A Novel Variant Marking HLA-DP Expression Levels Predicts Recovery from Hepatitis B Virus Infection
A Novel Variant Marking HLA-DP Expression Levels Predicts Recovery from Hepatitis B Virus Infection
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DOI：
10.1128/jvi.00406-12
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发表时间：
2012-06-01
影响因子：
5.4
通讯作者：
Carrington, Mary
中科院分区：
文献类型：
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作者：
Thomas, Rasmi;Thio, Chloe L.;Carrington, Mary
在亚洲人中，人类白细胞抗原-DP基因附近的变异与慢性乙肝病毒感染和乙肝病毒的恢复/持续显示出最强的全基因组相关性。为了测试人类白细胞抗原-DP区对乙肝病毒感染结局的影响，我们测定了662名欧美和非裔美国人的人类白细胞抗原-DPB1和DPA1编码外显子的多态以及相应的3‘非翻译区(3’UTRs)。在我们的欧洲和非洲裔美国人样本中，人类白细胞抗原-DPB1基因3‘端非编码区变异(rs9277535；550A/G)与亚洲人的慢性乙肝和乙肝病毒感染的结局最显著相关的全基因组关联研究(Gwas)变异(rs9277535；550A/G)对我们的欧洲人和非裔美国人样本中的乙肝病毒恢复几乎没有影响(优势比[OR]=0.39，P=0.01，合并种族)。然而，我们在HLADPB1 3‘非编码区发现了一个新的变异，496A/G(Rs9277534)，它与欧洲人和非裔美国人的乙肝病毒恢复有非常显著的相关性(OR=0.37，P=0.0001，合并种族)。496A/G变异区分了最具保护性的等位基因(DPB1*04：01)和最易感的等位基因(DPB1*01：01)，而550A/G则不区分。在我们的欧美队列中，496A/G比任何一个单独的HLA-DPB1或DPA1等位基因以及任何其他与乙肝病毒恢复相关的等位基因都有更强的作用。在健康献血者中，496GG基因与人类白细胞抗原-DP表面蛋白和转录水平显著升高呈隐性相关，提示人类白细胞抗原-DP基因表达的差异可能会增加持续感染的风险。
Variants near the HLA-DP gene show the strongest genome-wide association with chronic hepatitis B virus (HBV) infection and HBV recovery/persistence in Asians. To test the effect of the HLA-DP region on outcomes to HBV infection, we sequenced the polymorphic HLA-DPB1 and DPA1 coding exons and the corresponding 3' untranslated regions (3'UTRs) in 662 individuals of European-American and African-American ancestry. The genome-wide association study (GWAS) variant (rs9277535; 550A/G) in the 3'UTR of the HLA-DPB1 gene that associated most significantly with chronic hepatitis B and outcomes to HBV infection in Asians had a marginal effect on HBV recovery in our European- and African-American samples (odds ratio [OR] = 0.39, P = 0.01, combined ethnic groups). However, we identified a novel variant in the HLA-DPB1 3'UTR region, 496A/G (rs9277534), which associated very significantly with HBV recovery in both European and African-American populations (OR = 0.37, P = 0.0001, combined ethnic groups). The 496A/G variant distinguishes the most protective HLA-DPBI allele (DPB1*04:01) from the most susceptible (DPB1*01:01), whereas 550A/G does not. 496A/G has a stronger effect than any individual HLA-DPB1 or DPA1 allele and any other HLA alleles that showed an association with HBV recovery in our European-American cohort. The 496GG genotype, which confers recessive susceptibility to HBV persistence, also associates in a recessive manner with significantly higher levels of HLA-DP surface protein and transcript level expression in healthy donors, suggesting that differences in expression of HLA-DP may increase the risk of persistent HBV infection.