Identification of Gene Polymorphisms Associated with Infectious Diseases

与传染病相关的基因多态性的鉴定

• 批准号: 8348964
• 负责人: Cheryl Winkler
• 金额: $ 44.59万
• 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/8348964
• 关键词: 3p21; AIDS-Associated Nephropathy; Acquired Immunodeficiency Syndrome; Affect; Africa; African; African American; African Trypanosomiasis; Alleles; Amino Acids; Antiviral Agents; Asians; Attention; Base Pairing; Biological; CC chemokine receptor 7; CCR5 gene; CCR8 gene; CCRL2 gene; CX3CL1 gene; CXCR6 gene; Cancer Etiology; Carcinoma; Case-Control Studies; Chemokine Receptor Gene; China; Chronic; Chronic Hepatitis B; Cirrhosis; Clinical; Codon Nucleotides; Cohort Studies; Collaborations; Communicable Diseases; Complication; DNA Resequencing; Dendritic Cells; Development; Diagnosis; Disease; Disease Outcome; Epidemic; Gap Junctions; Genes; Genetic; Genetic Polymorphism; Genetic Screening; Genetic Variation; Genetic screening method; Genotype; Goals; HIV; HIV-1; HLA-DP Antigens; Hepatitis B; Hepatitis B Virus; Hepatitis C virus; Herpesviridae; High Prevalence; Human; Human Herpesvirus 4; Immune; Immunosuppression; Incidence; Individual; Infection; Inflammation; International; Journals; Kaposi Sarcoma; Kidney; Kidney Diseases; Kidney Glomerulus; Laboratories; Lead; Lung; Lymphoma; Malignant Neoplasms; Medicine; Methods; Minor; Nasopharynx Carcinoma; Natural History; Natural Immunity; Non-Small-Cell Lung Carcinoma; Nose; Outcome; Pathway interactions; Persons; Pharyngeal Carcinoma; Phenotype; Pneumocystis carinii Pneumonia; Population; Predisposition; Preventive; Primary carcinoma of the liver cells; Progressive Disease; Proteins; Publishing; Regulation; Resistance; Resistance to infection; Risk; Role; Sampling; Scanning; Screening procedure; Single Nucleotide Polymorphism; Smoking; Therapeutic; Therapeutic Intervention; Time; Vaccines; Variant; Viral; Virus; Virus Diseases; acquired immunity; antiretroviral therapy; base; cancer risk; carcinogenesis; chemokine receptor; clinically relevant; cohort; drug development; genetic association; genome wide association study; genome-wide; global health; health disparity; high risk; improved; insight; male; mutation carrier; non-diabetic; novel therapeutics; outcome forecast; response; trafficking; trait; virus pathogenesis

Our objectives are to identify genetic factors contributing to infectious diseases with the goals of identifying targets for drug development and improving diagnosis/prognosis. Infections are major causes of cancers: HIV, EBV, or the hepatitis C virus (HCV) and hepatitis B virus (HBV) contribute to AIDS-associated malignancies, nasopharyngeal carcinoma (NPC) and hepatocelluar carcinoma (HCC), respectively. Little is understood about the interplay between chronic infection and genetic variation leading to pathogenic outcomes including cancer in persons infected with these viruses. Both HCV and HIV have no preventive vaccines or no curative treatment and are highly prevalent in the global population. We focused on genetic factors associated with susceptibility/resistance to HIV-1, HCV, and HBV infections and disease outcomes. International collaborations for case-control and cohort studies in China and Africa, in addition to five U.S.-based HIV-1 longitudinal cohorts, have been developed to investigate HIV-1, HBV, and HCV as well as NPC and HCC. Both targeted and genome-wide association studies (GWAS), have been used to discover variation associated with viral infections and their outcomes. These studies explain in part the variance observed among individuals in viral infection, progression, and disease outcomes. In addition, we will gain insights of the contribution of genetic variation to disparate incidence rates for infectious diseases and their outcomes (e.g. HIV-associated nephropathy or NPC) among diverse human populations. These studies provide insights into biological pathways that may lead to new therapeutics or genetic testing to improve clinical outcomes. Accomplishments 1) Association of HLA-DP with HBV clearance: Chronic HBV infection is extremely common in China, a region with the worlds highest prevalence rates for chronic hepatitis B and HBV-associated hepatocellular carcinoma (HCC). A recent GWAS performed in Asian populations on Asian samples securely