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: 8552655
• 负责人: Cheryl Winkler
• 金额: $ 51.13万
• 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/8552655
• 关键词: 3p21; AIDS-Associated Nephropathy; Acquired Immunodeficiency Syndrome; Affect; African; African American; African Trypanosomiasis; Age; Aging; Alleles; American; Amino Acids; Antiviral Agents; Attention; Base Pairing; Biopsy; CC chemokine receptor 7; CCR; CCRL2 gene; CD4 Positive T Lymphocytes; Cancer Etiology; Cessation of life; Characteristics; Chemokine Receptor Gene; Chromosomes; Chronic; Clinical; Codon Nucleotides; Collaborations; Communicable Diseases; Complication; Computer software; DNA Resequencing; Data; Dendritic Cells; Development; Disease; Drug toxicity; Elderly; End stage renal failure; Enrollment; Epidemiology; Epigenetic Process; Eye diseases; Functional disorder; Gap Junctions; Gene Expression Profile; Genes; Genetic; Genetic Polymorphism; Genetic Risk; Genetic Variation; Genome; Genotype; Glomerular Filtration Rate; Goals; HIV; HIV-1; Haplotypes; Hepatitis B; Hepatitis B Virus; Hepatitis C virus; Herpesviridae; Human; Human Herpesvirus 4; Immunosuppression; Incidence; Individual; Infection; Inflammation; Inflammatory; International; Journals; Kaposi Sarcoma; Kidney; Kidney Diseases; Laboratories; Lead; Linear Regressions; Longitudinal Studies; Lung; Lymphoma; Malignant Neoplasms; Medicine; Meta-Analysis; Methods; Minor; Nasopharynx Carcinoma; Natural History; Natural Immunity; Nephrology; Non-Small-Cell Lung Carcinoma; Nose; Other Genetics; Outcome; Participant; Pathogenesis; Pathway Analysis; Pathway interactions; Patients; Persons; Pharyngeal Carcinoma; Phenotype; Pneumocystis carinii Pneumonia; Population; Predisposition; Primary carcinoma of the liver cells; Process; Proteins; Publications; Publishing; Quality Control; Renal function; Resistance; Risk; Role; Screening procedure; Smoking; Societies; Structure; System; Testing; Therapeutic; Time; Vaccines; Variant; Viral; Viral Load result; Virus; Virus Diseases; acquired immunity; antiretroviral therapy; base; body system; cancer risk; carcinogenesis; chemokine; chemokine receptor; cohort; disease phenotype; follow-up; genetic association; genome wide association study; genome-wide; glomerular filtration; high risk; immune activation; insight; lifetime risk; male; mutation carrier; non-diabetic; programs; symposium; trafficking; trait; virus pathogenesis

The goal of this project is to identify genetic and epigenetic factors contributing to human infectious diseases. HIV, EBV, and the hepatitis C virus (HCV) and hepatitis B virus (HBV) contribute to AIDS-associated malignancies, nasopharyngeal carcinoma (NPC) and hepatocellular carcinoma (HCC), respectively. Little is understood about the interplay between chronic viral infection and host genetic variation leading to pathogenic outcomes in persons infected with these viruses. Genome wide association studies (GWAS) have revealed that HLA class I alleles are most strongly associated with HBV clearance, HIV control of viral load, and with NPC. However, HLA explains only a small fraction of the variance for these infections and cancers. In addition, with advancing age of the HIV-infected population, diseases commonly associated with aging and affecting all organ systems are appearing at younger ages. We are embarking on genetic association studies to identify correlates of eye disease in the Longitudinal Study of Ocular Complications with AIDS (LSOCA) and of HIV-associated non-AIDS serious diseases in longitudinal natural and treated cohorts. Our laboratory is moving to integrate epigenetic signatures, gene expression, and results of GWAS and pathway analysis in a systems-based approach to further define genes and pathways important in the pathophysiology and carcinogenesis of infectious diseases.Accomplishments1. Pneumocystis pneumonia (PCP) is a major AIDS-defining condition and a common complication of immunosuppression. Chromosome 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. 