The HLA class II allele DRB1*1501 is over-represented in patients with idiopathic pulmonary fibrosis

Jianmin Xue, Bernadette R. Gochuico, Ahmad Samer Alawad, Carol A. Feghali-Bostwick, Imre Noth, Steven D. Nathan, Glenn D. Rosen, Ivan O. Rosas, Sanja Dacic, Iclal Ocak, Carl R. Fuhrman, Karen T. Cuenco, Mary A. Smith, Susan S. Jacobs, Adriana Zeevi, Penelope A. Morel, Joseph M. Pilewski, Vincent G. Valentine, Kevin F. Gibson, Naftali KaminskiFrank C. Sciurba, Yingze Zhang, Steven R. Duncan

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

Background: Idiopathic pulmonary fibrosis (IPF) is a progressive and medically refractory lung disease with a grim prognosis. Although the etiology of IPF remains perplexing, abnormal adaptive immune responses are evident in many afflicted patients. We hypothesized that perturbations of human leukocyte antigen (HLA) allele frequencies, which are often seen among patients with immunologic diseases, may also be present in IPF patients. Methods/Principal Findings: HLA alleles were determined in subpopulations of IPF and normal subjects using molecular typing methods. HLA-DRB1*15 was over-represented in a discovery cohort of 79 Caucasian IPF subjects who had lung transplantations at the University of Pittsburgh (36.7%) compared to normal reference populations. These findings were prospectively replicated in a validation cohort of 196 additional IPF subjects from four other U.S. medical centers that included both ambulatory patients and lung transplantation recipients. High-resolution typing was used to further define specific HLA-DRB1*15 alleles. DRB1*1501 prevalence in IPF subjects was similar among the 143 ambulatory patients and 132 transplant recipients (31.5% and 34.8%, respectively, p = 0.55). The aggregate prevalence of DRB1*1501 in IPF patients was significantly greater than among 285 healthy controls (33.1% vs. 20.0%, respectively, OR 2.0; 95%CI 1.3-2.9, p = 0.0004). IPF patients with DRB1*1501 (n = 91) tended to have decreased diffusing capacities for carbon monoxide (DLCO) compared to the 184 disease subjects who lacked this allele (37.8±1.7% vs. 42.8±1.4%, p = 0.036). Conclusions/Significance: DRB1*1501 is more prevalent among IPF patients than normal subjects, and may be associated with greater impairment of gas exchange. These data are novel evidence that immunogenetic processes can play a role in the susceptibility to and/or manifestations of IPF. Findings here of a disease association at the HLA-DR locus have broad pathogenic implications, illustrate a specific chromosomal area for incremental, targeted genomic study, and may identify a distinct clinical phenotype among patients with this enigmatic, morbid lung disease.

Original languageEnglish (US)
Article numbere14715
JournalPLoS One
Volume6
Issue number2
DOIs
StatePublished - 2011

Fingerprint

Idiopathic Pulmonary Fibrosis
HLA Antigens
fibrosis
Alleles
lungs
alleles
Pulmonary diseases
Transplants
Lung Transplantation
Carbon Monoxide
Immunogenetic Phenomena
Refractory materials
Lung Diseases
Gases
HLA antigens
respiratory tract diseases
immunologic diseases
pulmonary gas exchange
Molecular Typing
immunogenetics

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Xue, J., Gochuico, B. R., Alawad, A. S., Feghali-Bostwick, C. A., Noth, I., Nathan, S. D., ... Duncan, S. R. (2011). The HLA class II allele DRB1*1501 is over-represented in patients with idiopathic pulmonary fibrosis. PLoS One, 6(2), [e14715]. https://doi.org/10.1371/journal.pone.0014715

The HLA class II allele DRB1*1501 is over-represented in patients with idiopathic pulmonary fibrosis. / Xue, Jianmin; Gochuico, Bernadette R.; Alawad, Ahmad Samer; Feghali-Bostwick, Carol A.; Noth, Imre; Nathan, Steven D.; Rosen, Glenn D.; Rosas, Ivan O.; Dacic, Sanja; Ocak, Iclal; Fuhrman, Carl R.; Cuenco, Karen T.; Smith, Mary A.; Jacobs, Susan S.; Zeevi, Adriana; Morel, Penelope A.; Pilewski, Joseph M.; Valentine, Vincent G.; Gibson, Kevin F.; Kaminski, Naftali; Sciurba, Frank C.; Zhang, Yingze; Duncan, Steven R.

In: PLoS One, Vol. 6, No. 2, e14715, 2011.

