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

Dai, Juncheng; Li, Zhihua; Amos, Christopher I.; Hung, Rayjean J.; Tardon, Adonina; Andrew, Angeline S.; Chen, Chu; Christiani, David C.; Albanes, Demetrios and van der Heijden, Erik H.F.M., et al. (2019) In Carcinogenesis 40(3). p.432-440
Abstract

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... (More)

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.

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@article{a3bb558f-a028-44a5-88aa-2154baba8cc5,
  abstract     = {<p>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&gt;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&gt;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 &lt; 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.</p>},
  author       = {Dai, Juncheng and Li, Zhihua and Amos, Christopher I. and Hung, Rayjean J. and Tardon, Adonina and Andrew, Angeline S. and Chen, Chu and Christiani, David C. and Albanes, Demetrios and van der Heijden, Erik H.F.M. and Duell, Eric J. and Rennert, Gad and Mckay, James D. and Yuan, Jian Min and Field, John K. and Manjer, Jonas and Grankvist, Kjell and Le Marchand, Loic and Teare, M. Dawn and Schabath, Matthew B. and Aldrich, Melinda C. and Tsao, Ming Sound and Lazarus, Philip and Lam, Stephen and Bojesen, Stig E. and Arnold, Susanne and Wu, Xifeng and Haugen, Aage and Janout, Vladimir and Johansson, Mikael and Brhane, Yonathan and Fernandez-Somoano, Ana and Kiemeney, Lambertus A. and Davies, Michael P.A. and Zienolddiny, Shanbeh and Hu, Zhibin and Shen, Hongbing},
  issn         = {0143-3334},
  language     = {eng},
  number       = {3},
  pages        = {432--440},
  publisher    = {Oxford University Press},
  series       = {Carcinogenesis},
  title        = {Systematic analyses of regulatory variants in DNase I hypersensitive sites identified two novel lung cancer susceptibility loci},
  url          = {http://dx.doi.org/10.1093/carcin/bgy187},
  volume       = {40},
  year         = {2019},
}