Effects of genetic polymorphism in MHC, KIR, and related loci on human disease

MHC、KIR及相关位点遗传多态性对人类疾病的影响

• 批准号: 8552830
• 负责人: Mary N. Carrington
• 金额: $ 113.67万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8552830
• 关键词: 3' Untranslated Regions; Affect; African American; Alleles; American; Amino Acids; Antiviral Agents; Asians; Autoimmune Diseases; Binding; Biology; Blood; CD8B1 gene; Chronic Hepatitis B; Code; Collaborations; Commit; Communicable Diseases; Complex; Cytotoxic T-Lymphocytes; Data; Development; Disease; Disease Outcome; Effector Cell; Ethnic group; European; Evolution; Exons; Genes; Genetic; Genetic Determinism; Genetic Polymorphism; Genetic Variation; Genome; Genomics; Genotype; Goals; HIV; HIV-1; HLA Antigens; Hepatitis B Virus; Human; Immune; Immune Response Genes; Immune response; Immunoglobulin Variable Region; Immunoglobulins; In Vitro; Individual; Infection; Institutes; KIR3DS1; Killer Cells; Laboratories; Leukocytes; Ligands; Liver; Malignant - descriptor; Malignant Neoplasms; Mediating; Membrane Proteins; MicroRNAs; Molecular Genetics; NK cell receptor NKB1; Natural Killer Cells; Odds Ratio; Outcome; Pathogenesis; Patients; Peripheral; Play; Population; Predisposition; Proteins; Reagent; Receptor Gene; Recovery; Regulation; Reporting; Research Personnel; Resistance; Rewards; Risk; Role; Sampling; Site; Solid; T cell response; T-Lymphocyte; Testing; Transcript; Universities; Variant; Viral; Virus; Virus Diseases; Work; base; cohort; genetic association; genetic variant; genome wide association study; human disease; human leukocyte antigen gene; neutralizing antibody; novel; peripheral blood; pressure; receptor; therapeutic vaccine; trait; vector

The extensive variation at some of the immune response genes is central amongst the host genetic determinants that contribute to the variability in risk of virtually all human diseases. We have studied the genetic effects of the highly polymorphic KIR and HLA loci, as well as other related, less polymorphic loci on several diseases. Our contributions to the general understanding of these effects are summarized here.Several reports have pointed to variation in the human leukocyte antigen (HLA) class I and II genes as determinants of outcome after HBV infection. Recently the importance of HLA genes was further highlighted by the first genome-wide association study (GWAS) in Asian patients with chronic hepatitis B, where variants near the HLA-DP gene showed the strongest genome-wide association with chronic HBV infection and HBV recovery/persistence. 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 (3UTRs) in a cohort of 662 individuals of European-American and African-American ancestry. The GWAS variant (rs9277535; 550A/G) in the 3UTR of the HLA-DPB1 gene that associated most significantly with outcome to HBV infection in Asians had only a marginal effect on HBV recovery in the European- and African-American samples tested (odds ratio [OR] = 0.39, P = 0.01, combined ethnic groups). However, we identified a novel variant in the HLA-DPB1 3UTR 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). We further determined that the 496A/G variant distinguishes the most protective HLA-DPB1 allele (DPB1 04:01) from the most susceptible (DPB1 01:01), whereas 550A/G does not. 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. The results strongly implicate the 3UTR region of HLA-DP with HLA-DP expression and outcomes of HBV infection. However it will be necessary to determine the mechanism for varied expression of HLA-DP, which may involve regulation through differential microRNA activity as was previously shown for HLA-C by the group. If HLA-DP expression levels do indeed explain the association between HLA-DP and HBV disease pathogenesis, further work will be required to determine how varied expression of this molecule at the site of infection in the liver is affecting the immune response to HBV.There is marked intrinsic variation in the extent to which individuals are able to control HIV-1. Along with our collaborators from Duke University we identified a genetic copy number variable region (CNV) that plays a significant role in the control of HIV-1. This CNV is located in the genomic region that encodes the killer cell immunoglobulin-like receptors (KIRs) and specifically affects the KIR3DS1 and KIR3DL1 genes. Using both genetic association and functional evidence we demonstrated that increasing gene counts for KIR3DL1 confer increasing levels of protection against HIV-1, but only in the presence of at least one copy of KIR3DS1. This effect was associated with a dramatic increase in the abundance of KIR3DS1+ NK cells in the peripheral blood, and strongly associated with a more robust capacity of peripheral NK cells to suppress HIV-1 replication in vitro. This work provides one of the few examples of an association between a relatively common CNV and a human complex trait. There is strong evidence for selection pressure of CD8+ T cells on HIV sequence evolution over the course of infection. Following the peak in CD8+ T cell response the virus begins to show dramatic changes in sequence. It is now becoming apparent that NK cells can also mediate immune pressure on the virus in part via KIR-associated HIV-1 sequence polymorphisms. A collaborative effort with investigators from the Ragon Institute identified several amino acid polymorphisms within the HIV-1 sequence that were significantly associated with the presence of specific KIR genes. Functional analyses showed that polymorphisms in a region encoding the carboxy-terminal end of Vpu and the amino-terminal end of Env enhanced the binding of the inhibitory KIR2DL2 to HIV-1 infected targets, thereby reducing the antiviral activity of NK cells. These data demonstrate that KIR-positive NK cells can place immunological pressure on HIV-1, and that the virus can evade such NK-cell-mediated immune pressure by selecting for sequence polymorphisms, as has been described for virus-specific T cells and neutralizing antibodies. NK cells might therefore have a previously underappreciated role in contributing to viral evolution.Genetic diversity of immune response genes, such as HLA and KIR loci, holds promise for explaining, in large part, the variability in outcome to viral infection amongst exposed individuals. Understanding how this diversity influences the immune response presents new opportunities for development of effective therapeutics and vaccines, justifying close scrutiny of these genes in viral infections.

