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

Aida Ferreiro-Iglesias,Stacey Slone,Demetrios Albanes,David C Qian,Mattias Johansson,Hans Brunnström,Anush Mukeriya,Heike Bickeböller,Małgorzata Szołkowska,Michael Davies,Xiangjun Xiao,Ghislaine Scélo ,Albert Rosenberger,Christopher I Amos,M Dawn Teare,Yafang Li,Guillermo Fernández‐Tardón ,David C Christiani ,Stig E Bojesen ,Gad Rennert ,Vladimí­r Janout ,Geoffrey Liu,Stephen Lam,Olle Melander,Jolanta Lissowska,Xuemei Ji,Penella J Woll ,Ana Fernández-Somoano ,Melinda C Aldrich,John K Field,Erik H F M Van Der Heijden ,H‐Erich Wichmann ,Juncheng Dai,Eric J Duell ,Ciprian Bolca,Shanbeh Zienolddiny,Ahsan Kamal,Dakai Zhu,Hongbing Shen,Mikael Johansson,Milica Kontić ,Philip Lazarus,Milan Savić ,Kjell Grankvist,Miodrag Ognjanovic,Angela Risch,Rayjean J Hung,Chu Chen,Давид Заридзе ,Matthew B Schabath,Aage Haugen,Angeline S Andrew ,Ming‐Sound Tsao ,Jian‐Min Yuan ,Gary E Goodman ,Loı̈c Le Marchand ,Jinyoung Byun,Maria Teresa Landi,Xuchen Zong,Beata Świątkowska ,Neil E Caporaso ,James Mckay,Susanne M Arnold ,Ivana Holcátová ,Jennifer A Doherty ,Younghun Han,Corina Lesseur,Adonina Tardón ,Xifeng Wu,Simona Ognjanovic,Lambertus A Kiemeney,Yun-Chul Hong,Paul Brennan

doi:10.1038/s41467-018-05890-2

Abstract

The basis for associations between lung cancer and major histocompatibility complex genes is not completely understood. Here the authors further consider genetic variation within the MHC region in lung cancer patients and identify independent associations within HLA genes that explain MHC lung cancer associations in Europeans and Asian populations.

Highlights

Lung cancer has several genetic associations identified within the major histocompatibility complex (MHC); the basis for these associations remains elusive
Our results suggest that the genetic risk of the MHC region on lung cancer is different by population and by histology which points to different exposures or mechanisms interacting with Human Leukocyte Antigen (HLA)
HLA human leucocyte antigen, OR odds ratio, 95% CI confidence interval a Obtained from multivariate unconditional logistic regression assuming an additive genetic model with sex and principal components as covariates b Number of samples included in the analysis: 1192 cases and 1656 controls The study-wide significant threshold was P = 6 × 10−6 (Bonferroni correction) uncertainty as to the best model that relates to whether we find evidence of a three signal model at B-Thr-163, DRB1-Arg-74 and HLA-DQB1*06, or just two signals at B-Thr-163 and HLA-DQB1*06

Summary

Introduction

Lung cancer has several genetic associations identified within the major histocompatibility complex (MHC); the basis for these associations remains elusive. Identifying polymorphisms controlling expression of specific HLA molecules, affecting the peptide binding groove or the contact surface with the TCR may help to disentangle lung cancer MHC associations and may provide new insights into cancer risk and possible immunotherapy targets[12]. To this end, we analyze genetic variation in two populations of European and Asian ancestry densely genotyped across the MHC in relation to lung cancer risk.

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Methods

Results

Conclusion