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1. Genome-Wide Association Study of Fluorescent Oxidation Products Accounting for Tobacco Smoking Status in Adults from the French EGEA Study

Author

Laurent Orsi, Patricia Margaritte-Jeannin, Miora Andrianjafimasy, Orianne Dumas, Hamida Mohamdi, Emmanuelle Bouzigon, Florence Demenais, Régis Matran, Farid Zerimech, Rachel Nadif, and Marie-Hélène Dizier

Subjects
fluorescent oxidation products, oxidative stress, genome-wide association study, chronic diseases, asthma, smoking, Therapeutics. Pharmacology, RM1-950
Abstract

Oxidative stress (OS) is the main pathophysiological mechanism involved in several chronic diseases, including asthma. Fluorescent oxidation products (FlOPs), a global biomarker of damage due to OS, is of growing interest in epidemiological studies. We conducted a genome-wide association study (GWAS) of the FlOPs level in 1216 adults from the case-control and family-based EGEA study (mean age 43 years old, 51% women, and 23% current smokers) to identify genetic variants associated with FlOPs. The GWAS was first conducted in the whole sample and then stratified according to smoking status, the main exogenous source of reactive oxygen species. Among the top genetic variants identified by the three GWAS, those located in BMP6 (p = 3 × 10−6), near BMPER (p = 9 × 10−6), in GABRG3 (p = 4 × 10−7), and near ATG5 (p = 2 × 10−9) are the most relevant because of both their link to biological pathways related to OS and their association with several chronic diseases for which the role of OS in their pathophysiology has been pointed out. BMP6 and BMPER are of particular interest due to their involvement in the same biological pathways related to OS and their functional interaction. To conclude, this study, which is the first GWAS of FlOPs, provides new insights into the pathophysiology of chronic OS-related diseases.

Published
2022
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2. Identification of OCA2 as a novel locus for the co‐morbidity of asthma‐plus‐eczema

Author

Emmanuelle Bouzigon, Ashley Budu-Aggrey, Markus J. Ege, Hamida Mohamdi, Christophe Linhard, Patricia Margaritte-Jeannin, Marie-Hélène Dizier, Catherine Laprise, Florence Demenais, Anne-Marie Madore, Erika von Mutius, and Raquel Granell

Subjects
Candidate gene, Immunology, Eczema, Single-nucleotide polymorphism, Genome-wide association study, Locus (genetics), Comorbidity, immune system diseases, Missing heritability problem, medicine, Humans, Immunology and Allergy, Genetic Predisposition to Disease, Asthma, OCA2, Genetic heterogeneity, business.industry, Membrane Transport Proteins, medicine.disease, Rhinitis, Allergic, Albinism, Oculocutaneous, Morbidity, business, Genome-Wide Association Study
Abstract

BACKGROUND: Numerous genes have been associated with the three most common allergic diseases (asthma, allergic rhinitis or eczema) but these genes explain only a part of the heritability. In the vast majority of genetic studies, complex phenotypes such as co-morbidity of two of these diseases, have not been considered. This may partly explain missing heritability.OBJECTIVE: To identify genetic variants specifically associated with the co-morbidity of asthma-plus-eczema.METHODS: We first conducted a meta-analysis of four GWAS (Genome-Wide Association Study) of the combined asthma-plus-eczema phenotype (total of 8807 European-ancestry subjects of whom 1208 subjects had both asthma and eczema). To assess whether the association with SNP(s) was specific to the co-morbidity, we also conducted a meta-analysis of homogeneity test of association according to disease status ("asthma-plus-eczema" vs. the presence of only one disease "asthma only or eczema only"). We then used a joint test by combining the two test statistics from the co-morbidity-SNP association and the phenotypic heterogeneity of SNP effect meta-analyses.RESULTS: Seven SNPs were detected for specific association to the asthma-plus-eczema co-morbidity, two with significant and five with suggestive evidence using the joint test after correction for multiple testing. The two significant SNPs are located in the OCA2 gene (Oculocutaneous Albinism II), a new locus never detected for significant evidence of association with any allergic disease. This gene is a promising candidate gene, because of its link to skin and lung diseases, and to epithelial barrier and immune mechanisms.CONCLUSION: Our study underlines the importance of studying sub-phenotypes as co-morbidities to detect new susceptibility genes.

Published
2021
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3. Identification of novel genes influencing eosinophil-specific protein levels in asthma families

Author

Raphaël Vernet, Régis Matran, Farid Zerimech, Anne-Marie Madore, Marie-Eve Lavoie, Pierre-Alexandre Gagnon, Hamida Mohamdi, Patricia Margaritte-Jeannin, Valérie Siroux, Marie-Hélène Dizier, Florence Demenais, Catherine Laprise, Rachel Nadif, and Emmanuelle Bouzigon

Subjects
Eosinophils, Inflammation, Immunology, Eosinophil Cationic Protein, Hypersensitivity, Immunology and Allergy, Humans, Bayes Theorem, Eosinophil-Derived Neurotoxin, Blood Proteins, Eosinophil Granule Proteins, Asthma, Genome-Wide Association Study
Abstract

Eosinophils play a key role in the asthma allergic response by releasing cytotoxic molecules such as eosinophil cationic protein (ECP) and eosinophil-derived neurotoxin (EDN) that generate epithelium damages.We sought to identify genetic variants influencing ECP and EDN levels in asthma-ascertained families.We performed univariate and bivariate genome-wide association analyses of ECP and EDN levels in 1018 subjects from the EGEA study with follow-up in 153 subjects from the Saguenay-Lac-Saint-Jean study and combined the results of these 2 studies through meta-analysis. We then conducted Bayesian statistical fine mapping together with quantitative trait locus and functional annotation analyses to identify the most likely functional genetic variants and candidate genes.We identified 5 genome-wide significant loci (P amp;lt; 5 × 10lt;supgt;-8lt;/supgt;) including 7 distinct signals associated with ECP and/or EDN levels. The genes targeted by our fine mapping and functional search include RNASE2 and RNASE3 (14q11), which encode EDN and ECP, respectively, and 4 other genes that regulate ECP and EDN levels. These 4 genes were JAK1 (1p31), a transcription factor that plays a key role in the immune response and acts as a potential therapeutic target for eosinophilic asthma; ARHGAP25 (2p13), which is involved in leukocyte recruitment to inflammatory sites; NDUFA4 (7p21), which encodes a component of the mitochondrial respiratory chain and is involved in cellular response to stress; and CTSL (9q22), which is involved in immune response, extracellular remodeling, and allergic inflammation.Analysis of specific phenotypes produced by eosinophils allows the identification of genes that play a major role in allergic response and inflammation, and offers potential therapeutic targets for asthma.

