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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, TE and Zhang, W and Yang, IV and Ainsworth, HC and Russell, PH and Blumhagen, RZ and Schwarz, MI and Brown, KK and Steele, MP and Loyd, JE and Cosgrove, GP and Lynch, DA and Groshong, S and Collard, HR and Wolters, PJ and Bradford, WZ and Kossen, K and Seiwert, SD and Bois, RM and Garcia, CK and Devine, MS and Gudmundsson, G and Isaksson, HJ and Kaminski, N and Zhang, Y and Gibson, KF and Lancaster, LH and Maher, TM and Molyneaux, PL and Wells, AU and Moffatt, MF and Selman, M and Pardo, A and Kim, DS and Crapo, JD and Make, BJ and Regan, EA and Walek, DS and Daniel, JJ and Kamatani, Y and Zelenika, D and Murphy, E and Smith, K and McKean, D and Pedersen, BS and Talbert, J and Powers, J and Markin, CR and Beckman, KB and Lathrop, M and Freed, B and Langefeld, CD and Schwartz, DA (2016) Genome-wide imputation study identifies novel HLA locus for pulmonary fibrosis and potential role for auto-immunity in fibrotic idiopathic interstitial pneumonia. BMC Genetics, 17 (1).

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Abstract

© 2016 The Author(s). 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 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).


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Fingerlin, TE
Zhang, W
Yang, IV
Ainsworth, HC
Russell, PH
Blumhagen, RZ
Schwarz, MI
Brown, KK
Steele, MP
Loyd, JE
Cosgrove, GP
Lynch, DA
Groshong, S
Collard, HR
Wolters, PJ
Bradford, WZ
Kossen, K
Seiwert, SD
Bois, RM
Garcia, CK
Devine, MS
Gudmundsson, G
Isaksson, HJ
Kaminski, N
Zhang, Y
Gibson, KFkfg@pitt.eduKFG
Lancaster, LH
Maher, TM
Molyneaux, PL
Wells, AU
Moffatt, MF
Selman, M
Pardo, A
Kim, DS
Crapo, JD
Make, BJ
Regan, EA
Walek, DS
Daniel, JJ
Kamatani, Y
Zelenika, D
Murphy, E
Smith, K
McKean, D
Pedersen, BS
Talbert, J
Powers, J
Markin, CR
Beckman, KB
Lathrop, M
Freed, B
Langefeld, CD
Schwartz, DA
Date: 1 January 2016
Date Type: Publication
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Journal or Publication Title: BMC Genetics
Volume: 17
Number: 1
DOI or Unique Handle: 10.1186/s12863-016-0377-2
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Medicine
Refereed: Yes
Date Deposited: 25 Jul 2016 13:48
Last Modified: 27 Oct 2018 12:55
URI: http://d-scholarship.pitt.edu/id/eprint/28658

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