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: 7732987
• 负责人: CHERYL ANN WINKLER
• 金额: $ 73.95万
• 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/7732987
• 关键词: Acquired Immunodeficiency Syndrome; Admixture; Affect; Africa; African; African American; Alleles; American; Amino Acids; Antigen Receptors; Antiviral Agents; Asians; Biological Assay; Botswana; CD4 Positive T Lymphocytes; CUL5 gene; Cessation of life; China; Chromosomes, Human, Pair 22; Clinical; Cohort Studies; Collaborations; Common Carcinoma; Communicable Diseases; Complementary DNA; Complex; Confidence Intervals; Development; Disease; Disease Progression; Drug usage; Epidemic; European; Family; Frequencies; Gene Deletion; Gene Frequency; Gene Targeting; Genes; Genetic; Genetic Polymorphism; Genetic Transcription; Genotype; Goals; HIV; HIV-1; HLA-C Antigens; Haplotypes; Health; Hepatitis B; Hepatitis B Virus; Hepatitis C; Hepatitis C virus; Herpesviridae; Human; Human Herpesvirus 4; IL18 gene; Immune response; In Vitro; Infection; Injecting drug user; Integration Host Factors; Interleukin-18; Interleukins; International; Investigation; Kaposi Sarcoma; Kidney Diseases; Knowledge; Laboratories; Lymphoma; Malignant Neoplasms; Maps; Mediator of activation protein; Minor; Mutation; Natural History; Natural Immunity; Nose; Odds Ratio; Outcome; Pathogenesis; Pathway interactions; Persons; Pharyngeal Carcinoma; Phenotype; Plasma; Plasmodium vivax; Population; Predisposition; Primary carcinoma of the liver cells; Process; Proteins; Rate; Relative (related person); Reporting; Research; Resistance; Risk; Risk Factors; Role; Southern Africa; T-Cell Depletion; Testing; Therapeutic Intervention; Transfusion; Ubiquitination; Vaccines; Variant; Viral; Viral Load result; Viral Pathogenesis; Virion; Virus; Virus Diseases; acquired immunity; antiretroviral therapy; base; carcinogenesis; case control; chemokine receptor; cohort; genetic variant; genome wide association study; genotyping technology; hazard; human CEM15 protein; insight; member; pathogen; prevent; promoter; resistance factors; response; transmission process