Published
2021

5. PID1 is associated to a respiratory endotype related to occupational exposures to irritants

Author

Patricia Margaritte-Jeannin, Marie-Hélène Dizier, Régis Matran, Miora Valérie Andrianjafimasy, Hamida Mohamdi, Farid Zerimech, Orianne Dumas, Florence Demenais, Nicole Le Moual, Rachel Nadif, Laurent Orsi, Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Toxicité environnementale, cibles thérapeutiques, signalisation cellulaire (T3S - UMR_S 1124), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Impact de l'environnement chimique sur la santé humaine - ULR 4483 (IMPECS), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Merck Sharp and Dohme, MSD, Wellcome Trust, WT: WT084703MA, European Commission, EC: LSHB-CT-2006-018996- GABRIEL, Agence Nationale de la Recherche, ANR: CES-2009, Agence Française de Sécurité Sanitaire de l'Environnement et du Travail, AFSSET: EST- 09–15, PNR-EST 2017, Agence Nationale de Sécurité Sanitaire de l’Alimentation, de l’Environnement et du Travail, ANSES, Agir pour les Maladies Chroniques, This work was funded by the French Agency for Food, Environmental and Occupational Health & Safety (ANSES/ AFSSET , EST- 09–15 , PNR-EST 2017), Merck Sharp & Dohme (MSD) , the national hospital program of clinical research (PHRC-National 2012, EvAdA), the National Research Agency – Health Environment, Health-Work Program ( ANR-PRSP 2009 : IAGO, ANR CES-2009), the Region Hauts de France, and the Fonds AGIR pour les maladies chroniques. Genotyping of the Epidemiological study on the genetics and environment of asthma (EGEA) was supported by grants from the European Commission (No. LSHB-CT-2006-018996- GABRIEL ) and the Wellcome Trust ( WT084703MA )., This work was funded by the French Agency for Food, Environmental and Occupational Health & Safety (ANSES/AFSSET, EST- 09?15, PNR-EST 2017), Merck Sharp & Dohme (MSD), the national hospital program of clinical research (PHRC-National 2012, EvAdA), the National Research Agency ? Health Environment, Health-Work Program (ANR-PRSP 2009: IAGO, ANR CES-2009), the Region Hauts de France, and the Fonds AGIR pour les maladies chroniques. Genotyping of the Epidemiological study on the genetics and environment of asthma (EGEA) was supported by grants from the European Commission (No. LSHB-CT-2006-018996- GABRIEL) and the Wellcome Trust (WT084703MA)., and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)

Subjects
0301 basic medicine, Adult, Candidate gene, Endotype, medicine.medical_specialty, [SDV]Life Sciences [q-bio], Single-nucleotide polymorphism, Logistic regression, Biochemistry, Polymorphism, Single Nucleotide, 03 medical and health sciences, 0302 clinical medicine, Physiology (medical), Occupational Exposure, Epidemiology, medicine, SNP, Humans, Asthma, business.industry, Endotypes, Gene association study, medicine.disease, 3. Good health, 030104 developmental biology, Logistic Models, Oxidative stress, Immunology, Etiology, Irritants, business, Carrier Proteins, 030217 neurology & neurosurgery
Abstract

International audience; Background: Studying associations between genes and asthma endotypes and interactions with environment could help to identify new susceptibility genes. We used a previously identified asthma endotype characterized by adult-onset asthma, poor lung function, and high level of Fluorescent oxidation products, a marker of damages due to oxidative stress. This endotype was associated with high occupational exposure to irritants. We aimed to investigate the associations between genes related to oxidative stress and this endotype, and if the associations differed according to irritants exposure. Methods: We conducted association analyses between the asthma endotype and genetic variants (4715 SNPs) located in 422 genes involved in the “response to oxidative stress” in adults from the Epidemiological study on the Genetic and Environment of Asthma. Analyses using logistic regression were conducted first in all participants, and then separately among high vs. non-exposed participants to assess whether association differs according to irritants exposure. Results: An association was found between the SNP rs1419958 located in PID1 gene and the endotype (P = 2.2E-05), reaching significance level after correction for multiple testing. This association was even more significant in non-exposed participants (P = 1.06E-06) while there was no association in participants with high exposure to occupational irritants. Conclusion: This study showed a significant association between an asthma endotype and PID1, a promising candidate gene, the association being different according to the exposure to irritants. These results highlight the interest of studying asthma endotypes in association with genes from candidate pathways and their link with occupational irritants to decipher asthma etiology.

Published
2021
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6. Genome-wide association meta-analyses combining multiple risk phenotypes provide insights into the genetic architecture of cutaneous melanoma susceptibility

Author

Eduardo Nagore, Caroline Hayward, Christopher I. Amos, Douglas F. Easton, Zaida García-Casado, Julie Lang, Anjali K. Henders, Veronica Höiom, Lisa Bowdler, Kathryn P. Burdon, Laura Del Regno, Nick Orr, Per Arne Andresen, Tongwu Zhang, Rose Yang, Myriam Brossard, Eric K. Moses, Dirk Schadendorf, Laura Cattaneo, Casey Rowe, Essen-Heidelberg Investigators, Hans-Joachim Schulze, Jamie E Craig, D. Timothy Bishop, Anne E. Cust, Johan Hansson, David E. Elder, Nelleke A. Gruis, Donato Calista, Wei V. Chen, Abrar A. Qureshi, Amy Hutchinson, Pilar Galan, Leanne Wallace, Jennifer H. Barrett, Nilesh J. Samani, Maria Teresa Landi, Per Helsing, Andreas Hadjisavvas, Fengju Song, Celia Requena, Elizabeth M. Gillanders, Arantxa Rodriguez, Joan Anton Puig-Butille, Blair H. Smith, Mark Smithers, Michael Malasky, Marianna Sanna, Miriam Potrony, Maria A. Loizidou, Evangelos Evangelou, Richard A. Scolyer, Karen A. Pooley, Rachel E. Neale, Mario Falchi, Adèle C. Green, Monica Rodolfo, Ketty Peris, Licia Rivoltini, Mark M. Iles, Catherine M. Olsen, Alexander J. Stratigos, Tadeusz Dębniak, Weiyin Zhou, H. Peter Soyer, Xin Li, Margaret A. Tucker, Rajesh Kumar, Håkan Olsson, Anders Molven, Nicholas G. Martin, Anthony J. Swerdlow, Aurelie Vogt, Lars A. Akslen, Stuart MacGregor, Sarah V. Ward, Hamida Mohamdi, Bruna Dalmasso, Grant W. Montgomery, Rona M. MacKie, Esther Azizi, Gonçalo R. Abecasis, Chiara Menin, Alison M. Dunning, Ibd investigators, Kevin M. Brown, Jiali Han, Veryan Codd, Graham J. Mann, Nicholas K. Hayward, Marko Hočevar, Eitan Friedman, Richard A. Sturm, Paola Queirolo, Qtwin Investigators, Lawrie Wheeler, Lars G. Fritsche, Shenying Fang, Kiarash Khosrotehrani, Nicole A Kukutsch, Pol Gimenez-Xavier, Belynda Hicks, Matthew Zawistowski, Alessia Visconti, Jessica Harris, Chad M. Brummett, Paola Ghiorzo, andMe, David G. Hunter, Veronique Bataille, Julia Newton-Bishop, Srdjan Novaković, Amfs Investigators, Siranoush Manoukian, Jianxin Shi, Mitchell J. Machiela, G. Mark Lathrop, Josep Malvehy, Katerina P. Kypreou, Susana Puig, Dale R. Nyholt, I. Stefanaki, Maria Concetta Fargnoli, Lisa A. Simms, Kerrie McAloney, M. Malt, Adam J. Trower, Matthew Law, Lei Song, Paul D.P. Pharoah, Christian Ingvar, Jiyeon Choi, Alisa M. Goldstein, Jeffrey E. Lee, Mark Harland, Cristina Pellegrini, Daniela Massi, Sarah Simi, Scott D. Gordon, Jacobo Martinez, Florence Demenais, Kristine Jones, Graham L. Radford-Smith, David C. Whiteman, Lorenza Pastorino, Lisa Elefanti, Arcangela De Nicolo, Mario Mandalà, Juliette Randerson-Moor, Q-Mega, Jan Lubinski, Stephen J. Chanock, Marie-Françoise Avril, David L. Duffy, Helen Gogas, Nienke van der Stoep, Peter A. Kanetsky, Georgina V. Long, National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH), University of Leeds, QIMR Berghofer Medical Research Institute, National and Kapodistrian University of Athens (NKUA), Ospedale Policlinico San Martino [Genoa], Universita degli studi di Genova, Toxicité environnementale, cibles thérapeutiques, signalisation cellulaire (T3S - UMR_S 1124), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Maurizio Bufalini Hospital, University of L'Aquila [Italy] (UNIVAQ), Fondazione IRCCS Istituto Nazionale Tumori - National Cancer Institute [Milan], Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana [Espagne] (FISABIO), Cyprus Institute of Neurology and Genetics, University of Athens Medical School [Athens], The University of Sydney, Universitat de Barcelona (UB), Azienda Ospedaliera Ospedale Papa Giovanni XXIII [Bergamo, Italy], University of Michigan [Ann Arbor], University of Michigan System, Instituto Valenciano de Oncologia, Veneto Institute of Oncology IOV-IRCCS [Padua, Italy], IRCCS Istituto Nazionale dei Tumori [Milano], Ninewells Hospital and Medical School [Dundee], Cyprus Institute (CyI), Fondazione 'Policlinico Universitario A. Gemelli' [Rome], Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), University of Queensland [Brisbane], Haukeland University Hospital, University of Bergen (UiB), Geisel School of Medicine at Dartmouth, Oslo University Hospital [Oslo], Service de Dermatologie [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sackler Faculty of Medicine, Tel Aviv University [Tel Aviv], King‘s College London, Menzies School of Health Research [Australia], Charles Darwin University, The University of Texas M.D. Anderson Cancer Center [Houston], University of Leicester, Flinders University [Adelaide, Australia], West Pomeranian University of Technology Szczecin, Equipe 3: EREN- Equipe de Recherche en Epidémiologie Nutritionnelle (CRESS - U1153), Université Sorbonne Paris Nord-Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), National Human Genome Research Institute (NHGRI), Leiden University Medical Center (LUMC), Karolinska Institutet [Stockholm], Queensland University of Technology [Brisbane] (QUT), Institute of Oncology Ljubljana, Harvard T.H. Chan School of Public Health, Lund University [Lund], German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), University of Glasgow, Statistical Genetics, and Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute (NCI), National Institutes of Health (NIH) United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USAU19CA148112SEARCH team (Cancer Research UK) C490/A16561AOCS (US Army Medical Research and Material Command) DAMD17-01-1-0729Canadian Institutes of Health Research (CIHR)Cancer Council Victoria Queensland Cancer Fund Cancer Council New South Wales Cancer Council South Australia Cancer Council Western Australia Cancer Council Tasmania National Health and Medical Research Council of AustraliaID400413ID400281National Health and Medical Research Council of Australia National Health and Medical Research Council of Australia National Health and Medical Research Council of Australia National Health and Medical Research Council of Australia Intramural Research Program of the Division of Cancer Epidemiology and Genetics, NCI, NIH, DHHS Ministry of Health, Italy Associazione Italiana per la Ricerca sul Cancro (AIRC)IG 15460Spanish Fondo de Investigaciones Sanitarias grant - FEDER 'Una manera de hacer Europa' PI15/00716PI15/00956CIBER de Enfermedades Raras of the Instituto de Salud Carlos III, Spain - European Development Regional Fund 'A way to achieve Europe' ERDF AGAUR of the Catalan Government, Spain 2014_SGR_603European CommissionEuropean Commission Joint Research CentreLSHC-CT-2006-018702European Union (EU) 'Fundacio La Marato de TV3', Catalonia, Spain 201331-30'Fundacion Cientifica de la Asociacion Espanola Contra el Cancer', Spain GCB15152978SOENCERCA Programme/Generalitat de Catalunya Italian Ministry of the University and Scientific Research (PRIN-2012 grant) 2012JJX494Melanoma Research Alliance United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI)CA88363CA83115CA122838CA87969CA055075CA100264CA133996CA49449National Health and Medical Research Council of Australia200071241944339462380385389927389875389891389892389938443036442915442981496610496675496739552485552498APP1049894Cancer Council Queensland Cancer Institute New South Wales Australian GovernmentDepartment of Industry, Innovation and ScienceCooperative Research Centres (CRC) Programme Australian Cancer Research Foundation Wellcome TrustWT084766/Z/08/ZNational Health and Medical Research Council of Australia Australian Research Council Department of Health and Human Services (DHHS)

