Association study of human leukocyte antigen variants and idiopathic pulmonary fibrosis

Beatriz Guillen-Guio^{1

2

3}, Megan L Paynton^{1

3}, Richard J Allen^{1

2}, Daniel P W Chin^{1

2}, Lauren J Donoghue⁴, Amy Stockwell⁴, Olivia C Leavy^{1

2}, Tamara Hernandez-Beeftink^{1

2}, Carl Reynolds⁵, Paul Cullinan⁵, Fernando Martinez⁶, Helen L Booth⁷, William A Fahy⁸, Ian P Hall^{9

10}, Simon P Hart¹¹, Mike R Hill¹², Nik Hirani¹³, Richard B Hubbard^{9

10}, Robin J McAnulty¹⁴, Ann B Millar¹⁵, Vidya Navaratnam^{16

17

18}, Eunice Oballa⁸, Helen Parfrey¹⁹, Gauri Saini⁹, Ian Sayers²⁰, Martin D Tobin^{1

2}, Moira K B Whyte¹³, Ayodeji Adegunsoye²¹, Naftali Kaminski²², Shwu-Fan Ma²³, Mary E Strek²¹, Yingze Zhang²⁴, Tasha E Fingerlin²⁵, Maria Molina-Molina^{26

27

28}, Margaret Neighbors⁴, X Rebecca Sheng⁴, Justin M Oldham²⁹, Toby M Maher^{30

31}, Philip L Molyneaux^{30

32}, Carlos Flores^{28

33

34

35}, Imre Noth²³, David A Schwartz³⁶, Brian L Yaspan⁴, R Gisli Jenkins³⁰, Louise V Wain^{1

2

37}, Edward J Hollox^{38

37}

Affiliations

¹ Department of Population Health Sciences, University of Leicester, Leicester, UK.
² NIHR Leicester Biomedical Research Centre, Leicester, UK.
³ Joint first authors.
⁴ Genentech, San Francisco, CA, USA.
⁵ National Heart & Lung Institute, Imperial College London, London, UK.
⁶ Department of Medicine, Weill Cornell Medicine, New York, NY, USA.
⁷ University College Hospital, University College London, London, UK.
⁸ GlaxoSmithKline, London, UK.
⁹ School of Medicine, University of Nottingham, Nottingham, UK.
¹⁰ National Institute for Health Research, Nottingham Biomedical Research Centre, Nottingham, UK.
¹¹ Hull York Medical School, University of Hull, Hull, UK.
¹² MRC Population Health Unit, University of Oxford, Oxford, UK.
¹³ Centre for Inflammation Research, University of Edinburgh, Edinburgh, UK.
¹⁴ Division of Medicine, University College London, London, UK.
¹⁵ Bristol Medical School, University of Bristol, Bristol, UK.
¹⁶ Division of Epidemiology and Public Health, University of Nottingham, Nottingham, UK.
¹⁷ National Institute for Health Research, Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust, Nottingham, UK.
¹⁸ Queensland Lung Transplant Service, The Prince Charles Hospital, Brisbane, QLD, Australia.
¹⁹ Royal Papworth Hospital NHS Foundation Trust, Cambridge, UK.
²⁰ Centre for Respiratory Research, NIHR Nottingham Biomedical Research Centre, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham, UK.
²¹ Department of Medicine, University of Chicago, Chicago, IL, USA.
²² Pulmonary, Critical Care and Sleep Medicine, Yale School of Medicine, New Haven, CT, USA.
²³ Department of Medicine, University of Virginia, Charlottesville, VA, USA.
²⁴ Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
²⁵ Department of Immunology and Genomic Medicine, National Jewish Health, Denver, CO, USA.
²⁶ Servei de Pneumologia, Laboratori de Pneumologia Experimental, Instituto de Investigación Biomédica de Bellvitge (IDIBELL), Barcelona, Spain.
²⁷ Campus de Bellvitge, Universitat de Barcelona, Barcelona, Spain.
²⁸ Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Madrid, Spain.
²⁹ Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, MI, USA.
³⁰ National Heart and Lung Institute, Imperial College London, London, UK.
³¹ Division of Pulmonary and Critical Care Medicine, University of Southern California, Los Angeles, USA.
³² Royal Brompton and Harefield Hospitals, Guy's and St Thomas' NHS Foundation Trust, London, UK.
³³ Research Unit, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain.
³⁴ Genomics Division, Instituto Tecnologico y de Energias Renovables, Santa Cruz de Tenerife, Spain.
³⁵ Facultad de Ciencias de la Salud, Universidad Fernando Pessoa Canarias, Las Palmas de Gran Canaria, Spain.
³⁶ Department of Medicine, University of Colorado, Anscuhtz, CO, USA.
³⁷ Joint senior authors.
³⁸ Department of Genetics and Genome Biology, University of Leicester, Leicester, UK.

PMID: 38375425
PMCID: PMC10875457
DOI: 10.1183/23120541.00553-2023

Association study of human leukocyte antigen variants and idiopathic pulmonary fibrosis

Beatriz Guillen-Guio et al. ERJ Open Res. 2024.

. 2024 Feb 19;10(1):00553-2023.

doi: 10.1183/23120541.00553-2023. eCollection 2024 Jan.