Research output: Contribution to journalArticle

Xue, J, Gochuico, BR, Alawad, AS, Feghali-Bostwick, CA, Noth, I, Nathan, SD, Rosen, GD, Rosas, IO, Dacic, S, Ocak, I, Fuhrman, CR, Cuenco, KT, Smith, MA, Jacobs, SS, Zeevi, A, Morel, PA, Pilewski, JM, Valentine, VG, Gibson, KF, Kaminski, N, Sciurba, FC, Zhang, Y & Duncan, SR 2011, 'The HLA class II allele DRB1*1501 is over-represented in patients with idiopathic pulmonary fibrosis', PLoS One, vol. 6, no. 2, e14715. https://doi.org/10.1371/journal.pone.0014715
Xue, Jianmin ; Gochuico, Bernadette R. ; Alawad, Ahmad Samer ; Feghali-Bostwick, Carol A. ; Noth, Imre ; Nathan, Steven D. ; Rosen, Glenn D. ; Rosas, Ivan O. ; Dacic, Sanja ; Ocak, Iclal ; Fuhrman, Carl R. ; Cuenco, Karen T. ; Smith, Mary A. ; Jacobs, Susan S. ; Zeevi, Adriana ; Morel, Penelope A. ; Pilewski, Joseph M. ; Valentine, Vincent G. ; Gibson, Kevin F. ; Kaminski, Naftali ; Sciurba, Frank C. ; Zhang, Yingze ; Duncan, Steven R. / The HLA class II allele DRB1*1501 is over-represented in patients with idiopathic pulmonary fibrosis. In: PLoS One. 2011 ; Vol. 6, No. 2.
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abstract = "Background: Idiopathic pulmonary fibrosis (IPF) is a progressive and medically refractory lung disease with a grim prognosis. Although the etiology of IPF remains perplexing, abnormal adaptive immune responses are evident in many afflicted patients. We hypothesized that perturbations of human leukocyte antigen (HLA) allele frequencies, which are often seen among patients with immunologic diseases, may also be present in IPF patients. Methods/Principal Findings: HLA alleles were determined in subpopulations of IPF and normal subjects using molecular typing methods. HLA-DRB1*15 was over-represented in a discovery cohort of 79 Caucasian IPF subjects who had lung transplantations at the University of Pittsburgh (36.7{\%}) compared to normal reference populations. These findings were prospectively replicated in a validation cohort of 196 additional IPF subjects from four other U.S. medical centers that included both ambulatory patients and lung transplantation recipients. High-resolution typing was used to further define specific HLA-DRB1*15 alleles. DRB1*1501 prevalence in IPF subjects was similar among the 143 ambulatory patients and 132 transplant recipients (31.5{\%} and 34.8{\%}, respectively, p = 0.55). The aggregate prevalence of DRB1*1501 in IPF patients was significantly greater than among 285 healthy controls (33.1{\%} vs. 20.0{\%}, respectively, OR 2.0; 95{\%}CI 1.3-2.9, p = 0.0004). IPF patients with DRB1*1501 (n = 91) tended to have decreased diffusing capacities for carbon monoxide (DLCO) compared to the 184 disease subjects who lacked this allele (37.8±1.7{\%} vs. 42.8±1.4{\%}, p = 0.036). Conclusions/Significance: DRB1*1501 is more prevalent among IPF patients than normal subjects, and may be associated with greater impairment of gas exchange. These data are novel evidence that immunogenetic processes can play a role in the susceptibility to and/or manifestations of IPF. Findings here of a disease association at the HLA-DR locus have broad pathogenic implications, illustrate a specific chromosomal area for incremental, targeted genomic study, and may identify a distinct clinical phenotype among patients with this enigmatic, morbid lung disease.",
author = "Jianmin Xue and Gochuico, {Bernadette R.} and Alawad, {Ahmad Samer} and Feghali-Bostwick, {Carol A.} and Imre Noth and Nathan, {Steven D.} and Rosen, {Glenn D.} and Rosas, {Ivan O.} and Sanja Dacic and Iclal Ocak and Fuhrman, {Carl R.} and Cuenco, {Karen T.} and Smith, {Mary A.} and Jacobs, {Susan S.} and Adriana Zeevi and Morel, {Penelope A.} and Pilewski, {Joseph M.} and Valentine, {Vincent G.} and Gibson, {Kevin F.} and Naftali Kaminski and Sciurba, {Frank C.} and Yingze Zhang and Duncan, {Steven R.}",
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T1 - The HLA class II allele DRB1*1501 is over-represented in patients with idiopathic pulmonary fibrosis

AU - Xue, Jianmin

AU - Gochuico, Bernadette R.

AU - Alawad, Ahmad Samer

AU - Feghali-Bostwick, Carol A.

AU - Noth, Imre

AU - Nathan, Steven D.