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 PCP. CCRL2 is involved in lung dendritic cell trafficking and may affect PCP by inducing inflammation. This is the first genetic association with a major AIDS defining condition and brings renewed attention to the chemokine-chemokine receptor nexus in HIV pathogenesis. Highlighting the role of inflammation may lead to better therapeutic options for persons presenting with PCP infection. The results of this study were published in PLoS Genetics.2. GWAS is an agnostic, unbiased method for detecting genetic factors associated with disease and traits. Because of the large number of tests, rigorous criteria for genome wide significance (by convention, p<5 x 10-8) and independent replication are critical to avoid false positive associations. Since the number of persons with longitudinal clinical and laboratory data for infectious diseases is generally limited, the discovery of genetic factors associated with infectious disease phenotypes is problematic. To overcome this barrier, we have joined forces with the International HIV Consortium to contribute genotype-phenotypes from over 1000 HIV-infected participants with longitudinal follow-up for a meta-analysis. We are also part of the analytical team for viral load and CD4 T cell trajectories for this international collaboration.We are currently in the process of rigorous quality control (QC) for the genotype calls for three previous CCR GWAS for HBV and HIV clinical outcomes and for NPC. Using the ISHAPE software, we have determined the haplotype structure of participants enrolled in the NPC, HIV, and HBV studies with GWAS data. The next step will be to impute SNPs not represented on the Affymetric chip using data from the International HapMap Program and the 1000 Genome Project representing the major continental populations. With the enriched SNPs, we will reanalyze the data for association with multiple phenotypes using the 5 natural history cohorts and the LSOCA cohort, including HIV-associated non-AIDS and AIDS clinical outcomes.As mentioned above, a hindrance to the identification of host variants influencing HIV acquisition and pathogenesis is a lack of power to identify small effect size host variants. 3) The lifetime risk for African Americans for HIV-associated nephropathy is approximately 10% prior to widespread use of effective antiretroviral therapies. 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. We showed that 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, published in the Journal of American Society of Nephrology, suggests that screening for APOL1 risk variants may have a role in personalized medicine for persons with African ancestry and HIV infection. 4. To determine if APOL1 variants drive distinctive pathological characteristics, we genotyped 60 patients with biopsy-proven HIVAN. In this group, 37 had two risk alleles, 18 were heterozygous, and 5 had neither risk variant. There were no differences in the pathological findings of HIVAN and the number of APOL1 risk alleles. Further, the progression to end-stage kidney disease or death did not differ by the number of risk alleles. Median renal survival was 9.3 months in patients with zero or one risk allele compared to 11.7 months in patients with two APOL1 risk alleles. Our study suggests that although the majority of African-American patients with HIVAN have two APOL1 risk alleles other as yet unknown factors, including other genetic risk variants or environmental or viral factors, may influence the development of this disorder in those with zero or one APOL1 risk allele. This study was published in Kidney International.5. APOL1 variants are associated with reduced estimated glomerular filtration in treated HIV-infected persons. The epidemiology of HIV kidney disease has changed over time. In the pre-cART era, HIVAN was prominent, but in the post-cART era, HIVAN has waned but kidney disease still remains a major complication due in part to drug toxicities, immune activation, and chronic inflammatory state. We hypothesized that APOL1/ MYH9 risk alleles could be associated with decreased kidney function in HIV-infected subjects with African ancestry. HIV-infected persons with African ancestry from the SMART cohort were genotyped for APOL1 (G1 and G2 variants) and MYH9 (4 intronic SNPs composing the E1 haplotype) risk variants. Kidney function using estimates of glomerular filtration rates (eGFR), was evaluated at baseline and during a 60 month follow-up using linear regression and linear mixed effects regression, respectively. APOL1 risk alleles were strongly associated with decreased eGFR at baseline (P=3x10-8); MYH9 renal risk alleles were independently associated with eGFR; APOL1 and MYH9 risk alleles remained persistently associated with lower eGFR during follow-up. The results of this study were presented at the CROI conference and are being formalized for publication.

