Systematic analyses of regulatory variants in DNase I hypersensitive sites identified two novel lung cancer susceptibility loci

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  • Juncheng Dai
  • Zhihua Li
  • Christopher I Amos
  • Rayjean J Hung
  • Adonina Tardon
  • Angeline S Andrew
  • Chu Chen
  • David C Christiani
  • Demetrios Albanes
  • Erik H F M van der Heijden
  • Eric J Duell
  • Gad Rennert
  • James D Mckay
  • Jian-Min Yuan
  • John K Field
  • Jonas Manjer
  • Kjell Grankvist
  • Loic Le Marchand
  • M Dawn Teare
  • Matthew B Schabath
  • Melinda C Aldrich
  • Ming-Sound Tsao
  • Philip Lazarus
  • Stephen Lam
  • Susanne Arnold
  • Xifeng Wu
  • Aage Haugen
  • Vladimir Janout
  • Mikael Johansson
  • Yonathan Brhane
  • Ana Fernandez-Somoano
  • Lambertus A Kiemeney
  • Michael P A Davies
  • Shanbeh Zienolddiny
  • Zhibin Hu
  • Hongbing Shen

DNase I hypersensitive sites (DHS) are abundant in regulatory elements, such as promoter, enhancer and transcription factor binding sites. Many studies have revealed that disease-associated variants were concentrated in DHS-related regions. However, limited studies are available on the roles of DHS-related variants in lung cancer. In this study, we performed a large-scale case-control study with 20 871 lung cancer cases and 15 971 controls to evaluate the associations between regulatory genetic variants in DHS and lung cancer susceptibility. The expression quantitative trait loci (eQTL) analysis and pathway-enrichment analysis were performed to identify the possible target genes and pathways. In addition, we performed motif-based analysis to explore the lung-cancer-related motifs using sequence kernel association test. Two novel variants, rs186332 in 20q13.3 (C>T, odds ratio [OR] = 1.17, 95% confidence interval [95% CI]: 1.10-1.24, P = 8.45 × 10-7) and rs4839323 in 1p13.2 (T>C, OR = 0.92, 95% CI: 0.89-0.95, P = 1.02 × 10-6) showed significant association with lung cancer risk. The eQTL analysis suggested that these two SNPs might regulate the expression of MRGBP and SLC16A1, respectively. What's more, the expression of both MRGBP and SLC16A1 was aberrantly elevated in lung tumor tissues. The motif-based analysis identified 10 motifs related to the risk of lung cancer (P < 1.71 × 10-4). Our findings suggested that variants in DHS might modify lung cancer susceptibility through regulating the expression of surrounding genes. This study provided us a deeper insight into the roles of DHS-related genetic variants for lung cancer.

Udgave nummer3
Sider (fra-til)432-440
Antal sider9
StatusUdgivet - mar. 2019

Bibliografisk note

© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please email:

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