TY - JOUR
T1 - Genome-wide association study of cervical cancer suggests a role for ARRDC3 gene in human papillomavirus infection
AU - Takeuchi, Fumihiko
AU - Kukimoto, Iwao
AU - Li, Zhiqiang
AU - Li, Shuang
AU - Li, Ni
AU - Hu, Zhibin
AU - Takahashi, Atsushi
AU - Inoue, Shusaku
AU - Yokoi, Sana
AU - Chen, Jianhua
AU - Hang, Dong
AU - Kuroda, Makoto
AU - Matsuda, Fumihiko
AU - Mizuno, Mika
AU - Mori, Seiichiro
AU - Wu, Peng
AU - Tanaka, Naotake
AU - Matsuo, Keitaro
AU - Kamatani, Yoichiro
AU - Kubo, Michiaki
AU - Ma, Ding
AU - Shi, Yongyong
N1 - Publisher Copyright:
© The Author(s) 2018. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected].
PY - 2019/1/15
Y1 - 2019/1/15
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85059497992&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85059497992&partnerID=8YFLogxK
U2 - 10.1093/hmg/ddy390
DO - 10.1093/hmg/ddy390
M3 - Article
C2 - 30412241
AN - SCOPUS:85059497992
SN - 0964-6906
VL - 28
SP - 341
EP - 348
JO - Human molecular genetics
JF - Human molecular genetics
IS - 2
ER -
