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
Laboratory for Digestive Diseases, Center for Integrative Medical Sciences, RIKEN, Hiroshima, Japan ; Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan ; Liver Research Project Center, Hiroshima University, Hiroshima, Japan.
Laboratory for Statistical Analysis, Center for Integrative Medical Sciences, RIKEN, Yokohama, Japan.
PLoS One. 2013 Dec 20;8(12):e84226. doi: 10.1371/journal.pone.0084226. eCollection 2013.
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 (P(combined) = 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 DQB103 allele, which is common worldwide. In addition, we confirmed an association with the previously reported IFNL3-IFNL4 locus and propose that the effect of DQB103 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.
丙型肝炎病毒（HCV）在70%-80%的感染者中会引发慢性感染。由于人类白细胞抗原（HLA）在针对HCV感染的免疫反应中起关键作用，许多研究人员已对其在病毒持续存在方面的影响进行了研究，但几乎所有研究都未得出明确结论。为了确定慢性HCV感染的遗传风险因素，我们在一个日本队列中分析了481例慢性HCV患者和2963名对照者的458207个单核苷酸多态性（SNP）。接下来，我们在一个由4358例病例和1114名对照者组成的独立样本中进行了重复研究。我们在1379例病例和25817名对照者中进一步证实了这种关联。在全基因组关联研究（GWAS）阶段，我们发现了17个显示出提示性关联的SNP（P < 1×10⁻⁵）。在首次重复研究后，我们发现HLA-DQ基因座中的一个内含子SNP与慢性HCV感染相关，当我们将两项研究的数据合并时，该关联达到了全基因组显著性水平。在第二次重复研究中，我们再次证实了这种关联（合并P值 = 3.59×10⁻¹⁶，比值比[OR] = 0.79）。后续分析揭示了另一个关联更强的SNP，rs1130380（OR = 0.72）。这种核苷酸替换导致了HLA-DQB1蛋白中特定于DQB103等位基因的氨基酸替换（R55P），该等位基因在全球范围内都很常见。此外，我们证实了与先前报道的IFNL3-IFNL4基因座的关联，并提出DQB103对HCV持续存在的影响可能受IFNL4多态性的影响。我们的研究结果表明，HLA-DQB1中一种常见的氨基酸替换会影响日本人群对慢性HCV感染的易感性，并且可能并非独立于IFNL4基因型。