Subjects
Sequence Variants, Male, medicine.medical_specialty, Skin Neoplasms, Genotype, Medizin, Identifies 3, Genome-wide association study, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Malignant-melanoma, 0302 clinical medicine, Genetics, medicine, Genetic predisposition, Nevus, Humans, Hla Class-i, Genetic Predisposition to Disease, Polymorphism, Melanoma, 030304 developmental biology, Telomere Length, Cancer, 0303 health sciences, [SDV.GEN]Life Sciences [q-bio]/Genetics, Loci, Pigmentation, E-cadherin, Single Nucleotide, medicine.disease, Genetic architecture, Attributable Fraction, 3. Good health, Phenotype, Female, Genetic Loci, Genome-Wide Association Study, Cutaneous melanoma, Medical genetics, Settore MED/35 - MALATTIE CUTANEE E VENEREE, 030217 neurology & neurosurgery, Familial Melanoma
Abstract

Meta-analysis of 36,760 cases and 375,188 controls identifies 54 loci associated with susceptibility to cutaneous melanoma. Further analysis combining nevus count and hair color GWAS results provide insights into the genetic architecture of melanoma.Most genetic susceptibility to cutaneous melanoma remains to be discovered. Meta-analysis genome-wide association study (GWAS) of 36,760 cases of melanoma (67% newly genotyped) and 375,188 controls identified 54 significant (P < 5 x 10(-8)) loci with 68 independent single nucleotide polymorphisms. Analysis of risk estimates across geographical regions and host factors suggests the acral melanoma subtype is uniquely unrelated to pigmentation. Combining this meta-analysis with GWAS of nevus count and hair color, and transcriptome association approaches, uncovered 31 potential secondary loci for a total of 85 cutaneous melanoma susceptibility loci. These findings provide insights into cutaneous melanoma genetic architecture, reinforcing the importance of nevogenesis, pigmentation and telomere maintenance, together with identifying potential new pathways for cutaneous melanoma pathogenesis.

Published
2020
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7. Interactive effect between ATPase-related genes and early-life tobacco smoke exposure on bronchial hyper-responsiveness detected in asthma-ascertained families

Author

Marie-Claude Babron, Emmanuelle Bouzigon, Patricia Margaritte-Jeannin, Myriam Brossard, Florence Demenais, Mark Lathrop, Rachel Nadif, Nolwenn Lavielle, Jocelyne Just, Chloé Sarnowski, Marie-Hélène Dizier, Lucile Pain, Catherine Laprise, Hamida Mohamdi, Faraldo, Beatrice, Variabilité Génétique et Maladies Humaines, Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Diderot - Paris 7 (UPD7), Département des Sciences Fondamentales [Chicoutimi] (DSF), Université du Québec à Chicoutimi (UQAC), Centre de l'Asthme et des Allergies [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Department of Human Genetics [Montréal], McGill University = Université McGill [Montréal, Canada], Vieillissement et Maladies chroniques : approches épidémiologique et de santé publique (VIMA), and Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
0301 basic medicine, Pulmonary and Respiratory Medicine, Adult, Male, Positional cloning, Adolescent, [SDV]Life Sciences [q-bio], BHR, Locus (genetics), Single-nucleotide polymorphism, FBAT, Polymorphism, Single Nucleotide, Tobacco smoke, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Medicine, SNP, Humans, Genetic Predisposition to Disease, Phospholipid Transfer Proteins, Child, Gene, Asthma, Genetics, Adenosine Triphosphatases, business.industry, Age Factors, Axonemal Dyneins, asthma, medicine.disease, GxE interaction, ATP, [SDV] Life Sciences [q-bio], 030104 developmental biology, 030228 respiratory system, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Motile cilium, Female, Tobacco Smoke Pollution, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, France, Bronchial Hyperreactivity, business, ATP Binding Cassette Transporter 1, ETS
Abstract

