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

Tasha E. Fingerlin, Weiming Zhang, Ivana V. Yang, Hannah C. Ainsworth, Pamela H. Russell, Rachel Z. Blumhagen, Marvin I. Schwarz, Kevin K. Brown, Mark P. Steele, James E. Loyd, Gregory P. Cosgrove, David A. Lynch, Steve Groshong, Harold R. Collard, Paul J. Wolters, Williamson Z. Bradford, Karl Kossen, Scott D. Seiwert, Roland M. Bois, Christine Kim Garcia & 33 others Megan S. Devine, Gunnar Gudmundsson, Helgi J. Isaksson, Naftali Kaminski, Yingze Zhang, Kevin F. Gibson, Lisa H. Lancaster, Toby M. Maher, Philip L. Molyneaux, Athol U. Wells, Miriam F. Moffatt, Moises Selman, Annie Pardo, Dong Soon Kim, James D. Crapo, Barry J. Make, Elizabeth A. Regan, Dinesha S. Walek, Jerry J. Daniel, Yoichiro Kamatani, Diana Zelenika, Elissa Murphy, Keith Smith, David McKean, Brent S. Pedersen, Janet Talbert, Julia Powers, Cheryl R. Markin, Kenneth B. Beckman, Mark Lathrop, Brian Freed, Carl D. Langefeld, David A. Schwartz

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

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).

Original languageEnglish (US)
Article number74
JournalBMC Genetics
Volume17
Issue number1
DOIs
StatePublished - 2016

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Idiopathic Interstitial Pneumonias
Pulmonary Fibrosis
Immunity
Genome
RNA Sequence Analysis
Lung
Alleles
Genotype
Gene Expression
Chromosomes, Human, Pair 6
Linkage Disequilibrium
Lung Diseases
Single Nucleotide Polymorphism
Meta-Analysis
Transplants
Population
Genes

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

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.; Zhang, Weiming; Yang, Ivana V.; Ainsworth, Hannah C.; Russell, Pamela H.; Blumhagen, Rachel Z.; Schwarz, Marvin I.; Brown, Kevin K.; Steele, Mark P.; Loyd, James E.; Cosgrove, Gregory P.; Lynch, David A.; Groshong, Steve; Collard, Harold R.; Wolters, Paul J.; Bradford, Williamson Z.; Kossen, Karl; Seiwert, Scott D.; Bois, Roland M.; Garcia, Christine Kim; Devine, Megan S.; Gudmundsson, Gunnar; Isaksson, Helgi J.; Kaminski, Naftali; Zhang, Yingze; Gibson, Kevin F.; Lancaster, Lisa H.; Maher, Toby M.; Molyneaux, Philip L.; Wells, Athol U.; Moffatt, Miriam F.; Selman, Moises; Pardo, Annie; Kim, Dong Soon; Crapo, James D.; Make, Barry J.; Regan, Elizabeth A.; Walek, Dinesha S.; Daniel, Jerry J.; Kamatani, Yoichiro; Zelenika, Diana; Murphy, Elissa; Smith, Keith; McKean, David; Pedersen, Brent S.; Talbert, Janet; Powers, Julia; Markin, Cheryl R.; Beckman, Kenneth B.; Lathrop, Mark; Freed, Brian; Langefeld, Carl D.; Schwartz, David A.

In: BMC Genetics, Vol. 17, No. 1, 74, 2016.

