Genome-wide imputation study identifies novel HLA locus for pulmonary fibrosis and potential role for auto-immunity in fibrotic idiopathic interstitial pneumonia - Institut de Biologie François JACOB Access content directly
Journal Articles BMC Genetics Year : 2016

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

David A Lynch
  • Function : Author
Steve Groshong
  • Function : Author
Williamson Z Bradford
  • Function : Author
Scott D Seiwert
  • Function : Author
Roland M Du Bois
  • Function : Author
Christine Kim Garcia
  • Function : Author
Gunnar Gudmundsson
  • Function : Author
Helgi J Isaksson
  • Function : Author
Kevin F Gibson
  • Function : Author
Lisa H Lancaster
  • Function : Author
Toby M Maher
  • Function : Author
Philip L Molyneaux
  • Function : Author
Athol U Wells
  • Function : Author
Miriam F Moffatt
  • Function : Author
Moises Selman
  • Function : Author
Annie Pardo
  • Function : Author
Dong Soon Kim
  • Function : Author
James D Crapo
  • Function : Author
Barry J Make
  • Function : Author
Elizabeth A Regan
  • Function : Author
Dinesha S Walek
  • Function : Author
Jerry J Daniel
  • Function : Author
Yoichiro Kamatani
  • Function : Author
Diana Zelenika
  • Function : Author
Elissa Murphy
  • Function : Author
Keith Smith
  • Function : Author
David Mckean
  • Function : Author
Brent S Pedersen
  • Function : Author
Janet Talbert
  • Function : Author
Julia Powers
  • Function : Author
Cheryl R Markin
  • Function : Author
Kenneth B Beckman
  • Function : Author

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.
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cea-04552111 , version 1 (19-04-2024)

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Tasha E Fingerlin, Weiming Zhang, Ivana V Yang, Hannah C Ainsworth, Pamela H Russell, et al.. Genome-wide imputation study identifies novel HLA locus for pulmonary fibrosis and potential role for auto-immunity in fibrotic idiopathic interstitial pneumonia. BMC Genetics, 2016, 17 (74), ⟨10.1186/s12863-016-0377-2⟩. ⟨cea-04552111⟩
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