BackgroundA positional cloning study of bronchial hyper-responsiveness (BHR) at the 17p11 locus in the French Epidemiological study on the Genetics and Environment of Asthma (EGEA) families showed significant interaction between early-life environmental tobacco smoke (ETS) exposure and genetic variants located in DNAH9. This gene encodes the heavy chain subunit of axonemal dynein, which is involved with ATP in the motile cilia function.Our goal was to identify genetic variants at other genes interacting with ETS in BHR by investigating all genes belonging to the ‘ATP-binding’ and ‘ATPase activity’ pathways which include DNAH9, are targets of cigarette smoke and play a crucial role in the airway inflammation.MethodsFamily-based interaction tests between ETS-exposed and unexposed BHR siblings were conducted in 388 EGEA families. Twenty single-nucleotide polymorphisms (SNP) showing interaction signals (p≤5.10−3) were tested in the 253 Saguenay-Lac-Saint-Jean (SLSJ) families.ResultsOne of these SNPs was significantly replicated for interaction with ETS in SLSJ families (p=0.003). Another SNP reached the significance threshold after correction for multiple testing in the combined analysis of the two samples (p=10−5). Results were confirmed using both a robust log-linear test and a gene-based interaction test.ConclusionThe SNPs showing interaction with ETS belong to the ATP8A1 and ABCA1 genes, which play a role in the maintenance of asymmetry and homeostasis of lung membrane lipids.

Published
2019
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8. Influence of gene-by-sex interaction on time-to-asthma onset: a large-scale genome-wide meta-analysis

Author

Catherine Laprise, Bénédicte Leynaert, Hamida Mohamdi, Erika von Mutius, A. S. Karunas, Maxim B. Freidin, Deborah Jarvis, Elza Khusnutdinova, Ludmila O. Ogorodova, Emmanuelle Bouzigon, Alan James, Raquel Granell, Nicole Probst-Hensch, Dizier A. John Henderson, Markus J. Ege, Florence Demenais, null Marie-Helene, Chloé Sarnowski, Medea Imboden, Patricia Margaritte-Jeannin, and Raphael Veil

Subjects
Scale (ratio), business.industry, Computational biology, medicine.disease, Genome, 03 medical and health sciences, 0302 clinical medicine, 030228 respiratory system, Meta-analysis, medicine, 030212 general & internal medicine, business, Gene, Asthma
Published
2018
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9. Integrated pathway and epistasis analysis reveals interactive effect of genetic variants atTERF1andAFAP1L2loci on melanoma risk

Author

Shenying Fang, Qingyi Wei, Marie-Françoise Avril, Amaury Vaysse, Wei V. Chen, Mark Lathrop, Christopher I. Amos, Myriam Brossard, Nolwenn Lavielle, Hamida Mohamdi, Jeffrey E. Lee, Eve Maubec, Florence Demenais, and Pilar Galan

Subjects
Genetics, Cancer Research, Melanoma, Epistasis and functional genomics, Genetic variants, Genome-wide association study, Biology, medicine.disease, Pathway analysis, TERF1, Oncology, medicine, Gene, Genetic association
Abstract

Genome-wide association studies (GWASs) have characterized 13 loci associated with melanoma, which only account for a small part of melanoma risk. To identify new genes with too small an effect to be detected individually but which collectively influence melanoma risk and/or show interactive effects, we used a two-step analysis strategy including pathway analysis of genome-wide SNP data, in a first step, and epistasis analysis within significant pathways, in a second step. Pathway analysis, using the gene-set enrichment analysis (GSEA) approach and the gene ontology (GO) database, was applied to the outcomes of MELARISK (3,976 subjects) and MDACC (2,827 subjects) GWASs. Cross-gene SNP–SNP interaction analysis within melanoma-associated GOs was performed using the INTERSNP software. Five GO categories were significantly enriched in

Published
2015
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10. Rare missense variants in POT1 predispose to familial cutaneous malignant melanoma

Author

Ketty Peris, Zhaoming Wang, Donato Calista, Ji He, Lynn R. Goldin, Marie-Françoise Avril, Margaret A. Tucker, Lorenza Pastorino, Fanélie Jouenne, William Bruno, Melissa Rotunno, Mario Foglio, Florence Demenais, Giovanna Bianchi Scarrà, Weihang Chai, Bari J. Ballew, Paola Minghetti, Amaury Vaysse, Sarangan Ravichandran, Maria Concetta Fargnoli, Sharon A. Savage, Paola Queirolo, Maria Teresa Landi, Paula L. Hyland, Jianxin Shi, Alisa M. Goldstein, Joshua N. Sampson, Alexander M.M. Eggermont, Haritha Vallabhaneni, Yie Liu, Hamida Mohamdi, Paola Ghiorzo, Michael Cullen, Jinhu Yin, Mark Lathrop, Cristina Pellegrini, Eduardo Nagore, Neil E. Caporaso, Mary L. McMaster, Zaida García-Casado, Yasser Riazalhosseini, Xing Hua, Stephen J. Chanock, Jose Banuls-Roca, Xijun Zhang, Brigitte Bressac-de Paillerets, Xiaohong R. Yang, Giorgio Landi, and Meredith Yeager

Subjects
Models, Molecular, medicine.medical_specialty, Skin Neoplasms, Population, Molecular Sequence Data, Telomere-Binding Proteins, Mutation, Missense, Biology, medicine.disease_cause, Shelterin Complex, Article, CDKN2A, Genetics, medicine, melanoma, Missense mutation, Humans, Exome, Genetic Predisposition to Disease, Amino Acid Sequence, education, In Situ Hybridization, Fluorescence, Chromosome 7 (human), education.field_of_study, Mutation, Neoplasms, Connective Tissue, Base Sequence, Computational Biology, Telomere Homeostasis, Sequence Analysis, DNA, Shelterin, United States, 3. Good health, Telomere, Pedigree, Italy, Medical genetics, France, Settore MED/35 - MALATTIE CUTANEE E VENEREE, Sequence Alignment
Abstract

Although CDKN2A is the most frequent high-risk melanoma susceptibility gene, the underlying genetic factors for most melanoma-prone families remain unknown. Using whole-exome sequencing, we identified a rare variant that arose as a founder mutation in the telomere shelterin gene POT1 (chromosome 7, g.124493086C>T; p.Ser270Asn) in five unrelated melanoma-prone families from Romagna, Italy. Carriers of this variant had increased telomere lengths and numbers of fragile telomeres, suggesting that this variant perturbs telomere maintenance. Two additional rare POT1 variants were identified in all cases sequenced in two separate Italian families, one variant per family, yielding a frequency for POT1 variants comparable to that for CDKN2A mutations in this population. These variants were not found in public databases or in 2,038 genotyped Italian controls. We also identified two rare recurrent POT1 variants in US and French familial melanoma cases. Our findings suggest that POT1 is a major susceptibility gene for familial melanoma in several populations.

Published
2014

11. Corrigendum: A SUMOylation-defective MITF germline mutation predisposes to melanoma and renal carcinoma

Author

Olivier Caron, Etienne Rouleau, Hamida Mohamdi, F. Boitier, Jean-Luc Perrot, Eve Maubec, Arnaud de la Fouchardière, Stéphane Richard, Pierre Vabres, Luc Thomas, Rosette Lidereau, Simon Saule, Diana Zelenika, Pilar Galan, Tanguy Martin-Denavit, Lorenza Pastorino, N. Poulalhon, Jérôme Couturier, Bruno Labeille, Eve Corda, Caroline Robert, Philippe Dessen, Marie-Françoise Avril, Bernard Escudier, Christian Ingvar, Sandy Giuliano, Celia Badenas, Robert Ballotti, Benoit d’Hayer, Gilbert M. Lenoir, Betty Gardie, Stéphane Dalle, Laurence Brugières, Brigitte Bressac-de Paillerets, Audrey Remenieras, Valérie Chaudru, Paola Ghiorzo, Hélène Blanché, Philippe Bahadoran, Fabienne Lesueur, Håkan Olsson, Bin Tean Teh, Philippe Vielh, Corine Bertolotto, Pascale Andry-Benzaquen, Thomas Strub, Florence Demenais, Vincent Molinié, Mahaut de Lichy, Susana Puig, Karine Bille, Sophie Gad, Annick Rossi, Mark Lathrop, Nicolas Dupin, Irwin Davidson, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
0301 basic medicine, Mutation, Multidisciplinary, Melanoma, Carcinoma, SUMO protein, Cancer, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, medicine.disease_cause, medicine.disease, Microphthalmia-associated transcription factor, 3. Good health, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Germline mutation, medicine, Cancer research, Epigenetics, 030217 neurology & neurosurgery, ComputingMilieux_MISCELLANEOUS
Abstract

Nature 480, 94–98 (2011); doi:10.1038/nature10539 In this Letter, one image was mistakenly duplicated during preparation of the artwork. In the original Fig. 3d, the left image illustrating migration of RCC4 cells transduced with empty adenovirus (EV) at 24 h is a duplicate of the middle image showing migration of RCC4 cells transduced with an adenovirus encoding Mi-WT.

