Association study of human leukocyte antigen (HLA) variants and idiopathic pulmonary fibrosis.
Guillen-Guio B., Paynton ML., Allen RJ., Chin DPW., Donoghue LJ., Stockwell A., Leavy OC., Hernandez-Beeftink T., Reynolds C., Cullinan P., Martinez F., CleanUP-IPF Investigators of the Pulmonary Trials Cooperative None., Booth HL., Fahy WA., Hall IP., Hart SP., Hill MR., Hirani N., Hubbard RB., McAnulty RJ., Millar AB., Navaratnam V., Oballa E., Parfrey H., Saini G., Sayers I., Tobin MD., Whyte MKB., Adegunsoye A., Kaminski N., Shwu-Fan M., Strek ME., Zhang Y., Fingerlin TE., Molina-Molina M., Neighbors M., Sheng XR., Oldham JM., Maher TM., Molyneaux PL., Flores C., Noth I., Schwartz DA., Yaspan BL., Jenkins RG., Wain LV., Hollox EJ.
INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is a chronic interstitial pneumonia marked by progressive lung fibrosis and a poor prognosis. Recent studies have highlighted the potential role of infection in the pathogenesis of IPF and a prior association of the HLA-DQB1 gene with idiopathic fibrotic interstitial pneumonia (including IPF) has been reported. Due to the important role that the Human Leukocyte Antigen (HLA) region plays in the immune response, here we evaluated if HLA genetic variation was associated specifically with IPF risk. METHODS: We performed a meta-analysis of associations of the HLA region with IPF risk in individuals of European ancestry from seven independent case-control studies of IPF (comprising a total of 5,159 cases and 27,459 controls, including the prior study of fibrotic interstitial pneumonia). Single nucleotide polymorphisms, classical HLA alleles and amino acids were analysed and signals meeting a region-wide association threshold p<4.5×10-4 and a posterior probability of replication >90% were considered significant. We sought to replicate the previously reported HLA-DQB1 association in the subset of studies independent of the original report. RESULTS: The meta-analysis of all seven studies identified four significant independent single nucleotide polymorphisms associated with IPF risk. However, none met the posterior probability for replication criterion. The HLA-DQB1 association was not replicated in the independent IPF studies. CONCLUSION: Variation in the HLA region was not consistently associated with risk in studies of IPF. However, this does not preclude the possibility that other genomic regions linked to the immune response may be involved in the aetiology of IPF.