该项目的目标是确定导致人类传染病的遗传和表观遗传因素。HIV、EBV、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）。对于慢性病毒感染与宿主遗传变异之间的相互作用，导致感染这些病毒的人的致病性结果，人们知之甚少。全基因组关联研究（GWAS）表明，HLA I类等位基因与HBV清除、HIV病毒载量控制和鼻咽癌相关性最强。然而，HLA只能解释这些感染和癌症的一小部分差异。此外，随着艾滋病毒感染者年龄的增长，通常与衰老有关并影响所有器官系统的疾病出现在更年轻的年龄。我们正在开展遗传关联研究，以确定艾滋病眼部并发症纵向研究（LSOCA）和艾滋病毒相关的非艾滋病严重疾病在纵向自然和治疗队列中的相关性。我们的实验室正在整合表观遗传特征、基因表达、GWAS结果和通路分析，以系统为基础的方法进一步定义在传染病病理生理和致癌发生中重要的基因和通路。肺囊虫性肺炎（PCP）是艾滋病的主要定义条件和免疫抑制的常见并发症。染色体3p21-22包含两个趋化因子受体基因簇，其中一些作为HIV-1的主要或次要的辅助受体。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。我们在CCRL2 （Y167F）中发现了一种非保守的氨基酸变化，这种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主要定义条件的遗传关联，并使人们重新关注趋化因子-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。这项研究的结果发表在《公共科学图书馆遗传学》杂志上。GWAS是一种不可知论的、无偏倚的方法，用于检测与疾病和性状相关的遗传因素。由于大量的测试，严格的全基因组显著性标准（按照惯例，p<5 × 10-8）和独立复制对于避免假阳性关联至关重要。由于拥有传染病纵向临床和实验室数据的人数通常有限，发现与传染病表型相关的遗传因素是有问题的。为了克服这一障碍，我们与国际艾滋病毒联盟合作，对1000多名艾滋病毒感染参与者的基因型-表型进行了纵向随访，以进行荟萃分析。我们也是这次国际合作的病毒载量和CD4 T细胞轨迹分析团队的一员。我们目前正在对基因型的要求进行严格的质量控制（QC），包括针对HBV和HIV临床结果以及针对NPC的三个先前的CCR GWAS。使用ISHAPE软件，我们用GWAS数据确定了参加NPC、HIV和HBV研究的参与者的单倍型结构。下一步将是利用来自国际HapMap计划和1000基因组计划的数据，计算Affymetric芯片上没有显示的snp，这些数据代表了主要的大陆种群。有了富集的snp，我们将使用5个自然史队列和LSOCA队列重新分析与多种表型的关联数据，包括hiv相关的非艾滋病和艾滋病临床结果。如上所述，识别影响HIV获得和发病机制的宿主变异的一个障碍是缺乏识别小效应大小宿主变异的能力。3)在广泛使用有效的抗逆转录病毒疗法之前，非洲裔美国人患hiv相关肾病的终生风险约为10%。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。我们发现，携带两种APOL1变异的hiv感染的非洲裔美国人一生中hiv的发病率为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%）。这项发表在《美国肾脏病学会杂志》上的研究表明，对APOL1风险变异的筛查可能在非洲血统和HIV感染的人的个性化医疗中发挥作用。4. 为了确定APOL1变异是否驱动独特的病理特征，我们对60例活检证实的hiv患者进行了基因分型。在这一组中，37人有两个危险等位基因，18人是杂合的，5人没有危险变异。两组HIVAN病理表现及APOL1危险等位基因数量无差异。此外，进展到终末期肾脏疾病或死亡的风险等位基因的数量没有差异。0或1个风险等位基因患者的中位肾生存期为9.3个月，而2个APOL1风险等位基因患者的中位肾生存期为11.7个月。我们的研究表明，尽管大多数非洲裔美国hiv患者有两个APOL1风险等位基因，但其他未知因素，包括其他遗传风险变异或环境或病毒因素，可能会影响那些没有或只有一个APOL1风险等位基因的患者的病情发展。这项研究发表在《肾脏国际》杂志上。在接受治疗的hiv感染者中，APOL1变异与估计肾小球滤过率降低有关。随着时间的推移，HIV肾病的流行病学发生了变化。在cart之前的时代，HIVAN是突出的，但在后cart时代，HIVAN已经减弱，但肾脏疾病仍然是一个主要的并发症，部分原因是药物毒性、免疫激活和慢性炎症状态。我们假设APOL1/ MYH9风险等位基因可能与非洲血统hiv感染者肾功能下降有关。来自SMART队列的非洲血统hiv感染者的APOL1 （G1和G2变体）和MYH9（组成E1单倍型的4个内含子snp）风险变体的基因分型。使用肾小球滤过率（eGFR）估算肾功能，分别在基线和60个月随访期间使用线性回归和线性混合效应回归评估。APOL1风险等位基因与eGFR基线水平下降密切相关（P=3 × 10-8）；MYH9肾危险等位基因与eGFR独立相关；随访期间，APOL1和MYH9风险等位基因持续与较低的eGFR相关。这项研究的结果已在CROI会议上提出，并正在正式发表。