Identification of Genetic Factors Associated with Infectious Diseases

与传染病相关的遗传因素的鉴定

• 批准号: 10262058
• 负责人: Cheryl Winkler
• 金额: $ 31.22万
• 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/10262058
• 关键词: 3' Untranslated Regions; AIDS-Associated Nephropathy; AIDS/HIV problem; APOL1 gene; Acquired Immunodeficiency Syndrome; Acute Renal Failure with Renal Papillary Necrosis; Address; Affect; Africa South of the Sahara; African; African American; Aging; Antiviral Agents; Asians; Attenuated; Biopsy; COVID-19; CUL5 gene; Cancer Etiology; Cardiovascular Diseases; Categories; Cell Cycle; Cell Proliferation; Cell division; China; Chronic Disease; Chronic Hepatitis B; Cirrhosis; Clinical Management; Code; Collaborations; Communicable Diseases; Cytidine Deaminase; DNA; Data Set; Detection; Development; Diagnosis; Dialysis procedure; Disease; Disease Progression; Early Diagnosis; Environmental Risk Factor; Enzymes; Epidemiology; Epigenetic Process; Etiology; Exposure to; Family; Far East; Gene Expression Profile; Gene Frequency; Genes; Genetic; Genetic Variation; Genotype; Goals; HIV; HIV Infections; HIV-1; Haplotypes; Hepatitis B Virus; Hepatitis C; High Prevalence; Human; Immunologic Factors; In Vitro; Individual; Infection; International; Kidney; Kidney Diseases; Lead; Link; Lipids; Liver; Liver diseases; Malignant Neoplasms; Malignant neoplasm of liver; Meta-Analysis; Metabolic; Methods; MicroRNAs; Modification; Mutagens; Mutation; Mycoses; Natural Immunity; Odds Ratio; Oncogenes; Open Reading Frames; Opportunistic Infections; Organ; Other Genetics; Outcome; Participant; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Peer Review; Penetrance; Persons; Pharmacotherapy; Plasma; Population; Predisposition; Premature aging syndrome; Prevalence; Prevention; Primary carcinoma of the liver cells; Process; Prognostic Factor; Prognostic Marker; Prospective cohort; Proteins; Proteomics; Public Health; Publications; RNA; Research Design; Research Personnel; Retroelements; Retroviridae; Risk; Role; Sampling; Series; Severities; Sickle Cell Trait; Single-Stranded DNA; Somatic Mutation; South Africa; South African; Southern Africa; Sterol O-Acyltransferase; Subgroup; Susceptibility Gene; TP53 gene; Technology; Testing; The Cancer Genome Atlas; Time; Tissues; Tumor Suppressor Genes; Vaccines; Validation; Variant; Viral; Viral Load result; Virus Diseases; Virus Replication; Work; acquired immunity; antiretroviral therapy; carcinogenesis; cohort; differential expression; effective therapy; experience; follow-up; genetic variant; genome wide association study; global health; high risk; in vivo; infection rate; insight; lipid disorder; lipid metabolism; macrophage; malignant breast neoplasm; microRNA biomarkers; novel; outcome forecast; pandemic disease; prognostic signature; protective effect; protein expression; risk prediction model; risk variant; targeted treatment; tool; transcriptome sequencing; transcriptomics; transmission process; tumor