AU - Rosen, Glenn D.

AU - Rosas, Ivan O.

AU - Dacic, Sanja

AU - Ocak, Iclal

AU - Fuhrman, Carl R.

AU - Cuenco, Karen T.

AU - Smith, Mary A.

AU - Jacobs, Susan S.

AU - Zeevi, Adriana

AU - Morel, Penelope A.

AU - Pilewski, Joseph M.

AU - Valentine, Vincent G.

AU - Gibson, Kevin F.

AU - Kaminski, Naftali

AU - Sciurba, Frank C.

AU - Zhang, Yingze

AU - Duncan, Steven R.

PY - 2011

Y1 - 2011

N2 - Background: Idiopathic pulmonary fibrosis (IPF) is a progressive and medically refractory lung disease with a grim prognosis. Although the etiology of IPF remains perplexing, abnormal adaptive immune responses are evident in many afflicted patients. We hypothesized that perturbations of human leukocyte antigen (HLA) allele frequencies, which are often seen among patients with immunologic diseases, may also be present in IPF patients. Methods/Principal Findings: HLA alleles were determined in subpopulations of IPF and normal subjects using molecular typing methods. HLA-DRB1*15 was over-represented in a discovery cohort of 79 Caucasian IPF subjects who had lung transplantations at the University of Pittsburgh (36.7%) compared to normal reference populations. These findings were prospectively replicated in a validation cohort of 196 additional IPF subjects from four other U.S. medical centers that included both ambulatory patients and lung transplantation recipients. High-resolution typing was used to further define specific HLA-DRB1*15 alleles. DRB1*1501 prevalence in IPF subjects was similar among the 143 ambulatory patients and 132 transplant recipients (31.5% and 34.8%, respectively, p = 0.55). The aggregate prevalence of DRB1*1501 in IPF patients was significantly greater than among 285 healthy controls (33.1% vs. 20.0%, respectively, OR 2.0; 95%CI 1.3-2.9, p = 0.0004). IPF patients with DRB1*1501 (n = 91) tended to have decreased diffusing capacities for carbon monoxide (DLCO) compared to the 184 disease subjects who lacked this allele (37.8±1.7% vs. 42.8±1.4%, p = 0.036). Conclusions/Significance: DRB1*1501 is more prevalent among IPF patients than normal subjects, and may be associated with greater impairment of gas exchange. These data are novel evidence that immunogenetic processes can play a role in the susceptibility to and/or manifestations of IPF. Findings here of a disease association at the HLA-DR locus have broad pathogenic implications, illustrate a specific chromosomal area for incremental, targeted genomic study, and may identify a distinct clinical phenotype among patients with this enigmatic, morbid lung disease.

AB - Background: Idiopathic pulmonary fibrosis (IPF) is a progressive and medically refractory lung disease with a grim prognosis. Although the etiology of IPF remains perplexing, abnormal adaptive immune responses are evident in many afflicted patients. We hypothesized that perturbations of human leukocyte antigen (HLA) allele frequencies, which are often seen among patients with immunologic diseases, may also be present in IPF patients. Methods/Principal Findings: HLA alleles were determined in subpopulations of IPF and normal subjects using molecular typing methods. HLA-DRB1*15 was over-represented in a discovery cohort of 79 Caucasian IPF subjects who had lung transplantations at the University of Pittsburgh (36.7%) compared to normal reference populations. These findings were prospectively replicated in a validation cohort of 196 additional IPF subjects from four other U.S. medical centers that included both ambulatory patients and lung transplantation recipients. High-resolution typing was used to further define specific HLA-DRB1*15 alleles. DRB1*1501 prevalence in IPF subjects was similar among the 143 ambulatory patients and 132 transplant recipients (31.5% and 34.8%, respectively, p = 0.55). The aggregate prevalence of DRB1*1501 in IPF patients was significantly greater than among 285 healthy controls (33.1% vs. 20.0%, respectively, OR 2.0; 95%CI 1.3-2.9, p = 0.0004). IPF patients with DRB1*1501 (n = 91) tended to have decreased diffusing capacities for carbon monoxide (DLCO) compared to the 184 disease subjects who lacked this allele (37.8±1.7% vs. 42.8±1.4%, p = 0.036). Conclusions/Significance: DRB1*1501 is more prevalent among IPF patients than normal subjects, and may be associated with greater impairment of gas exchange. These data are novel evidence that immunogenetic processes can play a role in the susceptibility to and/or manifestations of IPF. Findings here of a disease association at the HLA-DR locus have broad pathogenic implications, illustrate a specific chromosomal area for incremental, targeted genomic study, and may identify a distinct clinical phenotype among patients with this enigmatic, morbid lung disease.

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