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BMC Genet. 2016 Jun 7;17(1):74. doi: 10.1186/s12863-016-0377-2.

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

Author information

1
Center for Genes, Environment and Health, National Jewish Health, Denver, CO, USA. fingerlint@njhealth.org.
2
Department of Biostatistics and Informatics, University of Colorado Denver, Aurora, CO, USA. fingerlint@njhealth.org.
3
Department of Biostatistics and Informatics, University of Colorado Denver, Aurora, CO, USA.
4
Department of Medicine, School of Medicine, University of Colorado Denver, Aurora, CO, USA.
5
Center for Public Health Genomics and Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA.
6
Department of Biochemistry and Molecular Genetics, School of Medicine, University of Colorado Denver, Aurora, CO, USA.
7
Center for Genes, Environment and Health, National Jewish Health, Denver, CO, USA.
8
Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA.
9
Department of Medicine, University of California San Francisco, San Francisco, CA, USA.
10
InterMune, Brisbane, CA, USA.
11
National Heart and Lung Institute, Imperial College, London, UK.
12
National Institute for Health Research Biomedical Research Unit, Royal Brompton Hospital, London, UK.
13
Department of Medicine, University of Texas Southwestern, Dallas, TX, USA.
14
Landspitali University Hospital and University of Iceland Faculty of Medicine, Reykjavik, Iceland.
15
Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
16
Instituto Nacional de Enfermedades Respiratorias, Mexico City, Mexico.
17
Universidad Nacional Autonoma de Mexico, Mexico City, Mexico.
18
Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
19
University of Minnesota Genomics Center, University of Minnesota, Minneapolis, MN, USA.
20
Fondation Jean Dausset, Centre d'Étude du Polymorphisme Humain, Paris, France.
21
Commissariat à l'Energie Atomique, Institut Génomique, Centre National de Génotypage, Evry, France.
22
Center for Genes, Environment and Health, National Jewish Health, Denver, CO, USA. david.schwartz@ucdenver.edu.
23
Department of Medicine, School of Medicine, University of Colorado Denver, Aurora, CO, USA. david.schwartz@ucdenver.edu.
24
Department of Immunology, School of Medicine, University of Colorado Denver, Aurora, CO, USA. david.schwartz@ucdenver.edu.

Abstract

BACKGROUND:

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.

RESULTS:

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)).

CONCLUSIONS:

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.

KEYWORDS:

Gene expression; HLA association; Imputation; Pulmonary fibrosis; RNA-Seq

PMID:
27266705
PMCID:
PMC4895966
DOI:
10.1186/s12863-016-0377-2
[Indexed for MEDLINE]
Free PMC Article

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