Advanced Lung Disease and Lung Transplantation 2-1-2011 The HLA Class II Allele Allele DRB 1 * 15 is over-represented in patients with Idiopathic Pulmonary Fibrosis

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 (37.861.7% vs. 42.861.4%, 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. Citation: Xue J, Gochuico BR, Alawad AS, Feghali-Bostwick CA, Noth I, et al. (2011) The HLA Class II Allele DRB1*1501 Is Over-Represented in Patients with Idiopathic Pulmonary Fibrosis. PLoS ONE 6(2): e14715. doi:10.1371/journal.pone.0014715 Editor: Melanie Koenigshoff, Comprehensive Pneumology Center, Germany Received July 11, 2010; Accepted January 26, 2011; Published February 23, 2011 This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. Funding: This research was supported in part by the United States National Institutes of Health grants 1RO1HL073241, 1P50 HL084932, 1 P50 HL084948, 5T32 HL007563, and the Intramural Research Program of the National Human Genome Research Institute. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: duncsr@upmc.edu . These authors contributed equally to this work.