Research Papers:

Pooled analysis of genome-wide association studies of cervical intraepithelial neoplasia 3 (CIN3) identifies a new susceptibility locus

Dan Chen _, Stefan Enroth, Han Liu, Yang Sun, Huibo Wang, Min Yu, Lian Deng, Shuhua Xu and Ulf Gyllensten

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Oncotarget. 2016; 7:42216-42224. https://doi.org/10.18632/oncotarget.9916

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Dan Chen1,2, Stefan Enroth2, Han Liu1, Yang Sun3, Huibo Wang4, Min Yu3, Lian Deng5,6, Shuhua Xu5,6,7,8, Ulf Gyllensten2

1Ministry of Education and Shanghai Key Laboratory of Children’s Environmental Health, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China

2Department of Immunology, Genetics and Pathology, Science for Life Laboratory Uppsala, Uppsala University, Uppsala, Sweden

3Laboratory of Biochemistry and Molecular Biology, School of Life Science,Yunnan University, Kunming, China

4Department of Neurosurgery, First Affiliated Hospital of Nanjing Medical University, Nanjing, China

5Chinese Academy of Sciences (CAS) Key Laboratory of Computational Biology, Max Planck Independent Research Group on Population Genomics, CAS-MPG Partner Institute for Computational Biology (PICB), Shanghai Institutes for Biological Sciences, CAS, Shanghai, China

6University of Chinese Academy of Sciences, Beijing, China

7School of Life Science and Technology, Shanghai Tech University, Shanghai, China

8Collaborative Innovation Center of Genetics and Development, Shanghai, China

Correspondence to:

Dan Chen, email: simpledandan1981@163.com, simpledandan@shsmu.edu.cn

Keywords: cervical intraepithelial neoplasia 3, genome-wide association study, genetic variants, expression quantitative trait locus, human leukocyte antigen

Received: December 15, 2015     Accepted: May 13, 2016     Published: June 07, 2016


Recent genome-wide association studies (GWASs) in subjects of European descent have identified associations between cervical cancer risk and three independent loci as well as multiple classical human leukocyte antigen (HLA) alleles at 6p21.3. To search for novel loci associated with development of cervical cancer, we performed a pooled analysis of data from two GWASs by imputing over 10 million genetic variants and 424 classical HLA alleles, for 1,553 intraepithelial neoplasia 3 (CIN3), 81 cervical cancer and 4,442 controls from the Swedish population. Notable findings were validated in an independent study of 961 patients (827 with CIN3 and 123 with cervical cancer) and 1,725 controls. Our data provided increased support for previously identified loci at 6p21.3 (rs9271898, P = 1.2 × 10-24; rs2516448, 1.1 × 10-15; and rs3130196, 2.3 × 10-9, respectively) and also confirmed associations with reported classical HLA alleles including HLA-B*07:02, -B*15:01, -DRB1*13:01, -DRB1*15:01, -DQA1*01:03, -DQB1*06:03 and -DQB1*06:02. In addition, we identified and subsequently replicated an independent signal at rs73730372 at 6p21.3 (odds ratio = 0.60, 95% confidence interval = 0.54–0.67, P = 3.0 × 10-19), which was found to be an expression quantitative trait locus (eQTL) of both HLA-DQA1 and HLA-DQB1. This is one of the strongest common genetic protective variants identified so far for CIN3. We also found HLA-C*07:02 to be associated with risk of CIN3. The present study provides new insights into pathogenesis of CIN3.

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