Our focus is on two major infectious diseases that impact global health. HIV-1 is pandemic and HBV infection and HBV-related hepatocellular carcinoma (HCC) is prevalent in East Asia and sub-Saharan Africa, globally affecting millions of people. Our objective is to identify genetic factors that contribute to the occurrence and development of these infectious diseases. The identification of host proteins involved in viral replication, in innate or acquired immunity, or in carcinogenesis pathways will provide critical insights for the rational development of antiviral drugs and effective vaccines. Our strategy is to identify genetic variants that differentially affect rates of infection, or the course of pathogenesis, and which thereby identify the variant-containing gene using targeted gene, genome wide association study (GWAS), and functional approaches. We have formed international collaborations with researchers in South Africa and China to address important public health questions (i.e. HIV in South Africa and HBV-associated liver cancer in China. Accomplishments in HIV disease: 1) APOL1 renal risk variants interact strongly with HIV to cause HIV-associated nephropathy with odds ratios ranging from 29 in African Americans to 89 in southern Africa. In vitro studies suggest that APOL1, an innate immune factor, impedes HIV replication. We hypothesized that APOL1 coding variants might attenuate the protective effect of ancestral APOL1 resulting in higher viral burden or increased transmission of HIV. This could possibly contribute to the high burden of HIV disease in sub-Saharan African were APOL1 risk variants are very common, with allele frequencies ranging from 10-50%. We therefore conducted genetic epidemiological association analyses of HIV patients with longitudinal follow-up spanning the pre- and post-antiretroviral treatment eras. We found that the variants do not increase the risk of HIV-1 infection and are not associated with viral load or progression to AIDS. This finding suggests that APOL1 variants do not contribute to the higher prevalence of HIV infections in sub-Saharan Africa or in African Americans (An et al. Front Immunol, 2019). 2) APOL1 variant alleles associate with reduced risk for opportunistic infections in HIV infection. Because APOL1 variants also dysregulate macrophage differentiation, we investigated the association of APOL1 with opportunistic infections in persons with HIV infection among 440 African Americans with HIV and performed a meta-analysis comprising 4 HIV/AIDS cohorts with 2066 participants. Carriage of two APOL1 variant alleles was associated with 71% reduction in odds of opportunistic infections. We validated this finding in the three HIV prospective cohorts in a meta-analysis. Carriage of two APOL1 variant alleles was associated with a 36% reduction in odds of opportunistic infections. Using a global test combining all four cohorts, carriage of two APOL1 variant alleles was associated with a 50% reduction in odds of opportunistic infections. Subgroup analysis of OI etiological categories revealed that OI protection is mainly attributable to specific protection from fungal infections. The study suggests a broader role of APOL1 variant alleles in innate immunity in vivo. Many patients with severe COVID-19 experience acute kidney injury requiring dialysis. We hypothesize that APOL1 renal high-risk genotypes and sickle cell trait, carried by 13% and 10% of African Americans, are associated with severity of AKI. Accomplishments in HBV-associated liver cancer: 1) We conducted the first study on the impact of the SOAT1 genetic variants and protein expression on HBV-related HCC. A recent proteomics study discovered