Fine mapping of MHC region in lung cancer highlights independent susceptibility loci by ethnicity

Abstract

Lung cancer has several genetic associations identified within the major histocompatibility complex (MHC); although the basis for these associations remains elusive. Here, we analyze MHC genetic variation among 26,044 lung cancer patients and 20,836 controls densely genotyped across the MHC, using the Illumina Illumina OncoArray or Illumina 660W SNP microarray. We impute sequence variation in classical HLA genes, fine-map MHC associations for lung cancer risk with major histologies and compare results between ethnicities. Independent and novel associations within HLA genes are identified in Europeans including amino acids in the HLA-B*0801 peptide binding groove and an independent HLA-DQB1*06 loci group. In Asians, associations are driven by two independent HLA allele sets that both increase risk in HLA-DQB1*0401 and HLA-DRB1*0701; the latter better represented by the amino acid Ala-104. These results implicate several HLA-tumor peptide interactions as the major MHC factor modulating lung cancer susceptibility.

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Item Type:	Article
Authors/Creators:	Ferreiro-Iglesias, A. Lesseur, C. McKay, J. Hung, R.J. Han, Y. Zong, X. Christiani, D. Johansson, M. Xiao, X. Li, Y. Qian, D.C. Ji, X. Liu, G. Caporaso, N. Scelo, G. Zaridze, D. Mukeriya, A. Kontic, M. Ognjanovic, S. Lissowska, J. Szołkowska, M. Swiatkowska, B. Janout, V. Holcatova, I. Bolca, C. Savic, M. Ognjanovic, M. Bojesen, S.E. https://orcid.org/0000-0002-4061-4133 Wu, X. https://orcid.org/0000-0001-5174-3769 Albanes, D. Aldrich, M.C. Tardon, A. Fernandez-Somoano, A. https://orcid.org/0000-0002-8135-9079 Fernandez-Tardon, G. Le Marchand, L. Rennert, G. https://orcid.org/0000-0002-8512-068X Chen, C. Doherty, J. Goodman, G. Bickeböller, H. Wichmann, H.-E. Risch, A. https://orcid.org/0000-0002-8026-5505 Rosenberger, A. Shen, H. Dai, J. Field, J.K. Davies, M. Woll, P. https://orcid.org/0000-0002-1118-0831 Teare, M.D. https://orcid.org/0000-0003-3994-0051 Kiemeney, L.A. van der Heijden, E.H.F.M. https://orcid.org/0000-0003-3596-518X Yuan, J.-M. Hong, Y.-C. Haugen, A. Zienolddiny, S. Lam, S. Tsao, M.-S. Johansson, M. Grankvist, K. https://orcid.org/0000-0003-4289-2097 Schabath, M.B. https://orcid.org/0000-0003-3241-3216 Andrew, A. Duell, E. Melander, O. Brunnström, H. Lazarus, P. Arnold, S. https://orcid.org/0000-0001-6542-9551 Slone, S. Byun, J. https://orcid.org/0000-0001-8579-1435 Kamal, A. Zhu, D. Landi, M.T. Amos, C.I. https://orcid.org/0000-0002-8540-7023 Brennan, P. https://orcid.org/0000-0002-0518-8714
Copyright, Publisher and Additional Information:	© The Author(s) 2018. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Dates:	Published: 25 September 2018 Published (online): 25 September 2018 Accepted: 30 July 2018
Institution:	The University of Sheffield
Academic Units:	The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > School of Health and Related Research (Sheffield) > ScHARR - Sheffield Centre for Health and Related Research
Funding Information:	Funder Grant number WESTON PARK HOSPITAL CANCER CHARITY CA101A (CCTC) WESTON PARK HOSPITAL CANCER CHARITY CA101A SHEFFIELD TEACHING HOSPITALS NHS FOUNDATION TRUST NONE NATIONAL INSTITUTE FOR HEALTH RESEARCH None NATIONAL INSTITUTE FOR HEALTH RESEARCH ECME FSF 2011/12 CANCER RESEARCH UK C5410/A7315 CANCER RESEARCH UK C5410/A7315. NATIONAL INSTITUTE FOR HEALTH RESEARCH None NATIONAL INSTITUTE FOR HEALTH RESEARCH ECMC CANCER RESEARCH UK C5410/A15588 CANCER RESEARCH UK (CRUK) C5410/A7315. CANCER RESEARCH UK C5410/A7315. SHEFFIELD HOSPITALS CHARITABLE TRUST 091002 SHEFFIELD TEACHING HOSPITALS NHS FOUNDATION TRUST NOne CANCER RESEARCH UK C5410/A7315. SHEFFIELD HOSPITALS CHARITABLE TRUST (SPECIAL TRUSTEES) 091002 WESTON PARK HOSPITAL CANCER CHARITY CA101A
Depositing User:	Symplectic Sheffield
Date Deposited:	09 Oct 2018 14:20
Last Modified:	08 May 2024 15:30
Status:	Published
Publisher:	Nature Research
Refereed:	Yes
Identification Number:	10.1038/s41467-018-05890-2
Related URLs:	PubMed URL
Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:136662

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Fine mapping of MHC region in lung cancer highlights independent susceptibility loci by ethnicity

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