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Variants associated with HHIP expression have sex-differential effects on lung function.
Fawcett, Katherine A; Obeidat, Ma'en; Melbourne, Carl; Shrine, Nick; Guyatt, Anna L; John, Catherine; Luan, Jian'an; Richmond, Anne; Moksnes, Marta R; Granell, Raquel; Weiss, Stefan; Imboden, Medea; May-Wilson, Sebastian; Hysi, Pirro; Boutin, Thibaud S; Portas, Laura; Flexeder, Claudia; Harris, Sarah E; Wang, Carol A; Lyytikäinen, Leo-Pekka; Palviainen, Teemu; Foong, Rachel E; Keidel, Dirk; Minelli, Cosetta; Langenberg, Claudia; Bossé, Yohan; Van den Berge, Maarten; Sin, Don D; Hao, Ke; Campbell, Archie; Porteous, David; Padmanabhan, Sandosh; Smith, Blair H; Evans, David M; Ring, Sue; Langhammer, Arnulf; Hveem, Kristian; Willer, Cristen; Ewert, Ralf; Stubbe, Beate; Pirastu, Nicola; Klaric, Lucija; Joshi, Peter K; Patasova, Karina; Massimo, Mangino; Polasek, Ozren; Starr, John M; Karrasch, Stefan; Strauch, Konstantin; Meitinger, Thomas.
Afiliação
  • Fawcett KA; Department of Health Sciences, University of Leicester, Leicester, LE1 7RH, UK.
  • Obeidat M; The University of British Columbia Centre for Heart Lung Innovation, St Paul's Hospital, Vancouver, BC, Canada.
  • Melbourne C; Department of Health Sciences, University of Leicester, Leicester, LE1 7RH, UK.
  • Shrine N; Department of Health Sciences, University of Leicester, Leicester, LE1 7RH, UK.
  • Guyatt AL; Department of Health Sciences, University of Leicester, Leicester, LE1 7RH, UK.
  • John C; Department of Health Sciences, University of Leicester, Leicester, LE1 7RH, UK.
  • Luan J; MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge, CB2 0QQ, UK.
  • Richmond A; MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU, UK.
  • Moksnes MR; K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.
  • Granell R; Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, BS8 2BN, UK.
  • Weiss S; Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, 17475, Germany.
  • Imboden M; Swiss Tropical and Public Health Institute, Basel, Switzerland.
  • May-Wilson S; University of Basel, Basel, Switzerland.
  • Hysi P; Centre for Global Health Research, Usher Institute, University of Edinburgh, Teviot Place, Edinburgh, EH8 9AG, UK.
  • Boutin TS; The Department of Twin Research & Genetic Epidemiology, King's College London, St Thomas' Campus, Lambeth Palace Road, London, UK.
  • Portas L; MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU, UK.
  • Flexeder C; Population Health and Occupational Disease, National Heart and Lung Institute, Imperial College London, London, UK.
  • Harris SE; Institute of Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, 85764, Germany.
  • Wang CA; Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, EH8 9JZ, UK.
  • Lyytikäinen LP; Psychology, University of Edinburgh, Edinburgh, EH8 9JZ, UK.
  • Palviainen T; School of Medicine and Public Health, Faculty of Medicine and Health, The University of Newcastle, Callaghan, Australia.
  • Foong RE; Department of Clinical Chemistry, Fimlab Laboratories, Tampere, 33520, Finland.
  • Keidel D; Department of Clinical Chemistry, Finnish Cardiovascular Research Center - Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, 33014, Finland.
  • Minelli C; Department of Cardiology, Heart Center, Tampere University Hospital, Tampere, 33521, Finland.
  • Langenberg C; Institute for Molecular Medicine FIMM, University of Helsinki, Helsinki, FI-00014, Finland.
  • Bossé Y; Telethon Kids Institute, Perth, Australia.
  • Van den Berge M; School of Physiotherapy and Exercise Science, Faculty of Health Sciences, Curtin University, Perth, Australia.
