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Hum Mol Genet. 2019 Jan 15;28(2):341-348. doi: 10.1093/hmg/ddy390.

Genome-wide association study of cervical cancer suggests a role for ARRDC3 gene in human papillomavirus infection.

Takeuchi F1, Kukimoto I2, Li Z3,4,5,6, Li S7, Li N8, Hu Z9,10, Takahashi A11,12, Inoue S13, Yokoi S14,15, Chen J4,5,16, Hang D9, Kuroda M17, Matsuda F18, Mizuno M19, Mori S2, Wu P7, Tanaka N20, Matsuo K13,21, Kamatani Y11,18, Kubo M22, Ma D7, Shi Y3,4,5,6,16.

Author information

1
Research Institute,National Center for Global Health and Medicine, Tokyo, Japan.
2
Pathogen Genomics Center, National Institute of Infectious Diseases,Musashimurayama-shi, Tokyo, Japan.
3
The Affiliated Hospital of Qingdao University & The Biomedical Sciences Institute of Qingdao University (Qingdao Branch of SJTU Bio-X Institutes), Qingdao University, Qingdao, P.R. China.
4
Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), the Collaborative Innovation Center for Brain Science, Shanghai Jiao Tong University, Shanghai, P.R. China.
5
Institute of Social Cognitive and Behavioral Sciences, Shanghai Jiao Tong University, Shanghai, P.R. China.
6
Institute of Neuropsychiatric Science and Systems Biological Medicine, Shanghai Jiao Tong University, Shanghai, P.R. China.
7
Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R. China.
8
Program Office for Cancer Screening in Urban China, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P.R. China.
9
Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center For Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Nanjing, P.R. China.
10
State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, P.R. China.
11
Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
12
Department of Genomic Medicine, Research Institute, National Cerebral and Cardiovascular Center, Osaka, Japan.
13
Division of Molecular and Clinical Epidemiology, Aichi Cancer Center Research Institute, Aichi, Japan.
14
Cancer Genome Center, Chiba Cancer Center Research Institute, Chiba, Japan.
15
Division of Genetic Diagnostics, Chiba Cancer Center, Chiba, Japan.
16
Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China.
17
Pathogen Genomics Center, National Institute of Infectious Diseases, Shinjuku-ku, Tokyo, Japan.
18
Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
19
Department of Gynecological Oncology, Aichi Cancer Center Hospital, Nagoya, Japan.
20
Division of Gynecology, Chiba Cancer Center, Chiba, Japan.
21
Department of Epidemiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
22
RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.

Abstract

The development of cervical cancer is initiated by human papillomavirus (HPV) infection and involves both viral and host genetic factors. Genome-wide association studies (GWAS) of cervical cancer have identified associations in the HLA locus and two loci outside HLA, but the principal genes that control infection and pathogenesis have not been identified. In the present study, we performed GWAS of cervical cancer in East Asian populations, involving 2609 cases and 4712 controls in the discovery stage and 1461 cases and 3295 controls in the follow-up stage. We identified novel-significant associations at 5q14 with the lead single nucleotide polymorphism (SNP) rs59661306 (P = 2.4 × 10-11) and at 7p11 with the lead SNP rs7457728 (P = 1.2 × 10-8). In 5q14, the chromatin region of the GWAS-significant SNPs was found to be in contact with the promoter of the ARRDC3 (arrestin domain-containing 3) gene. In our functional studies, ARRDC3 knockdown in HeLa cells caused significant reductions in both cell growth and susceptibility to HPV16 pseudovirion infection, suggesting that ARRDC3 is involved in the infectious entry of HPV into the cell. Our study advances the understanding of host genes that are responsible for cervical cancer susceptibility and guides future research on HPV infection and cancer development.

PMID:
30412241
DOI:
10.1093/hmg/ddy390
[Indexed for MEDLINE]

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