identified a single nucleotide polymorphism (rs3077) in the HLA-DP region as associated with decreased risk of chronic HBV infection. It was not determined if the association with chronic hepatitis B was due to resistance to infection or increased rate of spontaneous viral clearance. We showed for the first time that the HLA-DB region was specifically associated with a 2.4-fold increase in spontaneous HBV clearance, but that it was not associated with increased risk of cirrhosis or HCC. Elucidation of the mechanism of HLA-DP interaction with HBV will be a critical step in our understanding of immune regulation of HBV infection, clearance, and vaccine response and may lead to targeted epidemic control strategies. It may also provide needed insights into the development of an effective vaccine to induce clearance in persons with chronic hepatitis B. The results of this study were published in Journal of Infectious Diseases. 2) Association of CCRL2 with AIDS and Pneumocystis pneumonia (PCP): PCP is a major AIDS defining condition and a common complication of immunosuppression. Chr 3p21-22 harbors two clusters of chemokine receptor genes, several of which serve as major or minor coreceptors of HIV-1. We resequenced 7 chemokine receptors in 144 individuals representing extreme phenotypes for HIV progression and infection; six codon-changing SNPs were discovered. Both non-synonymous and synonymous SNPs were genotyped in CCR5, CCR2, CCR3, CCRL2, CXCR6, CCR8 and CX3CR1 in HIV-1/AIDS natural history cohorts. We identified a non-conservative amino acid change in CCRL2 (Y167F) associated with more rapid progression to AIDS defining conditions, and specifically to the AIDS defining condition pneumocystis pneumonia (PCP). CCRL2 is involved in lung dendritic cell trafficking and may affect PCP by inducing inflammation. This is the first genetic association with an AIDS defining condition and brings renewed attention to the chemokine receptor nexus in HIV pathogenesis. Highlighting the role of inflammation may lead to better therapeutic options for persons presenting with PCP infection. 3) GWAS for HIV Infection and progression: GWA studies are an agnostic, unbiased method for detecting genetic factors associated with disease and traits with the overarching goals of revealing new pathways and targets for therapeutic intervention and for disease prediction. Our laboratory has participated in several GWAS for different HIV phenotypes including long-term non-progression, HIV infection susceptibility, and rate of progression to AIDS. GWAS studies scan hundreds of thousands of SNPS for association with a disease or trait; therefore, rigorous criteria for genome wide significance (by convention, p450). The results of this study have clinical relevance in genetic screening to identify persons at risk for developing NPC. 5) Association of APOL1 variants with HIV-associated nephropathy (HIVAN): HIVAN is a rapidly progressive disease affecting the kidney glomerulus. HIVAN is extremely common affecting approximately 10% of African Americans prior to effective antiretroviral therapies; HIVAN is rarely diagnosed in persons of non-African origin. Two APOL1 variant alleles, one comprising two codon-changing SNPs and the other a 6 base pair deletion removing two amino acids are found in 35% of African Americans; these variants are also extremely frequent in west African populations, presumably driven by survival advantage in APOL1 mutation carriers, which confers resistance to African sleeping sickness. Carriers of two APOL1 risk alleles (approximately 13-15% of African Americans) are at a much higher risk of several forms of non-diabetic kidney disease. In a highly collaborative study we showed that carriage of two APOL1 renal risk alleles increase the risk by 40-fold; the lifetime incidence for HIVAN among HIV-infected African Americans carrying two APOL1 variants is 50%. The attributable risk (AR) (68%) and explained fraction (EF) (37%) for APOL1 variants with HIVAN are quantitatively similar to the role of smoking in non-small-cell lung cancer risk (AR, 90% for males; EF, 12%). This study suggests that screening for APOL1 risk variants may have a role in personalized medicine for persons with African ancestry; it also explains a major global health disparity.

