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



We 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 P meta  = 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)).



We 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.
Center for Genes, Environment and Health, National Jewish Health, Denver, CO, USA. fingerlint@njhealth.org.|Department of Biostatistics and Informatics, University of Colorado Denver, Aurora, CO, USA. fingerlint@njhealth.org.
Tasha E
TE
Fingerlin
Department of Biostatistics and Informatics, University of Colorado Denver, Aurora, CO, USA.
Weiming
W
Zhang
Department of Medicine, School of Medicine, University of Colorado Denver, Aurora, CO, USA.
Ivana V
IV
Yang
Center for Public Health Genomics and Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA.
Hannah C
HC
Ainsworth
Department of Biochemistry and Molecular Genetics, School of Medicine, University of Colorado Denver, Aurora, CO, USA.
Pamela H
PH
Russell
Center for Genes, Environment and Health, National Jewish Health, Denver, CO, USA.|Department of Biostatistics and Informatics, University of Colorado Denver, Aurora, CO, USA.
Rachel Z
RZ
Blumhagen
Department of Medicine, School of Medicine, University of Colorado Denver, Aurora, CO, USA.
Marvin I
MI
Schwarz
Center for Genes, Environment and Health, National Jewish Health, Denver, CO, USA.
Kevin K
KK
Brown
Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA.
Mark P
MP
Steele
Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA.
James E
JE
Loyd
Center for Genes, Environment and Health, National Jewish Health, Denver, CO, USA.
Gregory P
GP
Cosgrove
Center for Genes, Environment and Health, National Jewish Health, Denver, CO, USA.
David A
DA
Lynch
Center for Genes, Environment and Health, National Jewish Health, Denver, CO, USA.
Steve
S
Groshong
Department of Medicine, University of California San Francisco, San Francisco, CA, USA.
Harold R
HR
Collard
Department of Medicine, University of California San Francisco, San Francisco, CA, USA.
Paul J
PJ
Wolters
InterMune, Brisbane, CA, USA.
Williamson Z
WZ
Bradford
InterMune, Brisbane, CA, USA.
Karl
K
Kossen
InterMune, Brisbane, CA, USA.
Scott D
SD
Seiwert
National Heart and Lung Institute, Imperial College, London, UK.|National Institute for Health Research Biomedical Research Unit, Royal Brompton Hospital, London, UK.
Roland M
RM
du Bois
Department of Medicine, University of Texas Southwestern, Dallas, TX, USA.
Christine Kim
CK
Garcia
Department of Medicine, University of Texas Southwestern, Dallas, TX, USA.
Megan S
MS
Devine
Landspitali University Hospital and University of Iceland Faculty of Medicine, Reykjavik, Iceland.
Gunnar
G
Gudmundsson
Landspitali University Hospital and University of Iceland Faculty of Medicine, Reykjavik, Iceland.
Helgi J
HJ
Isaksson
Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
Naftali
N
Kaminski
Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
Yingze
Y
Zhang
Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
Kevin F
KF
Gibson
Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA.
Lisa H
LH
Lancaster
National Heart and Lung Institute, Imperial College, London, UK.|National Institute for Health Research Biomedical Research Unit, Royal Brompton Hospital, London, UK.
Toby M
TM
Maher
National Heart and Lung Institute, Imperial College, London, UK.|National Institute for Health Research Biomedical Research Unit, Royal Brompton Hospital, London, UK.
Philip L
PL
Molyneaux
National Heart and Lung Institute, Imperial College, London, UK.|National Institute for Health Research Biomedical Research Unit, Royal Brompton Hospital, London, UK.
Athol U
AU
Wells
National Heart and Lung Institute, Imperial College, London, UK.|National Institute for Health Research Biomedical Research Unit, Royal Brompton Hospital, London, UK.
Miriam F
MF
Moffatt
Instituto Nacional de Enfermedades Respiratorias, Mexico City, Mexico.
Moises
M
Selman
Universidad Nacional Autonoma de Mexico, Mexico City, Mexico.
Annie
A
Pardo
Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
Dong Soon
DS
Kim
Center for Genes, Environment and Health, National Jewish Health, Denver, CO, USA.
James D
JD
Crapo
Center for Genes, Environment and Health, National Jewish Health, Denver, CO, USA.
Barry J
BJ
Make
Center for Genes, Environment and Health, National Jewish Health, Denver, CO, USA.
Elizabeth A
EA
Regan
University of Minnesota Genomics Center, University of Minnesota, Minneapolis, MN, USA.
Dinesha S
DS
Walek
University of Minnesota Genomics Center, University of Minnesota, Minneapolis, MN, USA.
Jerry J
JJ
Daniel
Fondation Jean Dausset, Centre d'Étude du Polymorphisme Humain, Paris, France.
Yoichiro
Y
Kamatani
Commissariat à l'Energie Atomique, Institut Génomique, Centre National de Génotypage, Evry, France.
Diana
D
Zelenika
Department of Medicine, School of Medicine, University of Colorado Denver, Aurora, CO, USA.
Elissa
E
Murphy
Department of Medicine, School of Medicine, University of Colorado Denver, Aurora, CO, USA.
Keith
K
Smith
Department of Medicine, School of Medicine, University of Colorado Denver, Aurora, CO, USA.
David
D
McKean
Department of Medicine, School of Medicine, University of Colorado Denver, Aurora, CO, USA.
Brent S
BS
Pedersen
Department of Medicine, School of Medicine, University of Colorado Denver, Aurora, CO, USA.
Janet
J
Talbert
Department of Medicine, School of Medicine, University of Colorado Denver, Aurora, CO, USA.
Julia
J
Powers
Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA.
Cheryl R
CR
Markin
University of Minnesota Genomics Center, University of Minnesota, Minneapolis, MN, USA.
Kenneth B
KB
Beckman
Fondation Jean Dausset, Centre d'Étude du Polymorphisme Humain, Paris, France.|Commissariat à l'Energie Atomique, Institut Génomique, Centre National de Génotypage, Evry, France.
Mark
M
Lathrop
Department of Medicine, School of Medicine, University of Colorado Denver, Aurora, CO, USA.
Brian
B
Freed
Center for Public Health Genomics and Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA.
Carl D
CD
Langefeld
Center for Genes, Environment and Health, National Jewish Health, Denver, CO, USA. david.schwartz@ucdenver.edu.|Department of Medicine, School of Medicine, University of Colorado Denver, Aurora, CO, USA. david.schwartz@ucdenver.edu.|Department of Immunology, School of Medicine, University of Colorado Denver, Aurora, CO, USA. david.schwartz@ucdenver.edu.
David A
DA
Schwartz
D000328:Adult; D000368:Aged; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study / Q000379:methods*; D059866:HLA-DQ beta-Chains / Q000235:genetics*; D059811:HLA-DRB1 Chains / Q000235:genetics*; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000235:genetics*; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D011658:Pulmonary Fibrosis / Q000235:genetics*; D017423:Sequence Analysis, RNA / Q000379:methods*
D059866:HLA-DQ beta-Chains; C069051:HLA-DQB1 antigen; D059811:HLA-DRB1 Chains
Gene expression; HLA association; Imputation; Pulmonary fibrosis; RNA-Seq