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-00698016] The contribution of large genomic deletions at the CDKN2A locus to the burden of familial melanoma
Date: 26 juin 2022 - 14:22
Desc: [...]
[hal-03478564] Genetic and Environmental Factors Influencing the Placental Growth Factor (PGF) Variation in Two Populations
Date: 26 juin 2022 - 13:18
Desc: Placental Growth Factor (PGF) is a key molecule in angiogenesis. Several studies have revealed an important role of PGF primarily in pathological conditions (e.g.: ischaemia, tumour formation, cardiovascular diseases and inflammatory processes) suggesting its use as a potential therapeutic agent. However, to date, no information is available regarding the genetics of PGF variability. Furthermore, even though the effect of environmental factors (e.g.: cigarette smoking) on angiogenesis has been explored, no data on the influence of these factors on PGF levels have been reported so far. Here we have first investigated PGF variability in two cohorts focusing on non-genetic risk factors: a study sample from two isolated villages in the Cilento region, South Italy (N = 871) and a replication sample from the general Danish population (N = 1,812). A significant difference in PGF mean levels was found between the two cohorts. However, in both samples, we observed a strong correlation of PGF levels with ageing and sex, men displaying PGF levels significantly higher than women. Interestingly, smoking was also found to influence the trait in the two populations, although differently. We have then focused on genetic risk factors. The association between five single nucleotide polymorphisms (SNPs) located in the <italic>PGF</italic> gene and the plasma levels of the protein was investigated. Two polymorphisms (rs11850328 and rs2268614) were associated with the PGF plasma levels in the Cilento sample and these associations were strongly replicated in the Danish sample. These results, for the first time, support the hypothesis of the presence of genetic and environmental factors influencing PGF plasma variability.
[hal-02151167] Detecting the dominance component of heritability in isolated and outbred human populations
Date: 26 juin 2022 - 13:11
Desc: [...]
[hal-01662693] A second locus for Marfan syndrome maps to chromosome 3p24.2–p25
Date: 26 juin 2022 - 13:08
Desc: Marfan syndrome (MFS) is an autosomal dominant connective-tissue disorder characterized by skeletal, ocular and cardiovascular defects of highly variable expressivity. The diagnosis relies solely on clinical criteria requiring anomalies in at least two systems. By excluding the chromosome 15 disease locus, fibrillin 1 (FBN1), in a large French family with typical cardiovascular and skeletal anomalies, we raised the issue of genetic heterogeneity in MFS and the implication of a second locus (MFS2). Linkage analyses, performed in this family, have localized MFS2 to a region of 9 centiMorgans between D3S1293 and D3S1283, at 3p24.2–p25. In this region, the highest lod score was found with D3S2336, of 4.89 (θ=0.05). By LINKMAP analyses, the most probable position for the second locus in MFS was at D3S2335.
[inserm-01401555] Distinct deregulation of the hypoxia inducible factor by PHD2 mutants identified in germline DNA of patients with polycythemia
Date: 26 juin 2022 - 13:06
Desc: BACKGROUND: Congenital secondary erythrocytoses are due to deregulation of hypoxia inducible factor resulting in overproduction of erythropoietin. The most common germline mutation identified in the hypoxia signaling pathway is the Arginine 200-Tryptophan mutant of the von Hippel-Lindau tumor suppressor gene, resulting in Chuvash polycythemia. This mutant displays a weak deficiency in hypoxia inducible factor α regulation and does not promote tumorigenesis. Other von Hippel-Lindau mutants with more deleterious effects are responsible for von Hippel-Lindau disease, which is characterized by the development of multiple tumors. Recently, a few mutations in gene for the prolyl hydroxylase domain 2 protein (PHD2) have been reported in cases of congenital erythrocytosis not associated with tumor formation with the exception of one patient with a recurrent extra-adrenal paraganglioma. DESIGN AND METHODS: Five PHD2 variants, four of which were novel, were identified in patients with erythrocytosis. These PHD2 variants were functionally analyzed and compared with the PHD2 mutant previously identified in a patient with polycythemia and paraganglioma. The capacity of PHD2 to regulate the activity, stability and hydroxylation of hypoxia inducible factor α was assessed using hypoxia-inducible reporter gene, one-hybrid and in vitro hydroxylation assays, respectively. RESULTS: This functional comparative study showed that two categories of PHD2 mutants could be distinguished: one category with a weak deficiency in hypoxia inducible factor α regulation and a second one with a deleterious effect; the mutant implicated in tumor occurrence belongs to the second category. CONCLUSIONS: As observed with germline von Hippel-Lindau mutations, there are functional differences between the PHD2 mutants with regards to hypoxia inducible factor regulation. PHD2 mutation carriers do, therefore, need careful medical follow-up, since some mutations must be considered as potential candidates for tumor predisposition.
Autres contacts
Hôpital St Louis - Centre Hayem
1, avenue Claude Vellefaux
75475 PARIS CEDEX 10