Research output: Contribution to journalArticle

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, KF, 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 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, vol. 17, no. 1, 74. https://doi.org/10.1186/s12863-016-0377-2
Fingerlin, Tasha E. ; Zhang, Weiming ; Yang, Ivana V. ; Ainsworth, Hannah C. ; Russell, Pamela H. ; Blumhagen, Rachel Z. ; Schwarz, Marvin I. ; Brown, Kevin K. ; Steele, Mark P. ; Loyd, James E. ; Cosgrove, Gregory P. ; Lynch, David A. ; Groshong, Steve ; Collard, Harold R. ; Wolters, Paul J. ; Bradford, Williamson Z. ; Kossen, Karl ; Seiwert, Scott D. ; Bois, Roland M. ; Garcia, Christine Kim ; Devine, Megan S. ; Gudmundsson, Gunnar ; Isaksson, Helgi J. ; Kaminski, Naftali ; Zhang, Yingze ; Gibson, Kevin F. ; Lancaster, Lisa H. ; Maher, Toby M. ; Molyneaux, Philip L. ; Wells, Athol U. ; Moffatt, Miriam F. ; Selman, Moises ; Pardo, Annie ; Kim, Dong Soon ; Crapo, James D. ; Make, Barry J. ; Regan, Elizabeth A. ; Walek, Dinesha S. ; Daniel, Jerry J. ; Kamatani, Yoichiro ; Zelenika, Diana ; Murphy, Elissa ; Smith, Keith ; McKean, David ; Pedersen, Brent S. ; Talbert, Janet ; Powers, Julia ; Markin, Cheryl R. ; Beckman, Kenneth B. ; Lathrop, Mark ; Freed, Brian ; Langefeld, Carl D. ; Schwartz, David A. / Genome-wide imputation study identifies novel HLA locus for pulmonary fibrosis and potential role for auto-immunity in fibrotic idiopathic interstitial pneumonia. In: BMC Genetics. 2016 ; Vol. 17, No. 1.
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abstract = "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).",
author = "Fingerlin, {Tasha E.} and Weiming Zhang and Yang, {Ivana V.} and Ainsworth, {Hannah C.} and Russell, {Pamela H.} and Blumhagen, {Rachel Z.} and Schwarz, {Marvin I.} and Brown, {Kevin K.} and Steele, {Mark P.} and Loyd, {James E.} and Cosgrove, {Gregory P.} and Lynch, {David A.} and Steve Groshong and Collard, {Harold R.} and Wolters, {Paul J.} and Bradford, {Williamson Z.} and Karl Kossen and Seiwert, {Scott D.} and Bois, {Roland M.} and Garcia, {Christine Kim} and Devine, {Megan S.} and Gunnar Gudmundsson and Isaksson, {Helgi J.} and Naftali Kaminski and Yingze Zhang and Gibson, {Kevin F.} and Lancaster, {Lisa H.} and Maher, {Toby M.} and Molyneaux, {Philip L.} and Wells, {Athol U.} and Moffatt, {Miriam F.} and Moises Selman and Annie Pardo and Kim, {Dong Soon} and Crapo, {James D.} and Make, {Barry J.} and Regan, {Elizabeth A.} and Walek, {Dinesha S.} and Daniel, {Jerry J.} and Yoichiro Kamatani and Diana Zelenika and Elissa Murphy and Keith Smith and David McKean and Pedersen, {Brent S.} and Janet Talbert and Julia Powers and Markin, {Cheryl R.} and Beckman, {Kenneth B.} and Mark Lathrop and Brian Freed and Langefeld, {Carl D.} and Schwartz, {David A.}",
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TY - JOUR

T1 - Genome-wide imputation study identifies novel HLA locus for pulmonary fibrosis and potential role for auto-immunity in fibrotic idiopathic interstitial pneumonia

AU - Fingerlin, Tasha E.

AU - Zhang, Weiming

AU - Yang, Ivana V.

AU - Ainsworth, Hannah C.

AU - Russell, Pamela H.

AU - Blumhagen, Rachel Z.

AU - Schwarz, Marvin I.

AU - Brown, Kevin K.

AU - Steele, Mark P.

AU - Loyd, James E.

AU - Cosgrove, Gregory P.

AU - Lynch, David A.

AU - Groshong, Steve

AU - Collard, Harold R.

AU - Wolters, Paul J.

AU - Bradford, Williamson Z.

AU - Kossen, Karl

AU - Seiwert, Scott D.

AU - Bois, Roland M.

AU - Garcia, Christine Kim

AU - Devine, Megan S.

AU - Gudmundsson, Gunnar

AU - Isaksson, Helgi J.

AU - Kaminski, Naftali

AU - Zhang, Yingze

AU - Gibson, Kevin F.

AU - Lancaster, Lisa H.

AU - Maher, Toby M.

AU - Molyneaux, Philip L.

AU - Wells, Athol U.

AU - Moffatt, Miriam F.

AU - Selman, Moises

AU - Pardo, Annie

AU - Kim, Dong Soon

AU - Crapo, James D.

AU - Make, Barry J.

AU - Regan, Elizabeth A.

AU - Walek, Dinesha S.

AU - Daniel, Jerry J.

AU - Kamatani, Yoichiro

AU - Zelenika, Diana

AU - Murphy, Elissa

AU - Smith, Keith

AU - McKean, David

AU - Pedersen, Brent S.

AU - Talbert, Janet

AU - Powers, Julia

AU - Markin, Cheryl R.

AU - Beckman, Kenneth B.

AU - Lathrop, Mark

AU - Freed, Brian

AU - Langefeld, Carl D.

AU - Schwartz, David A.

PY - 2016

Y1 - 2016

N2 - 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).

AB - 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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DO - 10.1186/s12863-016-0377-2

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