Published
2016
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12. Characteristics of the coexistence of melanoma and renal cell carcinoma

Author

Hamida Mohamdi, Florence Demenais, Béatrice Crickx, Valérie Chaudru, Marie-Françoise Avril, Eve Maubec, Jean-Jacques Patard, Florent Grange, Stéphane Dalle, and Brigitte Bressac-de Paillerets

Subjects
Adult, Male, Cancer Research, medicine.medical_specialty, Pathology, Skin Neoplasms, Urology, urologic and male genital diseases, Asymptomatic, Neoplasms, Multiple Primary, Risk Factors, Renal cell carcinoma, CDKN2A, medicine, Carcinoma, Humans, Genetic Predisposition to Disease, Carcinoma, Renal Cell, Melanoma, neoplasms, Aged, Family Health, business.industry, Genes, p16, Cyclin-Dependent Kinase 4, Cancer, Middle Aged, medicine.disease, Kidney Neoplasms, female genital diseases and pregnancy complications, Oncology, Female, medicine.symptom, business, Kidney cancer, Kidney disease
Abstract

BACKGROUND: Patients with melanoma (MM) have an increased risk of kidney cancer, and there is an excess risk of MM among patients with renal cell carcinoma (RCC). The objective of the current study was to analyze a series of 42 patients with both MM and RCC to identify clinical and pathologic features as well as risk factors of this association. METHODS: Clinical and pathologic characteristics of 42 patients who developed both MM and RCC (the MM + RCC series) were compared with 2 published series in each cancer alone: a series of 293 patients with MM (MM series) and a series of 1527 patients with RCC (RCC series). RESULTS: RCC was diagnosed concomitantly or after MM in 83% of patients in the MM + RCC series. Those patients displayed a high proportion of asymptomatic RCC at diagnosis (70%) and a higher frequency of stage I tumors (61%) than patients in the RCC series. Compared with the MM series, patients in the MM + RCC series more often were men, had a higher frequency of blond/red hair, had poor tanning ability, and had a higher number of nevi. In addition, patients in the MM + RCC series had a high aggregation of other malignancies (mainly skin cancers) and a significantly higher frequency of family history of MM (P = .005). Only 2 cyclin-dependent kinase 2A gene (CDKN2A) germline mutations were identified among patients in the MM + RCC series who also were members of MM-prone families. CONCLUSIONS: The high aggregation of cancers among patients in the MM + RCC series and the familial clustering of MM argued for a genetic predisposition that may be partly independent of CDKN2A. Cancer 2010. © 2010 American Cancer Society.

Published
2010
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13. A comprehensive genome-wide analysis of melanoma Breslow thickness identifies interaction between CDC42 and SCIN genetic variants

Author

Amaury, Vaysse, Shenying, Fang, Myriam, Brossard, Qingyi, Wei, Wei V, Chen, Hamida, Mohamdi, Lynda, Vincent-Fetita, Patricia, Margaritte-Jeannin, Nolwenn, Lavielle, Eve, Maubec, Mark, Lathrop, Marie-Françoise, Avril, Christopher I, Amos, Jeffrey E, Lee, and Florence, Demenais

Subjects
Adult, Male, Skin Neoplasms, Epistasis, Genetic, Middle Aged, Polymorphism, Single Nucleotide, Article, Gene Ontology, Databases, Genetic, Humans, Female, cdc42 GTP-Binding Protein, Melanoma, Gelsolin, Genome-Wide Association Study
Abstract

Breslow thickness (BT) is a major prognostic factor of cutaneous melanoma (CM), the most fatal skin cancer. The genetic component of BT has only been explored by candidate gene studies with inconsistent results. Our objective was to uncover the genetic factors underlying BT using an hypothesis-free genome-wide approach. Our analysis strategy integrated a genome-wide association study (GWAS) of single nucleotide polymorphisms (SNPs) for BT followed by pathway analysis of GWAS outcomes using the gene-set enrichment analysis (GSEA) method and epistasis analysis within BT-associated pathways. This strategy was applied to two large CM datasets with Hapmap3-imputed SNP data: the French MELARISK study for discovery (966 cases) and the MD Anderson Cancer Center study (1,546 cases) for replication. While no marginal effect of individual SNPs was revealed through GWAS, three pathways, defined by gene ontology (GO) categories were significantly enriched in genes associated with BT (false discovery rate ≤5% in both studies): hormone activity, cytokine activity and myeloid cell differentiation. Epistasis analysis, within each significant GO, identified a statistically significant interaction between CDC42 and SCIN SNPs (pmeta-int =2.2 × 10(-6) , which met the overall multiple-testing corrected threshold of 2.5 × 10(-6) ). These two SNPs (and proxies) are strongly associated with CDC42 and SCIN gene expression levels and map to regulatory elements in skin cells. This interaction has important biological relevance since CDC42 and SCIN proteins have opposite effects in actin cytoskeleton organization and dynamics, a key mechanism underlying melanoma cell migration and invasion.

