analysis of the replication cohorts. The top-hit, rs6581895, almost reached genome-wide significance (P-value 4.68 × 10-7 ) and was an eQTL for FRS2 and CCT in lung tissue. Rs1420101 was a cis-eQTL in lung tissue for IL1RL1 and IL18R1 and a trans-eQTL for IL13. Conclusions and clinical relevance: By defining a strict remission phenotype, we identified 3 SNPs to be associated with complete asthma remission, where 2 SNPs have plausible biological relevance in FRS2, CCT, IL1RL1, IL18R1 and IL13.
[hal-02650683] A Genome-Wide Association Study of Upper Aerodigestive Tract Cancers Conducted within the INHANCE Consortium
Date: 27 fév 2021 - 16:02
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-01833917] Identification of a new VHL exon and complex splicing alterations in familial erythrocytosis or von Hippel-Lindau disease
Date: 24 fév 2021 - 15:25
Desc: Chuvash polycythemia is an autosomal recessive form of erythrocytosis associated with a homozygous p.Arg200Trp mutation in the von Hippel-Lindau (VHL) gene. Since this discovery, additional VHL mutations have been identified in patients with congenital erythrocytosis, in a homozygous or compound-heterozygous state. VHL is a major tumor suppressor gene, mutations in which were first described in patients presenting with von Hippel-Lindau disease, which is characterized by the development of highly vascularized tumors. Here, we identified a new VHL cryptic-exon (termed E1') deep in intron 1 that is naturally expressed in many tissues. More importantly, we identified mutations in E1' in seven families with erythrocytosis (one homozygous case and six compound-heterozygous cases with a mutation in E1' in addition to a mutation in VHL coding sequences) and in one large family with typical VHL disease but without any alteration in the other VHL exons. In this study we have shown that the mutations induced a dysregulation of the VHL splicing with excessive retention of E1' and are associated with a downregulation of VHL protein expression. In addition, we have demonstrated a pathogenic role for synonymous mutations in VHL-Exon 2 that alter splicing through E2-skipping in five families with erythrocytosis or VHL disease. In all the studied cases, the mutations differentially impact splicing, correlating with phenotype severity. This study demonstrates that cryptic-exon-retention or exon-skipping are new VHL alterations and reveals a novel complex splicing regulation of the VHL gene. These findings open new avenues for diagnosis and research into the VHL-related-hypoxia-signaling pathway.
[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: 24 fév 2021 - 11:26
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.
[hal-01320274] Variation in worldwide incidence of amyotrophic lateral sclerosis: a meta-analysis.
Date: 22 fév 2021 - 14:50
Desc: To assess the worldwide variation of amyotrophic lateral sclerosis (ALS) incidence, we performed a systematic review and meta-analysis of population-based data published to date. We reviewed Medline and Embase up to June 2015 and included all population-based studies of newly diagnosed ALS cases, using multiple sources for case ascertainment. ALS crude and standardized incidence (on age and sex using the US 2010 population) were calculated. Random effect meta-analysis and meta-regression were performed using the subcontinent as the main study level covariate. Sources of heterogeneity related to the characteristics of the study population and the study methodology were investigated. Among 3216 records, 44 studies were selected, covering 45 geographical areas in 11 sub-continents. A total of 13 146 ALS cases and 825 million person-years of follow-up (PYFU) were considered. The overall pooled worldwide crude ALS incidence was at 1.75 (1.55-1.96)/100 000 PYFU; 1.68 (1.50-1.85)/100 000 PYFU after standardization. Heterogeneity was identified in ALS standardized incidence between North Europe [1.89 (1.46-2.32)/100 000 PYFU] and East Asia [0.83 (0.42-1.24)/100 000 PYFU, China and Japan P = 0.001] or South Asia [0.73 (0.58-0.89)/100 000/PYFU Iran, P = 0.02]. Conversely, homogeneous rates have been reported in populations from Europe, North America and New Zealand [pooled ALS standardized incidence of 1.81 (1.66-1.97)/100 000 PYFU for those areas]. This review confirms a heterogeneous distribution worldwide of ALS, and sets the scene to sustain a collaborative study involving a wide international consortium to investigate the link between ancestry, environment and ALS incidence.
Autres contacts
Hôpital St Louis - Centre Hayem
1, avenue Claude Vellefaux
75475 PARIS CEDEX 10