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Region Hovedstaden - en del af Københavns Universitetshospital
Udgivet

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 Andrew
  • Chu Chen
  • David C Christiani
  • Demetrios Albanes
  • Erik H F M van der Heijden
  • Eric Duell
  • Gadi Rennert
  • Mckay D James
  • Jian-Min Yuan
  • John K Field
  • Manjer Jonas
  • Kjell Grankvist
  • Loic Le Marchand
  • M Dawn Teare
  • Matthew B Schabath
  • Melinda C Aldrich
  • Ming-Sound Tsao
  • Philip Lazarus
  • Lam Stephen
  • Stig E Bojesen
  • Arnold Susanne
  • Xifeng Wu
  • Aage Haugen
  • Janout Vladimir
  • Mikael Johansson
  • Brhane Yonathan
  • Ana Fernandez-Somoano
  • Lambertus A Kiemeney
  • Michael Davies
  • Shanbeh Zienolddiny
  • Zhibin Hu
  • Hongbing Shen
Vis graf over relationer

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 the current 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 eQTL (expression quantitative trait loci) analysis and pathway enrichment analysis were performed to identify the possible target genes and pathways. Additionally, we performed motif-based analysis to explore the lung cancer related motifs using sequence kernel association test (SKAT). Two novel variants, rs186332 in 20q13.3 (C>T, OR = 1.17, 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 were 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.

OriginalsprogEngelsk
TidsskriftCarcinogenesis
ISSN0143-3334
DOI
StatusUdgivet - maj 2019

ID: 56638621