一些免疫反应基因的广泛变异是宿主遗传决定因素的核心，这些决定因素导致几乎所有人类疾病风险的变异。 我们已经研究了高度多态性的KIR和HLA基因座，以及其他相关的，多态性较少的基因座对几种疾病的遗传效应。 我们的贡献，这些影响的一般理解总结here.Several报告指出，在人类白细胞抗原（HLA）的I类和II类基因的变异作为HBV感染后的结果的决定因素。最近，在亚洲慢性B肝炎患者中进行的第一项全基因组关联研究（GWAS）进一步强调了HLA基因的重要性，其中HLA-DP基因附近的变异显示出与慢性HBV感染和HBV恢复/持续的最强全基因组关联。为了测试HLA-DP区域对HBV感染结果的影响，我们对662名欧洲裔美国人和非洲裔美国人的多态性HLA-DPB 1和DPA 1编码外显子和相应的3个非翻译区（3UTR）进行了测序。与亚洲人HBV感染结果最显著相关的HLA-DPB 1基因3UTR中的GWAS变异（rs 9277535; 550 A/G）在欧洲和非洲裔美国人样本中对HBV恢复的影响很小（比值比[OR] = 0.39，P = 0.01，合并种族组）。然而，我们在HLA-DPB 1 3UTR区域发现了一种新的变异，496 A/G（rs 9277534），它与欧洲和非洲裔美国人人群中的HBV恢复非常显著相关（OR = 0.37，P = 0.0001，合并种族组）。我们进一步确定，496 A/G变异区分了最具保护性的HLA-DPB 1等位基因（DPB 1 04：01）和最易感的等位基因（DPB 1 01：01），而550 A/G则没有。496 GG基因型，这赋予隐性易感性HBV的持久性，也与隐性的方式显着较高水平的HLA-DP表面蛋白和转录水平的表达在健康的捐助者，这表明，在表达的差异HLA-DP可能会增加持续性HBV感染的风险。结果表明，HLA-DP的3UTR区域与HLA-DP的表达和HBV感染的结局密切相关。然而，有必要确定HLA-DP不同表达的机制，这可能涉及通过差异microRNA活性的调节，如该小组先前对HLA-C所示。如果HLA-DP表达水平确实解释了HLA-DP和HBV疾病发病机制之间的关联，则需要进一步的工作来确定这种分子在肝脏感染部位的不同表达如何影响对HBV的免疫应答。个体能够控制HIV-1的程度存在明显的内在差异。我们与杜克大学的合作者沿着鉴定了一个基因拷贝数可变区（CNV），它在HIV-1的控制中起着重要作用。这种CNV位于编码杀伤细胞免疫球蛋白样受体（KIR）的基因组区域，并特异性影响KIR 3DS 1和KIR 3DL 1基因。使用遗传关联和功能证据，我们证明了增加KIR 3DL 1的基因计数可以提高对HIV-1的保护水平，但仅在至少一个KIR 3DS 1拷贝存在的情况下。这种效应与外周血中KIR 3DS 1 + NK细胞丰度的急剧增加有关，并且与外周NK细胞在体外抑制HIV-1复制的能力更强密切相关。这项工作提供了一个相对常见的CNV和人类复杂性状之间的关联的少数例子之一。有强有力的证据表明，在感染过程中，CD 8 + T细胞对HIV序列进化的选择压力。在CD 8 + T细胞应答的峰值之后，病毒开始显示序列的显著变化。现在越来越明显的是，NK细胞也可以部分通过KIR相关的HIV-1序列多态性介导对病毒的免疫压力。 与Ragon研究所的研究人员合作，确定了HIV-1序列中与特定KIR基因存在显著相关的几种氨基酸多态性。 功能分析表明，在编码Vpu的羧基末端和Env的氨基末端的区域中的多态性增强了抑制性KIR 2DL 2与HIV-1感染的靶标的结合，从而降低了NK细胞的抗病毒活性。这些数据表明，KIR阳性NK细胞可以对HIV-1施加免疫压力，并且病毒可以通过选择序列多态性来逃避这种NK细胞介导的免疫压力，如已经描述的病毒特异性T细胞和中和抗体。因此，NK细胞可能有一个以前低估的作用，在促进病毒evolution.Genetic多样性的免疫反应基因，如HLA和KIR基因座，持有承诺解释，在很大程度上，暴露的个人之间的变异性，结果病毒感染。了解这种多样性如何影响免疫反应，为开发有效的治疗方法和疫苗提供了新的机会，证明了对病毒感染中这些基因的密切关注。