a lipid metabolism enzyme Sterol O-acyltransferase (SOAT1) involvement in the progression of HCC. To assess the impact of SOAT1 gene variation on risk of HCC occurrence, we genotyped three protein-coding region SOAT1 variants, in 221 biopsy proven HCC patients and 229 healthy individuals. The V323V variant (OR) = 0.58, P = 0.04) and a haplotype TGA (OR = 0.40, P = 0.01) were associated with reduced HCC risk (42-60% lower risks) after adjusting for lipid levels. Using IHC, we found that the protein expression of SOAT1 was significantly increased in the tumor compared with adjacent tissue (P 0.001). This study revealed for the first time association of SOAT1 genetic variation with HBV-HCC susceptibility. This work is under peer-review for publication. 2) Our group also collaborated in a series of studies to identify prognostic biomarkers for HCC prognosis by providing assistance with study design and analysis. We helped identify competing endogenous RNA (ceRNA) network using dysregulated RNAs between tumor and adjacent liver tissues in TCGA and to investigate underlying prognostic factors in HCC patients. This study constructed a ceRNA network and gene set enriched in pathways of the cell cycle, cell division, and cell proliferation. The prognostic signature may provide an independent tool for prediction of HCC survival (Liao et al., J Cancer, 2019). 3) There is a lack of validation across limited transcriptomic studies in HBV-related HCC. We performed a meta-analysis to assess changes in gene expression patterns by integrating HBV-HCC samples from TCGA and GEO datasets. Our analysis revealed that over 500 differentially expressed genes (DEG) were shared across all datasets, indicating that approximately 8% of differentially expressed genes from TCGA HBV-HCC are replicated across studies. The identified pathways and genes are valuable for development of targeted therapies and prevention once validated. 4) We are in the process identify microRNA markers for HCC diagnosis and prognosis. Detection of miRNA in serum/plasma can be a promising method for early HCC diagnosis enabling effective treatment. Collaborating with South African investigators, we are in the process using RNA-seq technology to systematically uncover the miRNA signatures in a cohort of HBV-associated HCC patients in South Africa. 5) Cytidine deaminases of the human APOBEC3 family (encoded by the APOBEC3 A-H genes) restrict retroviruses and mobile retroelements but also hypermutate host single strand (ss)DNA that may contribute to carcinogenesis. We previously identified several genetic variants in the A3G, A3B, A3F and CUL5 of A3-VIf pathway that affect HIV-1 infection or progression. A3B/A3A have been recently recognized as strong endogenous mutagens in multiple cancers. A 29.5-kb DNA germline deletion that fuses the coding region of APOBEC3A with the 3'UTR of APOBCE3B. The APOBEC3B (A3B) deletion is common in Asian but rare in other populations, and is associated with elevated risk to breast cancer. We found this germline A3B deletion was associated with a 2-fold higher HCC risk and 3-5-fold higher risk for one or two-copy deletion compared with no deletion. This result indicates that the common A3B deletion is a major HCC susceptibility locus. We further found that A3B deletion carriers had 2-fold higher risk to have