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，以确定药物开发和改善诊断/预后的目标。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）。对于慢性感染和导致致病性结果的遗传变异之间的相互作用，包括感染这些病毒的人的癌症，人们知之甚少。丙型肝炎病毒和艾滋病毒都没有预防性疫苗或治疗方法，在全球人口中高度流行。我们关注与HIV-1、HCV和HBV感染易感性/耐药性和疾病结局相关的遗传因素。在中国和非洲开展病例对照和队列研究的国际合作，以及在美国开展的5个HIV-1纵向队列研究，研究HIV-1、HBV、HCV以及NPC和HCC。靶向和全基因组关联研究（GWAS）已被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、进展和疾病结局方面观察到的差异。此外，我们将深入了解遗传变异对不同人群中不同传染病发病率及其结果（例如hiv相关肾病或NPC）的贡献。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检测，以改善临床结果。1) HLA-DP与HBV清除率的关系：慢性HBV感染在中国非常普遍，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安全鉴定出HLA-DP区域的单核苷酸多态性（rs3077）与慢性HBV感染风险降低相关。目前还不确定与慢性乙型肝炎的关联是由于对感染的抵抗力还是由于自发病毒清除率的增加。我们首次发现，HLA-DB区域与自发HBV清除率增加2.4倍特异性相关，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理解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。该研究结果发表在《感染性疾病杂志》上。2)CCRL2与艾滋病和肺囊虫肺炎（PCP）的关联：PCP是艾滋病的主要定义条件，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个个体中的7种趋化因子受体进行了重测序，这些个体代表了HIV进展和感染的极端表型；发现了6个改变密码子的snp。非同义snp和同义snp均在HIV-1/AIDS自然病史队列中的CCR5、CCR2、CCR3、CCRL2、CXCR6、CCR8和CX3CR1中进行基因分型。我们在CCRL2 （Y167F）中发现了一个非保守性氨基酸变化，该变化与更快地发展为艾滋病定义条件，特别是艾滋病定义条件肺囊虫性肺炎（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条件的遗传关联，并使人们重新关注趋化因子受体在HIV发病机制中的关系。强调炎症的作用可能会为PCP感染患者提供更好的治疗选择。3) GWAS用于HIV感染和进展：GWA研究是一种不可知性、无偏倚的方法，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靶点。我们实验室参与了几项针对不同HIV表型的GWAS，包括长期不进展、HIV感染易感性和进展为艾滋病的比率。GWAS研究扫描与疾病或特征相关的数十万个SNPS；因此，基因组广泛意义的严格标准（按惯例，第450页）。本研究的结果在基因筛查中具有临床相关性，以确定有发展为鼻咽癌风险的人。5) APOL1变异与hiv相关性肾病（HIVAN）的关联：HIVAN是一种影响肾小球的快速进展性疾病。艾滋病毒感染极为普遍，在接受有效的抗逆转录病毒治疗之前，约有10%的非洲裔美国人感染艾滋病毒；非非洲血统的人很少被诊断出艾滋病毒。在35%的非裔美国人中发现了两个APOL1变异等位基因，一个包含两个改变密码子的snp，另一个包含6个碱基对的缺失，删除了两个氨基酸；这些变异在西非人群中也非常常见，可能是由APOL1突变携带者的生存优势所驱动的，这赋予了对非洲昏睡病的抵抗力。携带两个APOL1风险等位基因的人（约占非裔美国人的13-15%）患几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；携带两种APOL1变异的hiv感染非洲裔美国人的终生hiv发病率为50%。携带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（男性AR， 90%； EF, 12%）。这项研究表明，筛选APOL1风险变异可能在非洲血统的人的个性化医疗中发挥作用；这也解释了全球健康状况的巨大差异。