HLA-DQB1*03 confers susceptibility to chronic hepatitis C in Japanese: A genome-wide association study

Daiki Miki, Hidenori Ochi, Atsushi Takahashi, C. Nelson Hayes, Yuji Urabe, Hiromi Abe, Tomokazu Kawaoka, Masataka Tsuge, Nobuhiko Hiraga, Michio Imamura, Yoshiiku Kawakami, Hiroshi Aikata, Shoichi Takahashi, Norio Akuta, Fumitaka Suzuki, Kenji Ikeda, Hiromitsu Kumada, Yoshiyasu Karino, Joji Toyota, Tatsuhiko TsunodaMichiaki Kubo, Naoyuki Kamatani, Yusuke Nakamura, Kazuaki Chayama

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Abstract

Hepatitis C virus (HCV) establishes a chronic infection in 70-80% of infected individuals. Many researchers have examined the effect of human leukocyte antigen (HLA) on viral persistence because of its critical role in the immune response against exposure to HCV, but almost all studies have proven to be inconclusive. To identify genetic risk factors for chronic HCV infection, we analyzed 458,207 single nucleotide polymorphisms (SNPs) in 481 chronic HCV patients and 2,963 controls in a Japanese cohort. Next, we performed a replication study with an independent panel of 4,358 cases and 1,114 controls. We further confirmed the association in 1,379 cases and 25,817 controls. In the GWAS phase, we found 17 SNPs that showed suggestive association (P < 1 × 10-5). After the first replication study, we found one intronic SNP in the HLA-DQ locus associated with chronic HCV infection, and when we combined the two studies, the association reached the level of genome-wide significance. In the second replication study, we again confirmed the association (Pcombined = 3.59 × 10-16, odds ratio [OR] = 0.79). Subsequent analysis revealed another SNP, rs1130380, with a stronger association (OR=0.72). This nucleotide substitution causes an amino acid substitution (R55P) in the HLA-DQB1 protein specific to the DQB1*03 allele, which is common worldwide. In addition, we confirmed an association with the previously reported IFNL3-IFNL4 locus and propose that the effect of DQB1*03 on HCV persistence might be affected by the IFNL4 polymorphism. Our findings suggest that a common amino acid substitution in HLA-DQB1 affects susceptibility to chronic infection with HCV in the Japanese population and may not be independent of the IFNL4 genotype.

Original languageEnglish
Article numbere84226
JournalPloS one
Volume8
Issue number12
DOIs
Publication statusPublished - 20-12-2013

Fingerprint

chronic hepatitis C
Hepatitis C virus
Genome-Wide Association Study
Chronic Hepatitis C
HLA Antigens
Viruses
Hepacivirus
Genes
Association reactions
Polymorphism
Nucleotides
single nucleotide polymorphism
Single Nucleotide Polymorphism
Substitution reactions
amino acid substitution
Virus Diseases
Amino Acid Substitution
infection
odds ratio
Odds Ratio