我们的目标是确定导致传染病的遗传因素，从而确定药物开发的目标并改善诊断/预后。感染是癌症的主要原因：HIV、EBV 或丙型肝炎病毒 (HCV) 和乙型肝炎病毒 (HBV) 分别导致与艾滋病相关的恶性肿瘤、鼻咽癌 (NPC) 和肝细胞癌 (HCC)。人们对慢性感染和导致感染这些病毒的人罹患癌症等致病结果的遗传变异之间的相互作用知之甚少。 HCV 和 HIV 都没有预防性疫苗或治疗方法，并且在全球人群中非常流行。 我们重点关注与 HIV-1、HCV 和 HBV 感染的易感性/耐药性以及疾病结果相关的遗传因素。除了美国的五个 HIV-1 纵向队列之外，还开展了中国和非洲病例对照和队列研究的国际合作，以研究 HIV-1、HBV 和 HCV 以及 NPC 和 HCC。靶向研究和全基因组关联研究 (GWAS) 均已用于发现与病毒感染及其结果相关的变异。 这些研究部分解释了个体之间在病毒感染、进展和疾病结果方面观察到的差异。此外，我们还将了解遗传变异对不同人群中传染病及其结果（例如 HIV 相关肾病或 NPC）不同发病率的影响。这些研究提供了对生物学途径的见解，可能会导致新的治疗方法或基因测试以改善临床结果。成就 1) HLA-DP与HBV清除的关联：慢性HBV感染在中国极为常见，是世界上慢性乙型肝炎和HBV相关肝细胞癌(HCC)患病率最高的地区。最近在亚洲人群中对亚洲样本进行的 GWAS 安全鉴定了 HLA-DP 区域的单核苷酸多态性 (rs3077)，该多态性与慢性 HBV 感染风险降低相关。目前尚不清楚与慢性乙型肝炎的相关性是否是由于对感染的抵抗力或自发病毒清除率的增加。我们首次证明 HLA-DB 区域与自发 HBV 清除率增加 2.4 倍特别相关，但与肝硬化或 HCC 风险增加无关。阐明 HLA-DP 与 HBV 相互作用的机制将是我们了解 HBV 感染、清除和疫苗反应的免疫调节的关键一步，并可能导致有针对性的流行病控制策略。它还可能为开发有效疫苗以诱导慢性乙型肝炎患者清除提供所需的见解。这项研究的结果发表在《传染病杂志》上。 2) CCRL2与艾滋病和肺孢子菌肺炎(PCP)的关联：PCP是艾滋病的主要定义病症，也是免疫抑制的常见并发症。 Chr 3p21-22 包含两个趋化因子受体基因簇，其中几个作为 HIV-1 的主要或次要辅助受体。我们对 144 名代表 HIV 进展和感染极端表型的个体的 7 种趋化因子受体进行了重新测序；发现了 6 个密码子改变的 SNP。在 HIV-1/AIDS 自然史队列的 CCR5、CCR2、CCR3、CCRL2、CXCR6、CCR8 和 CX3CR1 中对非同义和同义 SNP 进行了基因分型。我们发现 CCRL2 (Y167F) 中的非保守氨基酸变化与更快进展为 AIDS 定义条件，特别是与 AIDS 定义条件肺孢子虫肺炎 (PCP) 相关。 CCRL2 参与肺树突状细胞运输，并可能通过诱导炎症影响 PCP。这是第一个与艾滋病定义病症的遗传关联，并重新引起人们对艾滋病毒发病机制中趋化因子受体关系的关注。强调炎症的作用可能会为 PCP 感染患者带来更好的治疗选择。 3) HIV 感染和进展的 GWAS：GWA 研究是一种不可知、公正的方法，用于检测与疾病和性状相关的遗传因素，其总体目标是揭示治疗干预和疾病预测的新途径和目标。我们的实验室参与了多个针对不同 HIV 表型的 GWAS，包括长期无进展、HIV 感染易感性和艾滋病进展率。 GWAS 研究扫描了数十万个 SNPS，以查找与疾病或性状的关联；因此，对全基因组意义有严格的标准（按照惯例，p450）。这项研究的结果对于识别有患鼻咽癌风险的人群的基因筛查具有临床意义。 5) APOL1 变异与 HIV 相关肾病 (HIVAN) 的关联：HIVAN 是一种影响肾小球的快速进展性疾病。在接受有效的抗逆转录病毒治疗之前，HIVAN 极为常见，约 10% 的非洲裔美国人受到感染；非非洲血统的人很少被诊断出 HIVAN。在 35% 的非裔美国人中发现了两个 APOL1 变异等位基因，一个包含两个密码子改变的 SNP，另一个包含删除两个氨基酸的 6 个碱基对缺失；这些变异在西非人群中也极为常见，这可能是由于 APOL1 突变携带者的生存优势所致，这赋予了对非洲昏睡病的抵抗力。两个 APOL1 风险等位基因的携带者（约占非洲裔美国人的 13-15%）患多种非糖尿病肾病的风险要高得多。在一项高度合作的研究中，我们发现携带两个 APOL1 肾脏风险等位基因会使风险增加 40 倍；在携带两种 APOL1 变体的 HIV 感染非裔美国人中，HIVAN 的终生发病率为 50%。 HIVAN 的 APOL1 变异的归因风险 (AR) (68%) 和解释分数 (EF) (37%) 在数量上与吸烟在非小细胞肺癌风险中的作用相似（AR，男性为 90%；EF，12%）。这项研究表明，APOL1 风险变异的筛查可能在非洲血统的个体化医疗中发挥作用；它还解释了全球健康状况的重大差异。