Published
2016

14. Multiancestry association study identifies new asthma risk loci that colocalize with immune-cell enhancer marks

Author

Joachim Heinrich, Arthur W. Musk, Dan L. Nicolae, Magnus Wickman, Anita L. Kozyrskyj, George T. O'Connor, Sven Michel, John Beilby, Nicole Probst-Hensch, André G. Uitterlinden, Ulrike Gehring, Eugene R. Bleecker, Markku Heliövaara, Christer Janson, Janine Altmüller, Tatsuhiko Tsunoda, Kathleen C. Barnes, Johan G. Eriksson, Alexey Polonikov, Penelope E. Graves, Andrea von Berg, Philip J. Thompson, Sina A. Gharib, Johan C. de Jongste, Miriam F. Moffatt, Adaikalavan Ramasamy, Kristin M. Burkart, Thomas J. Hudson, Marjo-Riitta Järvelin, Rasika A. Mathias, Kathleen M. Donohue, Gonneke Willemsen, Yuliya Fedorova, Michael Kabesch, Jing Hua Zhao, Ashok Kumar, Kenji Matsumoto, Vivi Schlünssen, Dara G. Torgerson, Terri H. Beaty, Florence Demenais, Julie E. Park, Tari Haahtela, Aarno Palotie, Elisabeth Widen, Hamida Mohamdi, Vladimir P. Ivanov, Tarja Laitinen, Emiko Noguchi, Lewis J. Smith, Valérie Siroux, Christopher E. Brightling, P. A. Selivanova, Frank D. Gilliland, Johannes Waage, Deborah A. Meyers, Unnur Thorsteinsdottir, Melanie C. Matheson, Hiroshi Hirose, Sébastien Letort, Andrew Bush, Alan James, Kari Stefansson, Robert A. Scott, Isabelle Romieu, Mads Melbye, Albert M. Levin, Laura R. Loehr, Guo Li, Veikko Salomaa, Celeste Eng, Esteban G. Burchard, Ralf J. P. van der Valk, Bjarke Feenstra, Daan W. Loth, Atsushi Takahashi, Lies Lahousse, Denise Daley, Stephen S. Rich, Carla M. T. Tiesler, Liming Liang, L. Keoki Williams, Susanne Lau, Nicholas J. Wareham, Erik Melén, Cameron D. Palmer, Medea Imboden, Patricia Margaritte-Jeannin, Unnur S. Bjornsdottir, Ludmila M. Ogorodova, Erika von Mutius, Gerard H. Koppelman, Susan R. Heckbert, Rachel A. Myers, Martin Farrall, Moira Chan-Yeung, Jim Gauderman, Frank Geller, Sailaja Vedantam, Rajesh Kumar, Kian Fan Chung, Jon Genuneit, John Henderson, David B. Kantor, Carole Ober, Alexessander Couto Alves, Craig E. Pennell, Inge M. Wouters, Catherine Laprise, Terho Lehtimäki, Colin F. Robertson, Emmanuelle Bouzigon, Maxim B. Freidin, William O.C.M. Cookson, Bruno H. Stricker, John A. Curtin, Albert Hofman, Muhammad T. Salam, Blanca E. Del-Rio-Navarro, Young-Ae Lee, Liesbeth Duijts, Klaus Bønnelykke, Vincent W. V. Jaddoe, Göran Pershagen, Dirkje S. Postma, Pekka Jousilahti, Hans Bisgaard, Dorret I. Boomsma, Amaury Vaysse, Deborah Jarvis, Maria Solodilova, Gudmar Thorleifsson, James J. Yang, V. P. Puzyrev, Manuel A. R. Ferreira, Maartje A.E. Nieuwenhuis, Jouke J. Hottenga, Ingileif Jonsdottir, Graham Jones, Myriam Brossard, Jennie Hui, Judith M. Vonk, Allan B. Becker, Elza Khusnutdinova, Wendy L. McArdle, Benjamin A. Raby, Olli T. Raitakari, Wendy B. White, Mark Lathrop, Adnan Custovic, Ingo Marenholz, Joel N. Hirschhorn, Fernando J. Martinez, Mikko Kuokkanen, Michiaki Kubo, Patrick G. Holt, Torben Sigsgaard, Eskil Kreiner, Stephanie J. London, Daniel F. Gudbjartsson, Mika Kähönen, Guy Brusselle, Blanca E. Himes, R. Graham Barr, Scott T. Weiss, David P. Strachan, Hamdi Mbarek, Wei Ang, A. S. Karunas, Marie Standl, Angela Simpson, Dick Heederik, Zofia K. Z. Gajdos, Raquel Granell, Ani Manichaikul, Fondation Jean-Dausset-CEPH, INSERM U946, Institut National de la Santé et de la Recherche Médicale (INSERM), Variabilité Génétique et Maladies Humaines, Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Medicine [Aurora, CO, USA], University of Colorado [Denver], National Heart and Lung Institute (NHLI), Imperial College London, Cologne Center for Genomics (CCG), Cologne Center for Genomics-University of Cologne, Johns Hopkins University (JHU), Pediatrics and Child Health, University of Manitoba [Winnipeg], University of Arizona, King‘s College London, Méthodologie statistique et épidémiologie génétique de maladies multifactorielles, Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Respiratory Medicine and Thoracic Surgery, University of Leicester-Institute for Lung Health, Ghent University Hospital, Department of Paediatric Respiratory Medicine, Imperial College London-Royal Brompton Hospital-National Heart and Lung Institute [UK], Airway Disease Section, National Heart and Lung Institute, The Generation R Study group, Erasmus University Medical Centre, Medstar Research Institute, The Wellcome Trust Centre for Human Genetics [Oxford], University of Oxford [Oxford], Université Paris-Sorbonne - Paris 4 - École supérieure du professorat et de l'éducation - Académie de Paris (ESPE Paris), Université Paris-Sorbonne (UP4), Population Genetics Laboratory [Tomsk, Russia], Research Institute for Medical Genetics [Tomsk, Russia], University of Southern California (USC), Utrecht University [Utrecht], Institute of Epidemiology, Universität Ulm - Ulm University [Ulm, Allemagne], MRC Integrative Epidemiology Unit [Bristol, Royaume-Uni] (MRC IEU), University of Bristol [Bristol], Arizona Respiratory Center, Helsinki University Hospital, Division of Occupational and Environmental Health, Institute for Risk Assessment (IRAS), Ludwig Maximilian University [Munich] (LMU), National Institute of Health and Welfare, MRC Centre for Causal Analyses in Translational Epidemiology, School of Social and Community Medicine, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Department of Mathematics, University of Warwick, Warwick Mathematics Institute (WMI), University of Warwick [Coventry]-University of Warwick [Coventry], Sir Charles Gairdner Hospital, Swiss Tropical and Public Health Institute [Basel], The Generation R Study, Pediatrics, Epidemiology, Uppsala University, Institute of Health Sciences and Biocenter Oulu, University of Oulu, Tampere University Hospital, Institute of Biochemistry and Genetics of Ufa Scientific Centre, Russian Academy of Sciences [Moscow] (RAS), Pediatric Pulmonology, Allergology & Epidemiology, University of Groningen [Groningen]-University Medical Center Groningen [Groningen] (UMCG)-Beatrix Children's Hospital-Groningen Research Institute for Asthma and COPD, National Center for Atmospheric Research [Boulder] (NCAR), Epidemiology & Public Health, Swiss Tropical and Public Health Institute [Basel]-Medical School University of Basel, Department of Respiratory Medicine, Departments of Pulmonary Medicine and Medical Genetics, Université du Québec à Chicoutimi (UQAC), McGill University and Genome Quebec Innovation Centre, Department of Pediatric Pneumology and Immunology, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Max Delbrück Center for Molecular Medicine [Berlin] (MDC), Helmholtz-Gemeinschaft = Helmholtz Association, Faculty of Medicine and Life Sciences [Tampere], University of Tampere [Finland], Laboratoire des interactions plantes micro-organismes (LIPM), Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS), China Agricultural University (CAU), Harvard School of Public Health, Department of Epidemiology, University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC)-University of North Carolina System (UNC)-UNC Gillings School of Global Public Health-Carolina Center for Genome Sciences, National Institute for Environmental Health Sciences Research Triangle Park, National Institute for Materials Science (NIMS), Dept. of Epidemiology Research, Statens Serum Institut [Copenhagen], Institute of Environmental Medicine [Stockholm, Sweden], Karolinska Institutet [Stockholm]-Karolinska University Hospital [Stockholm]-Astrid Lindgren Children's Hospital, Center for Human Genomics, Wake Forest University, Université de Tsukuba = University of Tsukuba, Head of Medical Sequencing, Institute of environmental medicine, Karolinska Institute, Respiratory Epidemiology and Public Health, Imperial College London-School of public health, The University of Hong Kong (HKU)-The University of Hong Kong (HKU)-MRC-HPA Centre for Environment and Health, Centre International de Recherche contre le Cancer (CIRC), Department of Chronic Disease Prevention, National Institute for Health and Welfare [Helsinki], Aarhus University [Aarhus], Institute of Metabolic Science, MRC, Section of Environment Occupation & Health, University of Manchester [Manchester], Epidémiologie et Biostatistique, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Santé et de la Recherche Médicale (INSERM), deCODE Genetics, deCODE genetics [Reykjavik], Population Health Sciences and Education, St George's University of London, Drug Safety Unit, Inspectorate for Health Care, Tohoku University [Sendai], Department of Oceanography, University of Hawai‘i [Mānoa] (UHM), University of California [San Francisco] (UCSF), University of California, Asthma and Allergy Department, University Children's Hospital-Ludwig Maximilians University, IT University of Copenhagen, MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge [UK] (CAM), Sachs’ Children and Youth Hospital [Stockholm, Sweden], Genetic Epidemiology Unit, Addenbrooke's Hospital, University of Illinois [Chicago] (UIC), University of Illinois System, Titu Maiorescu University Bucharest, Titu Maiorescu University = Universitatea Titu Maiorescu [Buchares] (UTM), Pulmonary Medicine, Erasmus MC other, Internal Medicine, Biological Psychology, APH - Mental Health, APH - Methodology, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, Vaysse, Amaury, University of Oxford, University of California [San Francisco] (UC San Francisco), University of California (UC), University Children's Hospital-Ludwig-Maximilians University [Munich] (LMU), IT University of Copenhagen (ITU), Groningen Research Institute for Asthma and COPD (GRIAC), Medical Research Council (MRC), National Institute for Health Research, Wellcome Trust, Wareham, Nicholas [0000-0003-1422-2993], Zhao, Jing Hua [0000-0003-4930-3582], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, HAY-FEVER, Netherlands Twin Register (NTR), [SDV]Life Sciences [q-bio], Genome-wide association study, [SDV.GEN] Life Sciences [q-bio]/Genetics, VARIANTS, Australian Asthma Genetics Consortium (AAGC) collaborators, Epigenesis, Genetic, 0302 clinical medicine, Pleiotropy, immune system diseases, Leukocytes, Promoter Regions, Genetic, AUTOIMMUNE-DISEASE, 11 Medical and Health Sciences, ComputingMilieux_MISCELLANEOUS, Genetics & Heredity, 3. Good health, Histone Code, [SDV] Life Sciences [q-bio], Enhancer Elements, Genetic, Phenotype, TWINS, Hay fever, POPULATIONS, Life Sciences & Biomedicine, Risk, EXPRESSION, Coronacrisis-Taverne, Biology, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, 03 medical and health sciences, Immune system, SDG 3 - Good Health and Well-being, medicine, Genetics, Journal Article, Humans, Genetic Predisposition to Disease, Allele, GENOME-WIDE ASSOCIATION, Alleles, METAANALYSIS, Genetic association, Asthma, Autoimmune disease, [SDV.GEN]Life Sciences [q-bio]/Genetics, Science & Technology, Rhinitis, Allergic, Seasonal, 06 Biological Sciences, medicine.disease, GENE, respiratory tract diseases, 030104 developmental biology, 030228 respiratory system, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Genetic Loci, Immunology, Developmental Biology, Genome-Wide Association Study
Abstract