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Miki, D., Ochi, H., Takahashi, A., Hayes, C. N., Urabe, Y., Abe, H., ... Chayama, K. (2013). HLA-DQB1*03 confers susceptibility to chronic hepatitis C in Japanese: A genome-wide association study. PloS one, 8(12), [e84226]. https://doi.org/10.1371/journal.pone.0084226
Miki, Daiki ; Ochi, Hidenori ; Takahashi, Atsushi ; Hayes, C. Nelson ; Urabe, Yuji ; Abe, Hiromi ; Kawaoka, Tomokazu ; Tsuge, Masataka ; Hiraga, Nobuhiko ; Imamura, Michio ; Kawakami, Yoshiiku ; Aikata, Hiroshi ; Takahashi, Shoichi ; Akuta, Norio ; Suzuki, Fumitaka ; Ikeda, Kenji ; Kumada, Hiromitsu ; Karino, Yoshiyasu ; Toyota, Joji ; Tsunoda, Tatsuhiko ; Kubo, Michiaki ; Kamatani, Naoyuki ; Nakamura, Yusuke ; Chayama, Kazuaki. / HLA-DQB1*03 confers susceptibility to chronic hepatitis C in Japanese : A genome-wide association study. In: PloS one. 2013 ; Vol. 8, No. 12.
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abstract = "Hepatitis C virus (HCV) establishes a chronic infection in 70-80{\%} of infected individuals. Many researchers have examined the effect of human leukocyte antigen (HLA) on viral persistence because of its critical role in the immune response against exposure to HCV, but almost all studies have proven to be inconclusive. To identify genetic risk factors for chronic HCV infection, we analyzed 458,207 single nucleotide polymorphisms (SNPs) in 481 chronic HCV patients and 2,963 controls in a Japanese cohort. Next, we performed a replication study with an independent panel of 4,358 cases and 1,114 controls. We further confirmed the association in 1,379 cases and 25,817 controls. In the GWAS phase, we found 17 SNPs that showed suggestive association (P < 1 × 10-5). After the first replication study, we found one intronic SNP in the HLA-DQ locus associated with chronic HCV infection, and when we combined the two studies, the association reached the level of genome-wide significance. In the second replication study, we again confirmed the association (Pcombined = 3.59 × 10-16, odds ratio [OR] = 0.79). Subsequent analysis revealed another SNP, rs1130380, with a stronger association (OR=0.72). This nucleotide substitution causes an amino acid substitution (R55P) in the HLA-DQB1 protein specific to the DQB1*03 allele, which is common worldwide. In addition, we confirmed an association with the previously reported IFNL3-IFNL4 locus and propose that the effect of DQB1*03 on HCV persistence might be affected by the IFNL4 polymorphism. Our findings suggest that a common amino acid substitution in HLA-DQB1 affects susceptibility to chronic infection with HCV in the Japanese population and may not be independent of the IFNL4 genotype.",
author = "Daiki Miki and Hidenori Ochi and Atsushi Takahashi and Hayes, {C. Nelson} and Yuji Urabe and Hiromi Abe and Tomokazu Kawaoka and Masataka Tsuge and Nobuhiko Hiraga and Michio Imamura and Yoshiiku Kawakami and Hiroshi Aikata and Shoichi Takahashi and Norio Akuta and Fumitaka Suzuki and Kenji Ikeda and Hiromitsu Kumada and Yoshiyasu Karino and Joji Toyota and Tatsuhiko Tsunoda and Michiaki Kubo and Naoyuki Kamatani and Yusuke Nakamura and Kazuaki Chayama",
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Miki, D, Ochi, H, Takahashi, A, Hayes, CN, Urabe, Y, Abe, H, Kawaoka, T, Tsuge, M, Hiraga, N, Imamura, M, Kawakami, Y, Aikata, H, Takahashi, S, Akuta, N, Suzuki, F, Ikeda, K, Kumada, H, Karino, Y, Toyota, J, Tsunoda, T, Kubo, M, Kamatani, N, Nakamura, Y & Chayama, K 2013, 'HLA-DQB1*03 confers susceptibility to chronic hepatitis C in Japanese: A genome-wide association study', PloS one, vol. 8, no. 12, e84226. https://doi.org/10.1371/journal.pone.0084226

HLA-DQB1*03 confers susceptibility to chronic hepatitis C in Japanese : A genome-wide association study. / Miki, Daiki; Ochi, Hidenori; Takahashi, Atsushi; Hayes, C. Nelson; Urabe, Yuji; Abe, Hiromi; Kawaoka, Tomokazu; Tsuge, Masataka; Hiraga, Nobuhiko; Imamura, Michio; Kawakami, Yoshiiku; Aikata, Hiroshi; Takahashi, Shoichi; Akuta, Norio; Suzuki, Fumitaka; Ikeda, Kenji; Kumada, Hiromitsu; Karino, Yoshiyasu; Toyota, Joji; Tsunoda, Tatsuhiko; Kubo, Michiaki; Kamatani, Naoyuki; Nakamura, Yusuke; Chayama, Kazuaki.

In: PloS one, Vol. 8, No. 12, e84226, 20.12.2013.

