Pooled analysis of genome-wide association studies of cervical intraepithelial neoplasia 3 (CIN3) identifies a new susceptibility locus.
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.
Ministry 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.|Department of Immunology, Genetics and Pathology, Science for Life Laboratory Uppsala, Uppsala University, Uppsala, Sweden.
Dan
D
Chen
Department of Immunology, Genetics and Pathology, Science for Life Laboratory Uppsala, Uppsala University, Uppsala, Sweden.
Stefan
S
Enroth
Ministry 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.
Han
H
Liu
Laboratory of Biochemistry and Molecular Biology, School of Life Science,Yunnan University, Kunming, China.
Yang
Y
Sun
Department of Neurosurgery, First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
Huibo
H
Wang
Laboratory of Biochemistry and Molecular Biology, School of Life Science,Yunnan University, Kunming, China.
Min
M
Yu
Chinese 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.|University of Chinese Academy of Sciences, Beijing, China.
Lian
L
Deng
Chinese 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.|University of Chinese Academy of Sciences, Beijing, China.|School of Life Science and Technology, Shanghai Tech University, Shanghai, China.|Collaborative Innovation Center of Genetics and Development, Shanghai, China.
Shuhua
S
Xu
Department of Immunology, Genetics and Pathology, Science for Life Laboratory Uppsala, Uppsala University, Uppsala, Sweden.
Ulf
U
Gyllensten
D000483:Alleles; D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D055106:Genome-Wide Association Study; D005838:Genotype; D015235:HLA-B Antigens / Q000235:genetics; D015793:HLA-B7 Antigen / Q000235:genetics; D059848:HLA-DQ alpha-Chains / Q000235:genetics; D059866:HLA-DQ beta-Chains / Q000235:genetics; D059811:HLA-DRB1 Chains / Q000235:genetics; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D012306:Risk; D002583:Uterine Cervical Neoplasms / Q000235:genetics*; D002578:Uterine Cervical Dysplasia / Q000235:genetics*
D015235:HLA-B Antigens; C425023:HLA-B*07 antigen; D015793:HLA-B7 Antigen; D059848:HLA-DQ alpha-Chains; D059866:HLA-DQ beta-Chains; C069050:HLA-DQA1 antigen; C069051:HLA-DQB1 antigen; D059811:HLA-DRB1 Chains
cervical intraepithelial neoplasia 3; expression quantitative trait locus; genetic variants; genome-wide association study; human leukocyte antigen