We examined common variation in asthma risk by conducting a meta-analysis of worldwide asthma genome-wide association studies (23,948 asthma cases, 118,538 controls) of individuals from ethnically diverse populations. We identified five new asthma loci, found two new associations at two known asthma loci, established asthma associations at two loci previously implicated in the comorbidity of asthma plus hay fever, and confirmed nine known loci. Investigation of pleiotropy showed large overlaps in genetic variants with autoimmune and inflammatory diseases. The enrichment in enhancer marks at asthma risk loci, especially in immune cells, suggested a major role of these loci in the regulation of immunologically related mechanisms.

Published
2018
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15. Genital and anorectal mucosal melanoma is associated with cutaneous melanoma in patients and in families

Author

Hamida Mohamdi, H. Cazenave, Eve Maubec, Florence Demenais, Marie-Françoise Avril, Florent Grange, and Brigitte Bressac-de Paillerets

Subjects
Male, medicine.medical_specialty, Skin Neoplasms, Genital Neoplasms, Female, Dermatology, Intestinal mucosa, CDKN2A, medicine, Humans, Sex organ, Family history, Intestinal Mucosa, Index case, Melanoma, Nevus, Germ-Line Mutation, business.industry, Rectal Neoplasms, Mucosal melanoma, Middle Aged, medicine.disease, Anus Neoplasms, Pedigree, Phenotype, Cutaneous melanoma, Female, business, Pigmentation Disorders
Abstract

Summary Background Genital and anorectal mucosal melanomas (GAMMs) are rare compared with cutaneous melanoma (CM). Many epidemiological and genetic studies have been carried out on CM. In contrast, the genetic and environmental risk factors for GAMM have been poorly documented up to now. Objectives To compare the distribution of pigmentation and naevus phenotypes, sun exposure and family history of melanoma between patients with GAMM and CM. Methods We compared two series of patients, 81 with GAMM and 293 with CM. Results Patients with GAMM and CM did not show significant differences for phenotypic risk factors. However, patients with GAMM tended to display red hair (11% vs. 5·5%, P = 0·08) and a poor tanning ability (22% vs. 13·3%, P = 0·06) at a higher frequency than patients with CM. A family history of melanoma was significantly more frequent with GAMM than with CM (18% vs. 7·5%, P = 0·005). Apart from the GAMM index case, affected relatives had CM except in one family. The frequency of multiple primary melanomas (MPMs) was similar in the GAMM and CM series (6% vs. 5·3%, P = 0·43). All patients with GAMM and MPM had only one GAMM primary, while the other primary was cutaneous. No CDKN2A germline mutation was detected in patients with GAMM. Conclusions This study shows that GAMM and CM may occur in the same patient, and GAMM may develop in a familial setting. The association of both GAMM and CM in patients and families suggests shared genetic factors by these two types of melanoma.

Published
2013

16. Familial melanoma: Clinical factors associated with germline CDKN2A mutations according to the number of patients affected by melanoma in a family

Author

Christophe Blondel, Jean-Luc Perrot, Florence Demenais, Marie-Thérèse Leccia, Eve Maubec, F. Boitier, Hamida Mohamdi, Pierre Vabres, Eve Corda, Valérie Chaudru, Sandrine Mansard, Lynda Vincent-Fetita, Béatrice Crickx, Stéphane Dalle, Brigitte Bressac-de Paillerets, Sébastien Forget, Florent Grange, Hélène Zattara, Dominique Stoppa Lyonnet, Luc Thomas, Ludovic Martin, Marie-Françoise Avril, Patricia Margaritte-Jeannin, Pascal Joly, Groupe de Recherche en Economie Théorique et Appliquée (GREThA), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Service de dermatologie, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris]-Université Paris Diderot - Paris 7 (UPD7), Laboratoire de recherche européen pour la polyarthrite rhumatoïde (GenHotel - EA 3886), Université d'Évry-Val-d'Essonne (UEVE), Surgery, Informatics and Robotics (CHIR), Inria Sophia Antipolis - Méditerranée (CRISAM), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Génétique épidémiologique et structures des populations humaines (Inserm U535), Epidémiologie, sciences sociales, santé publique (IFR 69), Université Panthéon-Sorbonne (UP1)-Université Paris-Sud - Paris 11 (UP11)-École des hautes études en sciences sociales (EHESS)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Panthéon-Sorbonne (UP1)-Université Paris-Sud - Paris 11 (UP11)-École des hautes études en sciences sociales (EHESS)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Physique des Lasers (LPL), Université Sorbonne Paris Cité (USPC)-Institut Galilée-Université Paris 13 (UP13)-Centre National de la Recherche Scientifique (CNRS), Institut de Génomique Fonctionnelle (IGF), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), Génétique des Anomalies du Développement (GAD), Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC, Valorisation Recherche et Innovations Alimentaire (Valorial), Département de Génétique, Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), CHU Clermont-Ferrand, Centre Hospitalier Universitaire de Reims (CHU Reims), Département Pluridisciplinaire de Médecine, Dermatologie, CHU Grenoble-Hôpital Michallon, Laboratoire de Physique et Physiologie Intégratives de l'Arbre Fruitier et Forestier (PIAF), Institut National de la Recherche Agronomique (INRA)-Université Blaise Pascal - Clermont-Ferrand 2 (UBP), Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Génétique (Biologie pathologie), Département de biologie et pathologie médicales [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Méthodologie statistique et épidémiologie génétique des maladies multifactorielles, Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Diderot - Paris 7 (UPD7)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Variabilité Génétique et Maladies Humaines, Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Gustave Roussy (IGR), Université Paris 1 Panthéon-Sorbonne (UP1)-Université Paris-Sud - Paris 11 (UP11)-École des hautes études en sciences sociales (EHESS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris 1 Panthéon-Sorbonne (UP1)-Université Paris-Sud - Paris 11 (UP11)-École des hautes études en sciences sociales (EHESS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris 13 (UP13)-Centre National de la Recherche Scientifique (CNRS), AP-HP - Hôpital Cochin Broca Hôtel Dieu [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Curie [Paris], AP-HP - Hôpital Bichat - Claude Bernard [Paris], and IFR100 - Structure fédérative de recherche Santé-STIC-Université de Bourgogne (UB)