  • Sin DD; Swiss Tropical and Public Health Institute, Basel, Switzerland.
  • Hao K; University of Basel, Basel, Switzerland.
  • Campbell A; Population Health and Occupational Disease, National Heart and Lung Institute, Imperial College London, London, UK.
  • Porteous D; MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge, CB2 0QQ, UK.
  • Padmanabhan S; Institut universitaire de cardiologie et de pneumologie de Québec, Department of Molecular Medicine, Laval University, Québec, Canada.
  • Smith BH; University Medical Center Groningen, Department of Pulmonology, GRIAC Research Institute, University of Groningen, Groningen, The Netherlands.
  • Evans DM; The University of British Columbia Centre for Heart Lung Innovation, St Paul's Hospital, Vancouver, BC, Canada.
  • Ring S; Respiratory Division, Department of Medicine, University of British Columbia, Vancouver, BC, Canada.
  • Langhammer A; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, USA.
  • Hveem K; Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, EH4 2XU, UK.
  • Willer C; Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, EH4 2XU, UK.
  • Ewert R; British Heart Foundation Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, G12 8TA, UK.
  • Stubbe B; Division of Population Health Sciences, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, UK.
  • Pirastu N; Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, BS8 2BN, UK.
  • Klaric L; Population Health Sciences Bristol Medical School, University of Bristol, Bristol, BS8 2BN, UK.
  • Joshi PK; University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, QLD 4072, Australia.
  • Patasova K; Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, BS8 2BN, UK.
  • Massimo M; Population Health Sciences Bristol Medical School, University of Bristol, Bristol, BS8 2BN, UK.
  • Polasek O; Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.
  • Starr JM; K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.
  • Karrasch S; Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, USA.
  • Strauch K; Department of Internal Medicine, University of Michigan, Ann Arbor, USA.
  • Meitinger T; Department of Human Genetics, University of Michigan, Ann Arbor, USA.
Wellcome Open Res ; 5: 111, 2020.
Article em En | MEDLINE | ID: mdl-33728380
Background: Lung function is highly heritable and differs between the sexes throughout life. However, little is known about sex-differential genetic effects on lung function. We aimed to conduct the first genome-wide genotype-by-sex interaction study on lung function to identify genetic effects that differ between males and females. Methods: We tested for interactions between 7,745,864 variants and sex on spirometry-based measures of lung function in UK Biobank (N=303,612), and sought replication in 75,696 independent individuals from the SpiroMeta consortium. Results: Five independent single-nucleotide polymorphisms (SNPs) showed genome-wide significant (P<5x10 -8) interactions with sex on lung function, and 21 showed suggestive interactions (P<1x10 -6). The strongest signal, from rs7697189 (chr4:145436894) on forced expiratory volume in 1 second (FEV 1) (P=3.15x10 -15), was replicated (P=0.016) in SpiroMeta. The C allele increased FEV 1 more in males (untransformed FEV 1 ß=0.028 [SE 0.0022] litres) than females (ß=0.009 [SE 0.0014] litres), and this effect was not accounted for by differential effects on height, smoking or pubertal age. rs7697189 resides upstream of the hedgehog-interacting protein ( HHIP) gene and was previously associated with lung function and HHIP lung expression. We found HHIP expression was significantly different between the sexes (P=6.90x10 -6), but we could not detect sex differential effects of rs7697189 on expression. Conclusions: We identified a novel genotype-by-sex interaction at a putative enhancer region upstream of the HHIP gene. Establishing the mechanism by which HHIP SNPs have different effects on lung function in males and females will be important for our understanding of lung health and diseases in both sexes.
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Texto completo: 1 Base de dados: MEDLINE Tipo de estudo: Risk_factors_studies Idioma: En Revista: Wellcome Open Res Ano de publicação: 2020 Tipo de documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Tipo de estudo: Risk_factors_studies Idioma: En Revista: Wellcome Open Res Ano de publicação: 2020 Tipo de documento: Article