The major objective of my laboratory is to identify host factors that contribute to infectious and other complex diseases. The tremendous impact of infectious diseases on global health, and the association of many human pathogens with common cancers, call for multiple research strategies to elucidate the mechanisms of infection and pathogenesis. Our strategy is to search for genetic variants that differentially affect rates of infection, or the course of pathogenesis, and which thereby identify the gene containing the variant as participating in the process of infection or pathogenesis, increasing knowledge of the mechanisms of pathogenesis and pointing to targets for therapeutic intervention. Our focus has been to discover genetic factors modulating HIV-1, HCV, and HBV infections and associated diseases. To this end, we have developed international collaborations to establish case-control and cohort studies in China and southern Africa, in addition to five established U.S.-based HIV-1 longitudinal cohorts, to investigate HIV-1, HBV, and HCV as well as the common carcinomas, NPC and HCC, associated with the EBV and HB viruses, respectively. We have established a collaboration with the Botswana Harvard Partnership to investigate the genetic correlates of HIV-1 infection, progression, and response to antiretroviral therapy in a region severely impacted by HIV-1 subtype C infection, the subtype responsible for the majority of HIV-1 infections globally. Using both targeted gene and genome wide association approaches, we have employed high throughput genotyping technologies, including Illumina and Affymetrix, to discover genes associated with HIV-1-associated nephropathy and with progression to AIDS. Whenever a significant association is observed, the laboratory uses fine mapping to identify putative causal alleles and functional assays to assess effects on gene transcription and protein levels. Accomplishments: APOBEC3G is a human innate resistance factor to HIV-1 that is incorporated into budding virions. APOBEC3G, in the absence of HIV-1 encoded viral infectivity factor (vif), causes hypermutation of the nascent cDNA, effectively preventing viral infection. Human APOBEC3Gs anti-HIV-1 activity is, however, disarmed by HIV-1 vif by interaction with Cullin5 (CUL5) complex, in the ubiquitination pathway leading to the degradation of APOBEC3G. Through a study of HIV-1 natural history cohorts with different clinical outcomes,we have previously shown that polymorphism in the gene encoding APOBEC3G is associated with rate of progression to AIDS and trajectory of CD4+ T cell decline in HIV-1-infected persons. We also discovered that variant alleles and haplotype clusters in CUL5 influences the rate of CD4+ T-cell depletion. These findings highlight the importance of APOBEC3G-CUL5 pathway. Since there are seven APOBEC3 genes (A-H) clustered in a 100 kb region in chromosome 22 and most of which also confer anti-HIV-1 activity, We sought to test the influence of the genetic variants and haplotype in all APOBEC3 genes (A-H) on HIV-1 infection and disease courses. APOBEC3B gene deletion is an HIV risk factor: APOBEC3B, one of seven members of APOBEC3 family, has been shown to inhibit HIV-1 replication in vitro and is the only APOBEC3 protein not inhibited by HIV-1 vif. A 29.5-kb deletion, with an overall global frequency of 22%, removes the entire APOBEC3B gene and has been hypothesized to effect HIV-1 pathogenesis. We examined the impact of the APOBEC3B gene deletion on HIV-1 infection and disease progression in more than 4000 subjects. The hemizygous genotype had no effect on either infection or progression in either EA or AA. However, in EA, the homozygous deletion was significantly associated with increased susceptibility to infection (OR = 7.37, P=0.024), with none observed in 724 HIV-1 uninfected persons and 14 observed in 1950 HIV-1 infected persons. Homozygosity for the deletion allele was also associated with more rapid progression to AIDS (RH = 3.82, P=0.03) and higher viral load (slope on a log10 scale= +0.43, p=0.048). These findings indicate that deletion of APOBEC3B gene increases host susceptibility to HIV-1 infection and progression. These results, if confirmed, suggest that the APOBEC3B deletion may have considerable impact on the HIV-1 epidemic in populations with Asian ancestry where the APOBEC3B deletion allele is much more common. APOBEC3F genetic variants protect AIDS progression: APOBEC3F strongly inhibits HIV-1 and unlike APOBEC3G is partially resistant to vif. We found that two amino acid changing variants were associated with protection to progression to AIDS (RH=0.70, P= 0.007) in European Americans. Assessing of variants functional mechanism is ongoing. The relative contribution of each APOBEC3 gene and their interaction on viral infection are under investigation. DARC has no effect on HIV-1 infection susceptibility or progression to AIDS: Recently, it was reported that the Duffy antigen receptor for chemokine (DARC) null phenotype was significantly associated with a 40% increase in HIV-1 infection risk in African Americans and extrapolated their results to Africa, suggesting that 11% of the HIV-1 burden in Africa was due to the presence of the DARC null phenotype. The DARC null allele occurs in more than 90% of subSaharan Africans, and conveys resistance to Plasmodium vivax malariathe mutation is absent in non-African populations except by admixture. We examined the same polymorphism in a group of African Americans, more than 90% of whom were infected by injecting drug use and found no association between DARC null group and the DARC positive group for infection susceptibility. A HLA-C allele strongly protects AIDS progression: A recent genome-wide association study (GWAS) of host determinants for HIV-1 disease revealed that SNPs near or in genes HLA-C, ZNRD1 and ZNF39 were associated viral load setpoint or disease progression among European HIV-1 cohorts (Euro-CHAVI). We investigated the effect of the SNPs in this region on AIDS progression in five U.S-based HIV-1 longitudinal cohorts. After adjusting other known covariates including HLA alleles, HLA-C rs9264942 was strongly associated with protection of progression to AIDS (Relative hazard [RH] = 0.72, 95% CI, 0.60-0.86, P = 0.0003) and death (RH=0.64, 95% CI, 0.53-0.78, P=6.3 x 10-6) in European Americans. As this SNP is very common (allele frequency, 39%) in this population, its impact on HIV-1 epidemic is substantial. Minor effects of SNPs of ZNRD1 and RNF39 were also observed. Regulatory polymorphisms in the interleukin-18 promoter are associated with HCV clearance: The immune response is critical in determining the outcome of HCV infection. Interleukin (IL)-18 is a pivotal mediator of Th1/Th2 driven immune response. Two IL-18 promoter polymorphisms (-607 C/A and -137 G/C) and their haplotypes were known to affect the IL-18 expression. We examined the role of these polymorphisms in determining HCV clearance or persistence. Genotyping was performed among African American injecting drug users (IDUs) with HCV clearance and HCV persistence, and among European American hemophiliacs mainly infected through plasma transfusion. Among IDUs, IL18 -607A (Odds ratio [OR], 3.68; 95% confidence interval [CI],1.85-7.34) and IL [summary truncated at 7800 characters]