Subjects
Oncology, medicine.medical_specialty, Pathology, Skin Neoplasms, Dermatology, Germline, 03 medical and health sciences, cutaneous melanoma, 0302 clinical medicine, Germline mutation, CDKN2A, Pancreatic cancer, Internal medicine, family clustering, Humans, Medicine, Melanoma, neoplasms, Cyclin-Dependent Kinase Inhibitor p16, Germ-Line Mutation, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Genetic testing, 0303 health sciences, medicine.diagnostic_test, business.industry, Odds ratio, Middle Aged, medicine.disease, 3. Good health, multiple primary melanomas, 030220 oncology & carcinogenesis, Cutaneous melanoma, business, [SDV.MHEP.DERM]Life Sciences [q-bio]/Human health and pathology/Dermatology
Abstract

Background Features associated with an increased frequency of cyclin-dependent kinase inhibitor 2A (CDKN2A) mutations have been identified in families with 3 or more patients with cutaneous melanoma (CM). However, in families with 2 patients with CM, which represent the majority of familial melanoma, these factors have been rarely studied. Objective We investigated association of 3 clinical features with the presence of a CDKN2A mutation in a family by extent of CM family clustering (2 vs ≥3 patients with CM among first-degree relatives in a family). Methods We included 483 French families that comprised 387 families with 2 patients with CM (F2 families) and 96 families with 3 or more patients with CM (F3+ families). Three clinical factors were examined individually and in a joint analysis: median age at diagnosis younger than 50 years, and 1 or more patient in a family with multiple primary melanoma or with pancreatic cancer. Results The frequency of CDKN2A mutations was higher in F3+ families (32%) than in F2 families (13%). Although early age at melanoma diagnosis and occurrence of multiple primary melanoma in 1 or more patient were significantly associated with the risk of a CDKN2A mutation in F2 families, early age at melanoma diagnosis and occurrence of pancreatic cancer in a family were significantly associated with CDKN2A mutations in F3+ families. Limitations The study was not population based. Conclusions This study shows that factors associated with CDKN2A mutations differ by extent of CM family clustering. It indicates that, in France, families with 2 patients with CM are eligible for genetic testing especially when there is an early age at CM diagnosis and/or 1 or more patients with multiple primary melanoma.

Published
2012
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17. Protective effect of copy number polymorphism of glutathione S-transferase T1 gene on melanoma risk in presence of CDKN2A mutations, MC1R variants and host-related phenotypes

Author

M. T. Lo, Hamida Mohamdi, Karine Laud, Brigitte Bressac-de Paillerets, Valérie Chaudru, Fabienne Lesueur, Agnès Chompret, Michel Barrois, Florence Demenais, M. F. Avril, and Catalin Marian

Subjects
Adult, Male, Cancer Research, DNA Copy Number Variations, Biology, Polymerase Chain Reaction, 03 medical and health sciences, GSTP1, 0302 clinical medicine, CDKN2A, Risk Factors, Genotype, Genetics, medicine, Humans, Genetic Predisposition to Disease, Allele, neoplasms, Gene, Melanoma, Genetics (clinical), 030304 developmental biology, Glutathione Transferase, 0303 health sciences, Genes, p16, medicine.disease, Penetrance, Phenotype, 3. Good health, Oncology, Glutathione S-Transferase pi, 030220 oncology & carcinogenesis, Mutation, Cancer research, Female, Receptor, Melanocortin, Type 1
Abstract

The effect of CDKN2A, the major high-risk melanoma susceptibility gene, has been shown to be modified by host-related phenotypes and variants of MC1R gene. The glutathione S-transferase (GSTs) genes, implicated in detoxification of metabolites after UV exposure, are candidates for modulating CDKN2A penetrance. Few case-control studies have investigated the effect of GSTs on melanoma risk, and have led to controversial results while these genes have not yet been studied in CDKN2A melanoma-prone families. We examined the effect of GSTP1, GSTM1 and GSTT1 genotypes on melanoma risk in 25 multi-generational melanoma-prone families with CDKN2A mutations, in presence of MC1R gene variants, sun exposure, and host-related phenotypes. These data included 195 genotyped subjects for all studied genes. We applied the GEE (Generalized Estimating Equations) approach to test for the effect of GSTs while adjusting for age, sex and CDKN2A mutation status and including successively MC1R, sun exposure and host factors in the model. No significant effect of null GSTM1 allele and GSTP1 variants (p.I105V, p.A114V) on melanoma risk was found. However, a significant protective effect of carrying ≥1 null GSTT1 allele was shown: ORadjusted for age,sex,CDKN2A = 0.41 (0.18–0.94) and ORadjusted for age,sex,CDKN2A,MC1R = 0.24 (0.15–0.58). Altogether, the factors modifying significantly the melanoma risk associated with CDKN2A mutations (stepwise procedure) were: MC1R and dysplastic nevi (increasing the risk) and GSTT1 (decreasing the risk). This study shows that even when a high-risk gene (CDKN2A) has been identified, multiple genetic modifiers influence melanoma risk.

Published
2008

18. MC1R variant alleles and malignant melanoma risk in Israel

Author

Eitan Friedman, Hamida Mohamdi, Frida Barak, Alon Scope, Esther Azizi, Yael Laitman, Felix Pavlotsky, Florence Demenais, Valérie Chaudru, and Gilli Galore-Haskel

Subjects
Oncology, Adult, Male, Risk, Cancer Research, medicine.medical_specialty, Genotype, Molecular Sequence Data, symbols.namesake, Gene Frequency, Polymorphism (computer science), Internal medicine, medicine, Humans, Risk factor, Age of Onset, Israel, Allele frequency, Melanoma, Genetics, Polymorphism, Genetic, Base Sequence, business.industry, Case-control study, Middle Aged, medicine.disease, Ashkenazi jews, Bonferroni correction, Case-Control Studies, Jews, symbols, Female, Age of onset, business, Receptor, Melanocortin, Type 1
Abstract

To evaluate the contribution of MC1R variants to malignant melanoma risk in Israeli Jews, sequencing of the MC1R gene was performed in 132 melanoma patients and 184 ethnically matched controls. Overall, 22 MC1R variants were detected, two were novel (M73I and 496_497insG). Using age and sex-adjusted logistic regression, one specific variant, R151C, conferred significantly increased melanoma risk among Ashkenazim (OR=2.6, 95% CI: 1.3-5.3; p=0.05 after Bonferroni correction). A gene dosage effect was noted, with significantly increased melanoma risk being observed in subjects with at least two variants whether when all variants are pooled (OR=4.8, 95% CI: 2.0-11.2; p=0.002 after Bonferroni correction) or when red hair colour (RHC) variants and non-RHC variants are distinguished (OR=7.6, 95% CI: 2.8-20.3; p=0.0004 after Bonferroni correction). If further studies support these findings, the assessment of MC1R status may be useful in identifying Jewish Israeli individuals at high risk for melanoma.

Published
2008

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