cirrhosis. As the effect of the A3B deletion is so strong and carriage rate is so high in Asian, where HCC prevalence is the highest in the world, an inclusion of the A3B in the polygenic HCC risk prediction model is warranted. We speculate that A3B may modify HCC risk through interacting with key cancer genes including tumor suppressor genes or oncogenes. We particularly explored the relationship between the A3B deletion and tumor suppressor gene TP53. We found a higher TP53 mutation rate among non-carriers of the A3B deletion compared with the two-copy A3B deletion carriers (24% vs. 9%, p=0.02), suggesting A3B presence may cause TP53 mutation, and that its absence reduces the chance of mutation, consistent with the A3B role as a hypermutator, a novel mechanism that links between A3B and HCC through TP53.

我们的重点是两种影响全球健康的主要传染病。 HIV-1是大流行，HBV感染和与HBV相关的肝细胞癌（HCC）在东亚和撒哈拉以南非洲普遍存在，全球影响数百万人。我们的目标是确定有助于这些传染病的发生和发展的遗传因素。鉴定涉及病毒复制，先天或获得的免疫或致癌途径中的宿主蛋白将为抗病毒药物和有效疫苗的合理发展提供关键的见解。我们的策略是确定差异影响感染率或发病机理的遗传变异，从而使用靶向基因，基因组广泛的关联研究（GWAS）和功能方法来鉴定含有变体的基因。我们已经与南非和中国的研究人员建立了国际合作，以解决重要的公共卫生问题（即南非和中国与HBV相关的肝癌的HIV。艾滋病毒疾病的成就：1）APOL1肾脏风险与HIV相互作用，与HIV相互作用以引起HIV与HIV相关的肾病与与非洲妇女的比例相关的29岁。体外研究表明，天生的免疫因子Apol1阻碍了HIV复制。我们假设APOL1编码变体可能会减弱祖先APOL1的保护作用，从而导致较高的病毒负担或增加HIV的传播。这可能会导致撒哈拉以南非洲人的艾滋病毒疾病的高负担为APOL1风险变异，非常普遍，等位基因频率在10-50％不等。因此，我们对横向抗逆转录病毒治疗的纵向随访的HIV患者进行了遗传流行病学关联分析。我们发现这些变体不会增加HIV-1感染的风险，并且与病毒载量或向艾滋病的发展无关。这一发现表明，APOL1变体不会导致撒哈拉以南非洲或非洲裔美国人的艾滋病毒感染的较高患病率（An等人Front Immunol，2019年）。 2）APOL1变体等位基因与HIV感染中机会性感染风险降低相关。由于APOL1变体也使巨噬细胞分化失调，因此我们研究了APOL1与440名HIV的HIV感染患者的机会性感染的关联，并进行了荟萃分析，并进行了包括4 HIV/AIDS同类群体的荟萃分析。两个APOL1变体等位基因的运输与机会性感染几率降低了71％。我们在荟萃分析的三个艾滋病毒前瞻性人群中验证了这一发现。两个APOL1变体等位基因的运输与机会性感染几率降低36％有关。使用结合所有四个同类群的全球测试，两个Apol1变体等位基因的运输与机会性感染几率降低了50％。 OI病因类别的亚组分析表明，OI保护主要归因于特定的防护感染。该研究表明，Apol1变体等位基因在体内先天免疫中的更广泛作用。许多严重的Covid-19患者经历急性肾脏损伤，需要透析。我们假设APOL1肾脏高风险基因型和镰状细胞性状（占非洲裔美国人的13％和10％）与AKI的严重程度有关。与HBV相关的肝癌的成就：1）我们对SOAT1遗传变异和蛋白质表达对HBV相关HCC的影响进行了首次研究。最近的一项蛋白质组学研究发现，脂质代谢酶固醇O-酰基转移酶（SOAT1）参与HCC的进展。为了评估SOAT1基因变异对HCC发生风险的影响，我们在221名活检证明的HCC患者和229名健康个体中，基因分型蛋白质编码区SOAT1变异。 V323V变体（OR）= 0.58，p = 0.04）和单倍型TGA（OR = 0.40，p = 0.01）在调整脂质水平后HCC风险降低（降低了42-60％的风险）。使用IHC，我们发现与相邻组织相比，肿瘤中SOAT1的蛋白质表达显着增加（p 0.001）。这项研究揭示了SOAT1遗传变异与HBV-HCC敏感性的首次关联。这项工作是在同行评审下出版的。 2）我们的小组还合作进行了一系列研究，以通过为研究设计和分析提供帮助，以确定HCC预后的预后生物标志物。我们帮助使用TCGA中肿瘤和邻近肝组织之间的失调的RNA确定了竞争性的内源性RNA（CERNA）网络，并研究了HCC患者的潜在预后因素。这项研究构建了一个富含细胞周期，细胞分裂和细胞增殖途径的CERNA网络和基因集。预后签名可以为预测HCC生存的独立工具（Liao等，J Cancer，2019）。 3）在与HBV相关的HCC中，有限的转录组研究缺乏验证。我们进行了荟萃分析，通过整合来自TCGA和GEO数据集的HBV-HCC样品来评估基因表达模式的变化。我们的分析表明，在所有数据集中共享了500多个差异表达的基因（DEG），这表明在整个研究中，大约8％来自TCGA HBV-HCC的差异表达基因被复制。确定的途径和基因对于一旦得到验证的靶向疗法和预防的开发而言是有价值的。 4）我们正在此过程中确定用于HCC诊断和预后的microRNA标记。在血清/血浆中检测miRNA可以是早期肝癌诊断的有前途的方法。与南非调查员合作，我们正在使用RNA-Seq技术在南非的一组HBV相关HCC患者中系统地揭示MiRNA签名。 5）人类ApoBec3家族的胞苷脱氨酶（由APOBEC3 A-H基因编码）限制了逆转录病毒和移动恢复元素，但也可能导致癌变的过度挤压宿主单链（SS）DNA。我们先前鉴定出影响HIV-1感染或进展的A3G，A3b，A3F和CUL5中的几种遗传变异。 A3b/A3a最近被认为是多种癌症中强内源性诱变剂。一个29.5-kb的DNA种系缺失，将APOBEC3A的编码区与ApoBce3b的3'UTR融合在一起。 APOBEC3B（A3B）缺失在亚洲很常见，但在其他人群中很少见，并且与乳腺癌风险升高有关。我们发现，这种生殖线A3B缺失与无缺失相比，HCC风险高2倍，而一拷贝缺失的风险高2-5倍。该结果表明常见的A3B缺失是主要的HCC敏感性基因座。我们进一步发现，A3B缺失载体患有肝硬化的风险高2倍。由于A3B缺失的效果是如此强大，并且在亚洲人的运输速率如此之高，因此HCC患病率是世界上最高的，因此保证了多基因HCC风险预测模型中的A3B。我们推测A3B可以通过与包括肿瘤抑制基因或致癌基因在内的关键癌症基因相互作用来改变HCC风险。我们特别探讨了A3B缺失与肿瘤抑制基因TP53之间的关系。我们发现，与两拷贝A3B缺失载体相比，A3B删除的非携带者之间的TP53突变率更高（24％vs. 9％，9％，P = 0.02），这表明A3B的存在可能会导致TP53突变，并且它的不存在突变的机会，与A3B的角色保持一致，与A3B的角色保持一致。