Authors

Affiliations

¹ Department of Population Health Sciences, University of Leicester, Leicester, UK.
² NIHR Leicester Biomedical Research Centre, Leicester, UK.
³ Joint first authors.
⁴ Genentech, San Francisco, CA, USA.
⁵ National Heart & Lung Institute, Imperial College London, London, UK.
⁶ Department of Medicine, Weill Cornell Medicine, New York, NY, USA.
⁷ University College Hospital, University College London, London, UK.
⁸ GlaxoSmithKline, London, UK.
⁹ School of Medicine, University of Nottingham, Nottingham, UK.
¹⁰ National Institute for Health Research, Nottingham Biomedical Research Centre, Nottingham, UK.
¹¹ Hull York Medical School, University of Hull, Hull, UK.
¹² MRC Population Health Unit, University of Oxford, Oxford, UK.
¹³ Centre for Inflammation Research, University of Edinburgh, Edinburgh, UK.
¹⁴ Division of Medicine, University College London, London, UK.
¹⁵ Bristol Medical School, University of Bristol, Bristol, UK.
¹⁶ Division of Epidemiology and Public Health, University of Nottingham, Nottingham, UK.
¹⁷ National Institute for Health Research, Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust, Nottingham, UK.
¹⁸ Queensland Lung Transplant Service, The Prince Charles Hospital, Brisbane, QLD, Australia.
¹⁹ Royal Papworth Hospital NHS Foundation Trust, Cambridge, UK.
²⁰ Centre for Respiratory Research, NIHR Nottingham Biomedical Research Centre, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham, UK.
²¹ Department of Medicine, University of Chicago, Chicago, IL, USA.
²² Pulmonary, Critical Care and Sleep Medicine, Yale School of Medicine, New Haven, CT, USA.
²³ Department of Medicine, University of Virginia, Charlottesville, VA, USA.
²⁴ Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
²⁵ Department of Immunology and Genomic Medicine, National Jewish Health, Denver, CO, USA.
²⁶ Servei de Pneumologia, Laboratori de Pneumologia Experimental, Instituto de Investigación Biomédica de Bellvitge (IDIBELL), Barcelona, Spain.
²⁷ Campus de Bellvitge, Universitat de Barcelona, Barcelona, Spain.
²⁸ Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Madrid, Spain.
²⁹ Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, MI, USA.
³⁰ National Heart and Lung Institute, Imperial College London, London, UK.
³¹ Division of Pulmonary and Critical Care Medicine, University of Southern California, Los Angeles, USA.
³² Royal Brompton and Harefield Hospitals, Guy's and St Thomas' NHS Foundation Trust, London, UK.
³³ Research Unit, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain.
³⁴ Genomics Division, Instituto Tecnologico y de Energias Renovables, Santa Cruz de Tenerife, Spain.
³⁵ Facultad de Ciencias de la Salud, Universidad Fernando Pessoa Canarias, Las Palmas de Gran Canaria, Spain.
³⁶ Department of Medicine, University of Colorado, Anscuhtz, CO, USA.
³⁷ Joint senior authors.
³⁸ Department of Genetics and Genome Biology, University of Leicester, Leicester, UK.

PMID: 38375425
PMCID: PMC10875457
DOI: 10.1183/23120541.00553-2023

Abstract

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.

PubMed Disclaimer

Conflict of interest statement

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.

Figures

**FIGURE 1**
**Manhattan plot of meta-analysis results at chromosome 6 region**. Single nucleotide polymorphisms are shown in grey, amino acids in blue and classical human leukocyte antigen (HLA) alleles in purple. The four sentinel variants are highlighted in black. The y-axis shows the transformed p-values (–log₁₀) while the x-axis represents chromosome positions in Mb (GRCh38/hg38). The horizontal line corresponds to the significance threshold of the study after Bonferroni correction (p=4.50×10⁻⁴).

**FIGURE 2**
Forest plots of the association analysis results for the four sentinel variants.

See this image and copyright information in PMC

Update of

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; 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. Guillen-Guio B, et al. medRxiv [Preprint]. 2023 Jul 24:2023.07.20.23292940. doi: 10.1101/2023.07.20.23292940. medRxiv. 2023. Update in: ERJ Open Res. 2024 Feb 19;10(1):00553-2023. doi: 10.1183/23120541.00553-2023. PMID: 37546732 Free PMC article. Updated. Preprint.

References

1. Fujimoto H, Kobayashi T, Azuma A. Idiopathic pulmonary fibrosis: treatment and prognosis. Clin Med Insights Circ Respir Pulm Med 2015; 9: Suppl. 1, 179–185. - PMC - PubMed
1. Michalski JE, Schwartz DA. Genetic risk factors for idiopathic pulmonary fibrosis: insights into immunopathogenesis. J Inflamm Res 2020; 13: 1305–1318. doi:10.2147/JIR.S280958 - DOI - PMC - PubMed
1. Obeidat M, Hall IP. Genetics of complex respiratory diseases: implications for pathophysiology and pharmacology studies. Br J Pharmacol 2011; 163: 96–105. doi:10.1111/j.1476-5381.2011.01222.x - DOI - PMC - PubMed
1. Dendrou CA, Petersen J, Rossjohn J, et al. . HLA variation and disease. Nat Rev Immunol 2018; 18: 325–339. doi:10.1038/nri.2017.143 - DOI - PubMed
1. Fingerlin TE, Zhang W, Yang IV, et al. . Genome-wide imputation study identifies novel HLA locus for pulmonary fibrosis and potential role for auto-immunity in fibrotic idiopathic interstitial pneumonia. BMC Genet 2016; 17: 74. doi:10.1186/s12863-016-0377-2 - DOI - PMC - PubMed

Grants and funding

LinkOut - more resources

Full Text Sources
Research Materials
- NCI CPTC Antibody Characterization Program
Miscellaneous
- NCI CPTAC Assay Portal

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Association study of human leukocyte antigen variants and idiopathic pulmonary fibrosis

Affiliations

Association study of human leukocyte antigen variants and idiopathic pulmonary fibrosis

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

Update of

References

Grants and funding

LinkOut - more resources

Full Text Sources

Research Materials

Miscellaneous