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) 分别导致艾滋病相关恶性肿瘤、鼻咽癌 (NPC) 和肝细胞癌 (HCC)。 人们对慢性病毒感染和宿主遗传变异之间的相互作用知之甚少，而宿主遗传变异会导致感染这些病毒的人出现致病结果。全基因组关联研究 (GWAS) 表明，HLA I 类等位基因与 HBV 清除、HIV 病毒载量控制以及 NPC 密切相关。 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，通常与衰老相关并影响所有器官系统的疾病正在年轻化。 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) 中眼部疾病的相关性，以及纵向自然和治疗队列中与 HIV 相关的非艾滋病严重疾病的相关性。我们的实验室正在将表观遗传特征、基因表达以及 GWAS 和通路分析的结果整合到基于系统的方法中，以进一步定义在传染病的病理生理学和致癌作用中重要的基因和通路。肺孢子菌肺炎 (PCP) 是一种主要的艾滋病定义病症，也是免疫抑制的常见并发症。染色体 3p21-22 包含两簇趋化因子受体基因，其中一些基因充当 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。我们发现 CCRL2 (Y167F) 中的非保守氨基酸变化与更快进展为 AIDS 定义病症，特别是与 AIDS 定义病症 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-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。 这项研究的结果发表在 PLoS Genetics.2 上。 GWAS 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。由于测试数量众多，全基因组显着性的严格标准（按照惯例，p<5 x 10-8）和独立复制对于避免假阳性关联至关重要。 由于掌握传染病纵向临床和实验室数据的人数通常有限，因此与传染病表型相关的遗传因素的发现是有问题的。为了克服这一障碍，我们与国际 HIV 联盟联手，提供 1000 多名 HIV 感染者的基因型-表型，并进行纵向随访以进行荟萃分析。我们也是此次国际合作的病毒载量和 CD4 T 细胞轨迹分析团队的成员。目前，我们正在对之前 3 个针对 HBV 和 HIV 临床结果的 CCR GWAS 的基因型要求进行严格的质量控制 (QC)。对于NPC。使用 ISHAPE 软件，我们利用 GWAS 数据确定了参加 NPC、HIV 和 HBV 研究的参与者的单倍型结构。 下一步将是使用代表主要大陆人群的国际单体型图计划和千人基因组计划的数据来估算 Affymetric 芯片上未代表的 SNP。 借助丰富的 SNP，我们将使用 5 个自然历史队列和 LSOCA 队列重新分析与多种表型相关的数据，包括 HIV 相关的非艾滋病和艾滋病临床结果。如上所述，宿主变异鉴定的障碍影响 HIV 获得和发病机制的因素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，一个包含两个密码子改变的 SNP，另一个包含删除两个氨基酸的 6 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。我们发现，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%）。 这项发表在《美国肾病学会杂志》上的研究表明，筛查 APOL1 风险变异可能在非洲血统和 HIV 感染者的个性化医疗中发挥作用。 4. 为了确定 APOL1 变异是否导致独特的病理特征，我们对 60 名经活检证实患有 HIVAN 的患者进行了基因分型。在该组中，37 人具有两个风险等位基因，18 人为杂合子，5 人没有任何风险变异。 HIVAN的病理结果和APOL1风险等位基因的数量没有差异。此外，终末期肾病或死亡的进展并不因风险等位基因的数量而有所不同。具有零个或一个风险等位基因的患者的中位肾生存期为 9.3 个月，而具有两个 APOL1 风险等位基因的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 HIVAN 非洲裔美国患者具有两个 APOL1 风险等位基因，但其他尚未可知的因素，包括其他遗传风险变异或环境或病毒因素，可能会影响具有零个或一个 APOL1 的患者发生这种疾病。风险等位基因。这项研究发表在《Kidney International》5 上。 APOL1 变异与接受治疗的 HIV 感染者的估计肾小球滤过减少有关。 HIV肾病的流行病学随着时间的推移而发生了变化。 在前 cART 时代，HIVAN 很突出，但在后 cART 时代，HIVAN 已经减弱，但肾脏疾病仍然是主要并发症，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的 HIV 感染者的肾功能下降有关。对 SMART 队列中具有非洲血统的 HIV 感染者进行了 APOL1（G1 和 G2 变体）和 MYH9（构成 E1 单倍型的 4 个内含子 SNP）风险变体的基因分型。 分别使用线性回归和线性混合效应回归在基线和 60 个月的随访期间使用肾小球滤过率 (eGFR) 估计值评估肾功能。 APOL1 风险等位基因与基线时 eGFR 下降密切相关 (P=3x10-8)； MYH9 肾脏风险等位基因与 eGFR 独立相关；在随访期间，APOL1 和 MYH9 风险等位基因仍然与较低的 eGFR 持续相关。这项研究的结果已在 CROI 会议上公布，并正在正式出版。