Research output: Contribution to journalArticle

TY - JOUR

T1 - HLA-DQB1*03 confers susceptibility to chronic hepatitis C in Japanese

T2 - A genome-wide association study

AU - Miki, Daiki

AU - Ochi, Hidenori

AU - Takahashi, Atsushi

AU - Hayes, C. Nelson

AU - Urabe, Yuji

AU - Abe, Hiromi

AU - Kawaoka, Tomokazu

AU - Tsuge, Masataka

AU - Hiraga, Nobuhiko

AU - Imamura, Michio

AU - Kawakami, Yoshiiku

AU - Aikata, Hiroshi

AU - Takahashi, Shoichi

AU - Akuta, Norio

AU - Suzuki, Fumitaka

AU - Ikeda, Kenji

AU - Kumada, Hiromitsu

AU - Karino, Yoshiyasu

AU - Toyota, Joji

AU - Tsunoda, Tatsuhiko

AU - Kubo, Michiaki

AU - Kamatani, Naoyuki

AU - Nakamura, Yusuke

AU - Chayama, Kazuaki

PY - 2013/12/20

Y1 - 2013/12/20

N2 - Hepatitis C virus (HCV) establishes a chronic infection in 70-80% of infected individuals. Many researchers have examined the effect of human leukocyte antigen (HLA) on viral persistence because of its critical role in the immune response against exposure to HCV, but almost all studies have proven to be inconclusive. To identify genetic risk factors for chronic HCV infection, we analyzed 458,207 single nucleotide polymorphisms (SNPs) in 481 chronic HCV patients and 2,963 controls in a Japanese cohort. Next, we performed a replication study with an independent panel of 4,358 cases and 1,114 controls. We further confirmed the association in 1,379 cases and 25,817 controls. In the GWAS phase, we found 17 SNPs that showed suggestive association (P < 1 × 10-5). After the first replication study, we found one intronic SNP in the HLA-DQ locus associated with chronic HCV infection, and when we combined the two studies, the association reached the level of genome-wide significance. In the second replication study, we again confirmed the association (Pcombined = 3.59 × 10-16, odds ratio [OR] = 0.79). Subsequent analysis revealed another SNP, rs1130380, with a stronger association (OR=0.72). This nucleotide substitution causes an amino acid substitution (R55P) in the HLA-DQB1 protein specific to the DQB1*03 allele, which is common worldwide. In addition, we confirmed an association with the previously reported IFNL3-IFNL4 locus and propose that the effect of DQB1*03 on HCV persistence might be affected by the IFNL4 polymorphism. Our findings suggest that a common amino acid substitution in HLA-DQB1 affects susceptibility to chronic infection with HCV in the Japanese population and may not be independent of the IFNL4 genotype.

AB - Hepatitis C virus (HCV) establishes a chronic infection in 70-80% of infected individuals. Many researchers have examined the effect of human leukocyte antigen (HLA) on viral persistence because of its critical role in the immune response against exposure to HCV, but almost all studies have proven to be inconclusive. To identify genetic risk factors for chronic HCV infection, we analyzed 458,207 single nucleotide polymorphisms (SNPs) in 481 chronic HCV patients and 2,963 controls in a Japanese cohort. Next, we performed a replication study with an independent panel of 4,358 cases and 1,114 controls. We further confirmed the association in 1,379 cases and 25,817 controls. In the GWAS phase, we found 17 SNPs that showed suggestive association (P < 1 × 10-5). After the first replication study, we found one intronic SNP in the HLA-DQ locus associated with chronic HCV infection, and when we combined the two studies, the association reached the level of genome-wide significance. In the second replication study, we again confirmed the association (Pcombined = 3.59 × 10-16, odds ratio [OR] = 0.79). Subsequent analysis revealed another SNP, rs1130380, with a stronger association (OR=0.72). This nucleotide substitution causes an amino acid substitution (R55P) in the HLA-DQB1 protein specific to the DQB1*03 allele, which is common worldwide. In addition, we confirmed an association with the previously reported IFNL3-IFNL4 locus and propose that the effect of DQB1*03 on HCV persistence might be affected by the IFNL4 polymorphism. Our findings suggest that a common amino acid substitution in HLA-DQB1 affects susceptibility to chronic infection with HCV in the Japanese population and may not be independent of the IFNL4 genotype.

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