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.

Metadata

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

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Dates:

Accepted: 30 July 2018
Published: 25 September 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