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

Abstract

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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12863-016-0377-2) contains supplementary material, which is available to authorized users.

Genetic loci associated with chronic obstructive pulmonary disease overlap with loci for lung function and pulmonary fibrosis

“…Nine of these 13 loci have been associated with lung function in general population samples 2–7 ; however, 4 ( EEFSEC , DSP , MTCL1 , and SFTPD ) are novel. We noted 2 loci shared with pulmonary fibrosis 8,9 ( FAM13A and DSP ) but with opposite risk alleles for COPD. None of our loci overlapped with genome-wide associations for asthma; however, one locus has been implicated in the joint susceptibility to asthma and obesity 10 .…”

“…To further examine overlapping loci for COPD and pulmonary fibrosis, we combined summary statistics from our study and the pulmonary fibrosis GWAS by Fingerlin et al 8,9 using gwas-pw 37 .…”

Genetics of idiopathic pulmonary fibrosis: from mechanistic pathways to personalised medicine

“…This study confirmed known associations with TERC , TERT and MUC5B and identified seven novel risk loci within genes involved in host defence, cell-cell adhesion and DNA repair. Recently, the same authors extended their previous work to imputed genome-wide genotypes in 1616 non-Hispanic White cases and 4683 controls followed by validation and replication in 878 cases and 2017 controls, and identified a genome-wide significant association between the human leucocyte antigen (HLA) region and fIIP 68. Notably, two HLA alleles associated with fIIP (eg, DRB1*1501 and DQB1*0602) induced differential expression of HLA genes in lung tissue, suggesting that specific immune response against unknown pulmonary targets may contribute to disease pathogenesis at least in a subset of patients.…”

Systems medicine advances in interstitial lung disease

“…Furthermore, by imputing the data of genome-wide genotypes and conducting RNA sequencing studies, they identified new fIIP risk loci in lung tissue. Fibrotic lung tissue showed a deregulation in the human leukocyte antigen region of chromosome 6 (rs7887), involving and reaffirming the role of an immune deregulation in fibrotic ILDs [46].…”