Association study of human leukocyte antigen variants and idiopathic pulmonary fibrosis.

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. Owing 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 5159 cases and 27 459 controls, including a 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 of 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.
Competing Interests: Conflict of interest: L.J. Donoghue, A. Stockwell, M. Neighbours, X.R. Sheng and B.L. Yaspan are full-time employees of Genentech; A. Stockwell, M. Neighbours, X.R. Sheng and B.L. Yaspan hold stock options in Roche. J.M. Oldham reports personal fees from Boehringer Ingelheim, Genentech, United Therapeutics, AmMax Bio and Lupin Pharmaceuticals outside the submitted work. D.A. Schwartz is the founder and chief scientific officer of Eleven P15, a company focused on the early detection and treatment of pulmonary fibrosis. R.G. Jenkins reports honoraria from Chiesi, Roche, PatientMPower, AstraZeneca, GlaxoSmithKline and Boehringer Ingelheim, and consulting fees from Bristol Myers Squibb, Daewoong, Veracyte, Resolution Therapeutics, RedX, Pliant and Chiesi. L.V. Wain reports research funding from GlaxoSmithKline, Roche and Orion Pharma, and consultancy for GlaxoSmithKline and Galapagos, outside of the submitted work. S.P. Hart and P.L. Molyneaux are associate editors of this journal. The other authors declare no competing interests.
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