我实验室的主要目标是确定导致传染病和其他复杂疾病的宿主因素。传染病对全球健康的巨大影响，以及许多人类病原体与常见癌症的关联，需要多种研究策略来阐明感染和发病机制。我们的策略是寻找对感染率或发病过程有不同影响的遗传变异，从而识别出包含变异的基因参与感染或发病过程，增加对发病机制的了解并指出治疗干预的目标。我们的重点是发现调节 HIV-1、HCV 和 HBV 感染及相关疾病的遗传因素。为此，除了在美国建立的五个 HIV-1 纵向队列外，我们还开展了国际合作，在中国和南部非洲建立了病例对照和队列研究，以研究 HIV-1、HBV 和 HCV 以及分别与 EBV 和 HB 病毒相关的常见癌症、NPC 和 HCC。我们与博茨瓦纳哈佛合作伙伴关系建立了合作关系，在受 HIV-1 C 亚型感染严重影响的地区调查 HIV-1 感染、进展和抗逆转录病毒治疗反应的遗传相关性，该亚型是全球大多数 HIV-1 感染的原因。通过使用靶向基因和全基因组关联方法，我们采用了高通量基因分型技术（包括 Illumina 和 Affymetrix）来发现与 HIV-1 相关肾病以及进展为 AIDS 相关的基因。 每当观察到显着关联时，实验室就会使用精细绘图来识别假定的因果等位基因，并使用功能分析来评估对基因转录和蛋白质水平的影响。成就：APOBEC3G 是一种人类对 HIV-1 的先天抵抗因子，它被整合到出芽的病毒粒子中。 APOBEC3G 在缺乏 HIV-1 编码的病毒感染因子 (vif) 的情况下，会导致新生 cDNA 发生超突变，从而有效预防病毒感染。然而，人类 APOBEC3G 的抗 HIV-1 活性会被 HIV-1 vif 通过与 Cullin5 (CUL5) 复合物相互作用而解除，在泛素化途径中导致 APOBEC3G 降解。通过对具有不同临床结果的 HIV-1 自然史队列的研究，我们之前已经表明，编码 APOBEC3G 的基因的多态性与 HIV-1 感染者的 AIDS 进展速度和 CD4+ T 细胞下降轨迹相关。我们还发现 CUL5 中的变异等位基因和单倍型簇影响 CD4+ T 细胞的耗竭率。这些发现强调了 APOBEC3G-CUL5 通路的重要性。由于有 7 个 APOBEC3 基因 (A-H) 聚集在 22 号染色体的 100 kb 区域，其中大多数也具有抗 HIV-1 活性，因此我们试图测试所有 APOBEC3 基因 (A-H) 中的遗传变异和单倍型对 HIV-1 感染和疾病进程的影响。 APOBEC3B 基因缺失是 HIV 的危险因素：APOBEC3B 是 APOBEC3 家族的七个成员之一，已被证明可以在体外抑制 HIV-1 复制，并且是唯一不受 HIV-1 vif 抑制的 APOBEC3 蛋白。 29.5 kb 的缺失（总体总体频率为 22%）删除了整个 APOBEC3B 基因，并被假设会影响 HIV-1 发病机制。我们在 4000 多名受试者中研究了 APOBEC3B 基因缺失对 HIV-1 感染和疾病进展的影响。半合子基因型对 EA 或 AA 的感染或进展没有影响。然而，在 EA 中，纯合性缺失与感染易感性增加显着相关（OR = 7.37，P = 0.024），在 724 名 HIV-1 未感染者中未观察到纯合性缺失，而在 1950 名 HIV-1 感染者中观察到 14 例。缺失等位基因的纯合性还与艾滋病进展更快（RH = 3.82，P = 0.03）和更高的病毒载量（log10 尺度上的斜率 = +0.43，p = 0.048）相关。 这些发现表明 APOBEC3B 基因的缺失会增加宿主对 HIV-1 感染和进展的易感性。这些结果如果得到证实，表明 APOBEC3B 缺失可能对亚洲血统人群中的 HIV-1 流行产生相当大的影响，而亚洲血统人群中 APOBEC3B 缺失等位基因更为常见。 APOBEC3F 基因变异可保护艾滋病进展：APOBEC3F 强烈抑制 HIV-1，并且与 APOBEC3G 不同的是，APOBEC3G 对 vif 具有部分抵抗力。