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

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?

SUBMITTER: Fingerlin TE

PROVIDER: S-EPMC4895966 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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

Fingerlin Tasha E TE Zhang Weiming W Yang Ivana V IV Ainsworth Hannah C HC Russell Pamela H PH Blumhagen Rachel Z RZ Schwarz Marvin I MI Brown Kevin K KK Steele Mark P MP Loyd James E JE Cosgrove Gregory P GP Lynch David A DA Groshong Steve S Collard Harold R HR Wolters Paul J PJ Bradford Williamson Z WZ Kossen Karl K Seiwert Scott D SD du Bois Roland M RM Garcia Christine Kim CK Devine Megan S MS Gudmundsson Gunnar G Isaksson Helgi J HJ Kaminski Naftali N Zhang Yingze Y Gibson Kevin F KF Lancaster Lisa H LH Maher Toby M TM Molyneaux Philip L PL Wells Athol U AU Moffatt Miriam F MF Selman Moises M Pardo Annie A Kim Dong Soon DS Crapo James D JD Make Barry J BJ Regan Elizabeth A EA Walek Dinesha S DS Daniel Jerry J JJ Kamatani Yoichiro Y Zelenika Diana D Murphy Elissa E Smith Keith K McKean David D Pedersen Brent S BS Talbert Janet J Powers Julia J Markin Cheryl R CR Beckman Kenneth B KB Lathrop Mark M Freed Brian B Langefeld Carl D CD Schwartz David A DA

BMC genetics 20160607 1

<h4>Background</h4>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 ...[more]

PMID: 27266705

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Project description:BackgroundPirfenidone is the first antifibrotic drug approved for the treatment of idiopathic pulmonary fibrosis (IPF) and it is used in the treatment of other interstitial pneumonias, such as unclassifiable interstitial lung disease (ILD) and connective tissue-related ILD. This study examined the efficacy of pirfenidone in patients with IPF and fibrotic idiopathic non-specific interstitial pneumonia (f-iNSIP).MethodsIn a retrospective real-life study, 67 IPF and 24 f-iNSIP patients were enrolled and classified into a pirfenidone group and a non-antifibrotic group. The level of forced vital capacity (FVC) and diffusing capacity of lung for carbon monoxide (DLco) at baseline, 6, 12 and 24 months were recorded. The level of KL-6 in serum was detected by chemiluminescence enzyme immunoassay (CLEIA). The prognosis and safety outcomes were collected from patients.ResultsIn IPF patients, pirfenidone decreased the mean change of FVC and DLco, and decreased the proportion of patients with a ⩾10% decline in FVC or a ⩾15% decline in DLco compared with the non-antifibrotic group. There was no difference in the mean change of FVC and DLco between smokers and non-smokers who received pirfenidone treatment. There was an improvement in progression-free survival, defined as the time to the first occurrence of acute exacerbation or death related to pulmonary fibrosis. Moreover, the ratio of patients who experienced acute exacerbation and death related to pulmonary fibrosis was lower in the pirfenidone group. There was no change in lung function and prognosis between the pirfenidone and non-antifibrotic groups in f-iNSIP patients. The KL-6 level slightly decreased after 1 year of pirfenidone treatment but not significantly. Gastrointestinal and skin-related adverse events were most common, and four patients ceased treatment due to the side effects.ConclusionsPirfenidone safely reduced disease progression by improving the lung function and progression-free survival in IPF patients, with acceptable side effects. The efficacy of pirfenidone on f-iNSIP was not significant, suggesting the need for further studies.The reviews of this paper are available via the supplemental material section.

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

Publications

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

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