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 language | English |
|---|---|
| Article number | e84226 |
| Journal | PloS one |
| Volume | 8 |
| Issue number | 12 |
| DOIs | |
| Publication status | Published - 20-12-2013 |
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All Science Journal Classification (ASJC) codes
- Biochemistry, Genetics and Molecular Biology(all)
- Agricultural and Biological Sciences(all)
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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 journal › Article
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.
UR - http://www.scopus.com/inward/record.url?scp=84893472976&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84893472976&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0084226
DO - 10.1371/journal.pone.0084226
M3 - Article
C2 - 24376798
AN - SCOPUS:84893472976
VL - 8
JO - PLoS One
JF - PLoS One
SN - 1932-6203
IS - 12
M1 - e84226
ER -