Genome-wide imputation study identifies novel HLA locus for pulmonary fibrosis and potential role for auto-immunity in fibrotic idiopathic interstitial pneumonia

BMC Genetics

Research Article

Dong Soon Kim¹  David A. Lynch²  Kevin K. Brown²  Gregory P. Cosgrove²  James D. Crapo²  Barry J. Make²  Elizabeth A. Regan²  Steve Groshong²  Tasha E. Fingerlin³  Rachel Z. Blumhagen³  David A. Schwartz⁴  Hannah C. Ainsworth⁵  Carl D. Langefeld⁵  Diana Zelenika⁶  Pamela H. Russell⁷  Weiming Zhang⁸  Elissa Murphy⁹  Ivana V. Yang⁹  Marvin I. Schwarz⁹  Keith Smith⁹  Janet Talbert⁹  Brent S. Pedersen⁹  Brian Freed⁹  Julia Powers⁹  David McKean⁹  Harold R. Collard^1,10  Paul J. Wolters^1,10  Kevin F. Gibson^1,11  Naftali Kaminski^1,11  Yingze Zhang^1,11  Megan S. Devine^1,12  Christine Kim Garcia^1,12  Cheryl R. Markin^1,13  Lisa H. Lancaster^1,13  Mark P. Steele^1,13  James E. Loyd^1,13  Yoichiro Kamatani^1,14  Mark Lathrop^1,15  Moises Selman^1,16  Williamson Z. Bradford^1,17  Karl Kossen^1,17  Scott D. Seiwert^1,17  Gunnar Gudmundsson^1,18  Helgi J. Isaksson^1,18  Roland M. du Bois^1,19  Miriam F. Moffatt^1,19  Philip L. Molyneaux^1,19  Athol U. Wells^1,19  Toby M. Maher^1,19  Annie Pardo^2,20  Dinesha S. Walek^2,21  Kenneth B. Beckman^2,21  Jerry J. Daniel^2,21 

[1]Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea

[2]Center for Genes, Environment and Health, National Jewish Health, Denver, CO, USA

[3]Center for Genes, Environment and Health, National Jewish Health, Denver, CO, USA

[4]Department of Biostatistics and Informatics, University of Colorado Denver, Aurora, CO, USA

[5]Center for Genes, Environment and Health, National Jewish Health, Denver, CO, USA

[6]Department of Medicine, School of Medicine, University of Colorado Denver, Aurora, CO, USA

[7]Department of Immunology, School of Medicine, University of Colorado Denver, Aurora, CO, USA

[8]Center for Public Health Genomics and Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA

[9]Commissariat à l’Energie Atomique, Institut Génomique, Centre National de Génotypage, Evry, France

[10]Department of Biochemistry and Molecular Genetics, School of Medicine, University of Colorado Denver, Aurora, CO, USA

[11]Department of Biostatistics and Informatics, University of Colorado Denver, Aurora, CO, USA

[12]Department of Medicine, School of Medicine, University of Colorado Denver, Aurora, CO, USA

[13]Department of Medicine, University of California San Francisco, San Francisco, CA, USA

[14]Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA

[15]Department of Medicine, University of Texas Southwestern, Dallas, TX, USA

[16]Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA

[17]Fondation Jean Dausset, Centre d’Étude du Polymorphisme Humain, Paris, France

[18]Fondation Jean Dausset, Centre d’Étude du Polymorphisme Humain, Paris, France

[19]Commissariat à l’Energie Atomique, Institut Génomique, Centre National de Génotypage, Evry, France

[20]Instituto Nacional de Enfermedades Respiratorias, Mexico City, Mexico

[21]InterMune, Brisbane, CA, USA

[22]Landspitali University Hospital and University of Iceland Faculty of Medicine, Reykjavik, Iceland

[23]National Heart and Lung Institute, Imperial College, London, UK

[24]National Institute for Health Research Biomedical Research Unit, Royal Brompton Hospital, London, UK

[25]Universidad Nacional Autonoma de Mexico, Mexico City, Mexico

[26]University of Minnesota Genomics Center, University of Minnesota, Minneapolis, MN, USA

关键词: Pulmonary fibrosis;    HLA association;    Imputation;    Gene expression;    RNA-Seq;   

DOI  :  10.1186/s12863-016-0377-2

 received in 2015-11-23, accepted in 2016-05-20,  发布年份 2016

来源: Springer

【 摘 要 】

BackgroundFibrotic idiopathic interstitial pneumonias (fIIP) are a group of fatal lung diseases with largely unknown etiology and without definitive treatment other than lung transplant to prolong life. There is strong evidence for the importance of both rare and common genetic risk alleles in familial and sporadic disease. We have previously used genome-wide single nucleotide polymorphism data to identify 10 risk loci for fIIP. Here we extend that work to imputed genome-wide genotypes and conduct new RNA sequencing studies of lung tissue to identify and characterize new fIIP risk loci.ResultsWe performed genome-wide genotype imputation association analyses in 1616 non-Hispanic white (NHW) cases and 4683 NHW controls followed by validation and replication (878 cases, 2017 controls) genotyping and targeted gene expression in lung tissue. Following meta-analysis of the discovery and replication populations, we identified a novel fIIP locus in the HLA region of chromosome 6 (rs7887 Pmeta = 3.7 × 10−09). Imputation of classic HLA alleles identified two in high linkage disequilibrium that are associated with fIIP (DRB1*15:01 P = 1.3 × 10−7 and DQB1*06:02 P = 6.1 × 10−8). Targeted RNA-sequencing of the HLA locus identified 21 genes differentially expressed between fibrotic and control lung tissue (Q < 0.001), many of which are involved in immune and inflammatory response regulation. In addition, the putative risk alleles, DRB1*15:01 and DQB1*06:02, are associated with expression of the DQB1 gene among fIIP cases (Q < 1 × 10−16).ConclusionsWe have identified a genome-wide significant association between the HLA region and fIIP. Two HLA alleles are associated with fIIP and affect expression of HLA genes in lung tissue, indicating that the potential genetic risk due to HLA alleles may involve gene regulation in addition to altered protein structure. These studies reveal the importance of the HLA region for risk of fIIP and a basis for the potential etiologic role of auto-immunity in fIIP.

【 授权许可】

CC BY   
© The Author(s). 2016