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

Xue, J and Gochuico, BR and Alawad, AS and Feghali-Bostwick, CA and Noth, I and Nathan, SD and Rosen, GD and Rosas, IO and Dacic, S and Ocak, I and Fuhrman, CR and Cuenco, KT and Smith, MA and Jacobs, SS and Zeevi, A and Morel, PA and Pilewski, JM and Valentine, VG and Gibson, KF and Kaminski, N and Sciurba, FC and Zhang, Y and Duncan, SR (2011) The HLA class II allele DRB1*1501 is over-represented in patients with idiopathic pulmonary fibrosis. PLoS ONE, 6 (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.

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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Xue, Jjix28@pitt.eduJIX28
Gochuico, BR
Alawad, AS
Feghali-Bostwick, CA
Noth, I
Nathan, SD
Rosen, GD
Rosas, IO
Dacic, Ssad7@pitt.eduSAD7
Ocak, Iico2@pitt.eduICO2
Fuhrman, CRfuhrman1@pitt.eduFUHRMAN1
Cuenco, KTktc14@pitt.eduKTC14
Smith, MA
Jacobs, SS
Zeevi, Azeevi@pitt.eduZEEVI
Morel, PAmorel@pitt.eduMOREL
Pilewski, JMpilewski@pitt.eduPILEWSKI
Valentine, VG
Gibson, KFkfg@pitt.eduKFG
Kaminski, N
Sciurba, FCfcs@pitt.eduFCS
Zhang, Yzhang3@pitt.eduZHANG3
Duncan, SR
Date: 2 March 2011
Date Type: Publication
Journal or Publication Title: PLoS ONE
Volume: 6
Number: 2
DOI or Unique Handle: 10.1371/journal.pone.0014715
Schools and Programs: School of Medicine > Immunology
Refereed: Yes
MeSH Headings: Aged; Alleles; Case-Control Studies; Cohort Studies; Female; Gene Frequency; Genetic Linkage; Genetic Predisposition to Disease; HLA-DR Antigens--genetics; HLA-DRB1 Chains; Histocompatibility Antigens Class II--genetics; Humans; Idiopathic Pulmonary Fibrosis--epidemiology; Idiopathic Pulmonary Fibrosis--genetics; Male; Middle Aged; Prevalence
Other ID: NLM PMC3044131
PubMed Central ID: PMC3044131
PubMed ID: 21373184
Date Deposited: 07 Aug 2012 15:52
Last Modified: 22 Jun 2021 13:56
URI: http://d-scholarship.pitt.edu/id/eprint/13421

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