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.

Biomedical Data Science Geisel School of Medicine Dartmouth College Hanover NH USA

British Columbia Cancer Agency Vancouver British Columbia Canada

Clalit National Cancer Control Center Carmel Medical Center Haifa Israel

Copenhagen General Population Study Herlev and Gentofte Hospital Copenhagen University Hospital Copenhagen Denmark

Department of Cancer Epidemiology H Lee Moffitt Cancer Center and Research Institute Tampa FL USA

Department of Chemical and Biological Work Environment National Institute of Occupational Health Oslo Norway

Department of Clinical Biochemistry Herlev and Gentofte Hospital Copenhagen University Hospital Copenhagen Denmark

Department of Environmental Health Harvard T H Chan School of Public Health Boston MA USA

Department of Epidemiology and Public Health Faculty of Health Sciences Palacky University Olomouc Czech Republic

Department of Epidemiology Center for Global Health International Joint Research Center School of Public Health Nanjing Medical University Nanjing China

Department of Epidemiology Harvard T H Chan School of Public Health Boston MA USA

Department of Epidemiology University of Texas MD Anderson Cancer Center Houston TX USA

Department of Medical Biosciences Umeå University Umeå Sweden

Department of Pharmaceutical Sciences College of Pharmacy Washington State University Spokane WA USA

Department of Radiation Sciences Umeå University Umeå Sweden

Department of Surgery Skåne University Hospital Malmö Sweden

Department of Thoracic Surgery Division of Epidemiology Vanderbilt University Medical Center Nashville TN USA

Department of Thoracic Surgery The 1st Affiliated Hospital of Nanjing Medical University Nanjing China

Division of Cancer Epidemiology and Genetics National Cancer Institute Bethesda MD USA

Division of Epidemiology Dalla Lana School of Public Health University of Toronto Toronto Ontario Canada

Division of Medical Oncology Markey Cancer Center Lexington KY USA

Epidemiology Program University of Hawai'i Cancer Center Honolulu HI USA

Faculty of Health and Medical Sciences University of Copenhagen Copenhagen Denmark

Faculty of Medicine IUOPA University of Oviedo and CIBERESP Oviedo Spain

International Agency for Research on Cancer World Health Organization Lyon France

Jiangsu Key Lab of Cancer Biomarkers Prevention and Treatment Jiangsu Collaborative Innovation Center of Cancer Personalized Medicine Nanjing Medical University Nanjing China

Lunenfeld Tanenbaum Research Institute Sinai Health System Toronto Ontario Canada

Norris Cotton Cancer Center Geisel School of Medicine Hanover NH USA

Princess Margaret Cancer Centre Toronto Ontario Canada

Public Health Sciences Division Fred Hutchinson Cancer Research Center Seattle WA USA

Radboud University Medical Center Radboud Institute for Health Sciences Nijmegen The Netherlands

Roy Castle Lung Cancer Research Programme Department of Molecular and Clinical Cancer Medicine University of Liverpool The William Duncan Building Liverpool UK

School of Health and Related Research University of Sheffield Sheffield South Yorkshire UK

Unit for Breast Surgery Department of Surgery Lund University Malmö Sweden

Unit of Nutrition and Cancer Catalan Institute of Oncology Barcelona Spain

University of Pittsburgh Cancer Institute Pittsburgh PA USA

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