我们发现，在欧洲裔美国人中，两种氨基酸变化变异与预防艾滋病进展相关（RH=0.70，P=0.007）。对变体功能机制的评估正在进行中。每个 APOBEC3 基因的相对贡献及其对病毒感染的相互作用正在研究中。 DARC 对 HIV-1 感染易感性或艾滋病进展没有影响：最近有报道称，趋化因子达菲抗原受体 (DARC) 无效表型与非裔美国人的 HIV-1 感染风险增加 40% 显着相关，并将其结果外推到非洲，表明非洲 11% 的 HIV-1 负担是由于 DARC 无效表型的存在。 DARC 无效等位基因存在于超过 90% 的撒哈拉以南非洲人中，并具有对间日疟原虫疟疾的抵抗力。除了混合以外，非非洲人群中不存在该突变。我们在一组非裔美国人中检查了相同的多态性，其中 90% 以上是通过注射毒品感染的，发现 DARC 无效组和 DARC 阳性组之间的感染易感性没有关联。 HLA-C 等位基因强烈保护艾滋病进展：最近一项针对 HIV-1 疾病宿主决定因素的全基因组关联研究 (GWAS) 表明，HLA-C、ZNRD1 和 ZNF39 基因附近或基因中的 S​​NP 与欧洲 HIV-1 队列 (Euro-CHAVI) 中的病毒载量设定点或疾病进展相关。我们在美国的五个 HIV-1 纵向队列中研究了该地区的 SNP 对艾滋病进展的影响。调整包括 HLA 等位基因在内的其他已知协变量后，HLA-C rs9264942 与预防 AIDS 进展（相对危险 [RH] = 0.72，95% CI，0.60-0.86，P = 0.0003）和死亡（RH=0.64，95% CI，0.53-0.78，P=6.3 x）密切相关。 10-6）在欧洲裔美国人中。由于该 SNP 在该人群中非常常见（等位基因频率为 39%），因此它对 HIV-1 流行的影响是巨大的。还观察到 ZNRD1 和 RNF39 的 SNP 的轻微影响。 IL-18 启动子的调节多态性与 HCV 清除相关：免疫反应对于决定 HCV 感染的结果至关重要。白细胞介素 (IL)-18 是 Th1/Th2 驱动的免疫反应的关键介质。已知两个 IL-18 启动子多态性（-607 C/A 和 -137 G/C）及其单倍型影响 IL-18 表达。我们检查了这些多态性在确定 HCV 清除或持久性中的作用。 在丙型肝炎病毒清除和丙型肝炎病毒持续存在的非裔美国人注射吸毒者 (IDU) 以及主要通过血浆输血感染的欧裔美国人血友病患者中进行了基因分型。在注射吸毒者中，IL18 -607A（优势比 [OR]，3.68；95% 置信区间 [CI]，1.85-7.34）和 IL [摘要截断为 7800 个字符]

项目成果

Patterns of ethnic diversity among the genes that influence AIDS.

影响艾滋病的基因中的种族多样性模式。

• DOI: 10.1093/hmg/ddh075
• 发表时间: 2004
• 期刊: Human molecular genetics
• 影响因子: 3.5
• 作者: Winkler,Cheryl;An,Ping;O'Brien,StephenJ
• 通讯作者: O'Brien,StephenJ

[Association study of chromosome 4 STRs polymorphisms with nasopharyngeal carcinoma]

4号染色体STR多态性与鼻咽癌的关联研究

• 发表时间: 2006
• 期刊: Yi chuan = Hereditas / Zhongguo yi chuan xue hui bian ji
• 作者: Guo,Xiu-Chan;O'Brien,StephenJ;Winkler,Cheryl;Scott,Kevin;Hutcheson,Holli;David,Victor;Kessing,Bailey;Zheng,Yu-Ming;Liao,Jian;Lui,Yan;Guy,deThe;Zeng,Yi
• 通讯作者: Zeng,Yi