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

Fumihiko Takeuchi, Iwao Kukimoto, Zhiqiang Li, Shuang Li, Ni Li, Zhibin Hu, Atsushi Takahashi, Shusaku Inoue, Sana Yokoi, Jianhua Chen, Dong Hang, Makoto Kuroda, Fumihiko Matsuda, Mika Mizuno, Seiichiro Mori, Peng Wu, Naotake Tanaka, Keitaro Matsuo, Yoichiro Kamatani, Michiaki KuboDing Ma, Yongyong Shi

Research output: Contribution to journalArticle

1 Citation (Scopus)

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.

Original languageEnglish
Pages (from-to)341-348
Number of pages8
JournalHuman molecular genetics
Volume28
Issue number2
DOIs
Publication statusPublished - 15-01-2019

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Arrestin
Papillomavirus Infections
Genome-Wide Association Study
Uterine Cervical Neoplasms
Single Nucleotide Polymorphism
Genes
Infection Control
HeLa Cells
Chromatin
Growth
Infection
Population
Neoplasms
Lead

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Takeuchi, Fumihiko ; Kukimoto, Iwao ; Li, Zhiqiang ; Li, Shuang ; Li, Ni ; Hu, Zhibin ; Takahashi, Atsushi ; Inoue, Shusaku ; Yokoi, Sana ; Chen, Jianhua ; Hang, Dong ; Kuroda, Makoto ; Matsuda, Fumihiko ; Mizuno, Mika ; Mori, Seiichiro ; Wu, Peng ; Tanaka, Naotake ; Matsuo, Keitaro ; Kamatani, Yoichiro ; Kubo, Michiaki ; Ma, Ding ; Shi, Yongyong. / Genome-wide association study of cervical cancer suggests a role for ARRDC3 gene in human papillomavirus infection. In: Human molecular genetics. 2019 ; Vol. 28, No. 2. pp. 341-348.
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Takeuchi, F, Kukimoto, I, Li, Z, Li, S, Li, N, Hu, Z, Takahashi, A, Inoue, S, Yokoi, S, Chen, J, Hang, D, Kuroda, M, Matsuda, F, Mizuno, M, Mori, S, Wu, P, Tanaka, N, Matsuo, K, Kamatani, Y, Kubo, M, Ma, D & Shi, Y 2019, 'Genome-wide association study of cervical cancer suggests a role for ARRDC3 gene in human papillomavirus infection', Human molecular genetics, vol. 28, no. 2, pp. 341-348. https://doi.org/10.1093/hmg/ddy390

Genome-wide association study of cervical cancer suggests a role for ARRDC3 gene in human papillomavirus infection. / Takeuchi, Fumihiko; Kukimoto, Iwao; Li, Zhiqiang; Li, Shuang; Li, Ni; Hu, Zhibin; Takahashi, Atsushi; Inoue, Shusaku; Yokoi, Sana; Chen, Jianhua; Hang, Dong; Kuroda, Makoto; Matsuda, Fumihiko; Mizuno, Mika; Mori, Seiichiro; Wu, Peng; Tanaka, Naotake; Matsuo, Keitaro; Kamatani, Yoichiro; Kubo, Michiaki; Ma, Ding; Shi, Yongyong.

In: Human molecular genetics, Vol. 28, No. 2, 15.01.2019, p. 341-348.

Research output: Contribution to journalArticle

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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

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.

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