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: 10702326
• 负责人: Cheryl Winkler
• 金额: $ 4.08万
• 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/10702326
• 关键词: 3' Untranslated Regions; AIDS-Associated Nephropathy; APOL1 gene; Address; Affect; Africa; Africa South of the Sahara; African; African American population; African ancestry; Aging; Asian; Biological Markers; Biopsy; Black race; COVID-19 survivors; CUL5 gene; Cancer Etiology; Cardiovascular Diseases; Categories; Cell Cycle; Cell Proliferation; Cell division; Characteristics; China; Chronic Disease; Chronic Hepatitis B; Chronic Kidney Failure; 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; Epigenetic Process; Ethnic Origin; Etiology; Exposure to; Family; Far East; Focal and Segmental Glomerulosclerosis; Gene Expression Profile; General Population; Genes; Genetic; Genotype; Goals; HIV; HIV Infections; HIV-1; HIV/AIDS; Haplotypes; Hepatitis B Virus; Hepatitis C; High Prevalence; Human; Immunochemistry; Impairment; Individual; Infection; Inflammation; Inflammatory; Innate Immune System; Interferons; International; Kidney; Kidney Diseases; Lead; Liver; Liver diseases; Malignant Neoplasms; Malignant neoplasm of liver; Meta-Analysis; Metabolic; Methods; MicroRNAs; Modification; Mutagens; Mutation; Mycoses; Natural Immunity; Nigeria; Oncogenes; Open Reading Frames; Opportunistic Infections; Organ; Other Genetics; Outcome; Participant; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Penetrance; Persons; Pharmacotherapy; Plasma; Population; Predisposition; Premature aging syndrome; Prevalence; Primary carcinoma of the liver cells; Prognosis; Prognostic Factor; Prospective cohort; Proteins; Proteinuria; Proteomics; Public Health; RNA; Renal function; Reporting; Research Personnel; Retroelements; Retroviridae; Risk; Risk Factors; Role; Sampling; Sepsis; Series; Single-Stranded DNA; Somatic Mutation; South Africa; South African; Stains; Sterol O-Acyltransferase; Subgroup; Susceptibility Gene; TP53 gene; Technology; Testing; The Cancer Genome Atlas; Tissues; Tumor Suppressor Genes; Universities; Variant; Viral; Virus Diseases; Virus Replication; antiretroviral therapy; carcinogenesis; cohort; college; cytokine; differential expression; effective therapy; genetic variant; genome wide association study; high risk; in vivo; infection rate; insight; kidney biopsy; lipid disorder; lipid metabolism; macrophage; malignant breast neoplasm; member; microRNA biomarkers; pandemic disease; prognostic signature; protein expression; risk prediction model; risk variant; targeted treatment; tool; transcriptome sequencing; tumor; virus related cancer

Project Summary HIV-1 is pandemic and HBV infection and HBV- 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. 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 is a member of the innate immune system and up-regulated by inflammatory cytokines, particularly the interferons. 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. Using a global test combining all four cohorts, carriage of two APOL1 variant alleles, carried by 13% of African Americans, was associated with a 50% reduction in odds of opportunistic infections. Subgroup analysis of OI etiological categories indicated that OI protection is mainly attributable to specific protection from fungal infections (An et al. Commun Biol, 2021).We also found that APOL1 is associated with a 25 percent increased risk of incident sepsis, which disproportionality affects African Americans (Chaudhary et al., Clin J Amn Soc Nephrol, 2020). These studies suggest a broader role of APOL1 variant alleles in innate immunity and inflammation in vivo. In collaborative studies with investigators at Vanderbilt University and Kings College in the UK, we are investigating the long-term consequences of APOL1 genotypes in the setting of treated HIV-infection and in the general population of COVID survivors. We found that among Black Africans with treated HIV infection now living in the UK, the risk of chronic kidney disease was highest in West Africa. Of the 2468 black participants,193 had renal impairment, 87 advanced CKD or where on dialysis, 126 proteinuria, and 43 HIVAN/FSGS or arterionephrosclerosis. After adjusting for demographic characteristics, HIV and several CKD risk factors and with East African ancestry as referent, West African ancestry was associated with more than a 2-fold increased odds of renal impairment and stage 5 CKD (PR 2.23 [1.23-4.04]). West African ancestry (as compared to East/South African ancestry) was also strongly associated with a diagnosis of HIVAN/FSGS or arterionephrosclerosis on kidney biopsy (PR 6.44 [2.42-17.14]) (Hong et al., eClinicalMedicine, 2021). These results indicate that people of West African ancestry with HIV are at increased risk of kidney disease. A subsequent study showed that APOL1 high-risk genotypes, present in 25% of West Africans but only 1% of East Africans, and 3-5% of Central or Southern Africans was the cause of the high prevalence of progressive CKD in West Africans, as has been reported in African Americans, whom share ancestry with West Africans (submitted, 2021). In a different study, conducted in Nigeria, we found that APOL1 high risk status varied greatly by ethnicity, and was strongly associated with decreased kidney function and nephrotic range proteinuria in persons with treated HIV infection (Wudil et al., KI, 2021). Accomplishments in HBV-associated liver cancer: 1) A recent proteomics study reported a lipid metabolism enzyme Sterol O-acyltransferase (SOAT1) involvement in the progression of HCC. We conducted the first study of SOAT1 genetic variants and protein expression on HBV-related HCC. We genotyped three protein-coding region SOAT1 variants, in 221 biopsy proven HCC patients and 229 healthy individuals. The V323V variant and a haplotype TGA were strongly associated with reduced HCC risk (42-60% lower risks). Using immunochemistry staining, we found that the protein expression of SOAT1 was significantly increased in the tumor compared with adjacent tissue (P 0.001) (Chen et al. BMC Cancer 2021). 2) Our group collaborated on a series of studies to identify biomarkers for HCC prognosis. The team identified 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) 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 invaluable for development of targeted therapies. 4) We are identifying 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. We are using RNA-seq technology to systematically uncover the miRNA signatures in a cohort of HBV-associated HCC patients from South Africa. We anticipate to concluding the project in 2 months. 5) Cytidine deaminases of the human APOBEC3 family 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. The APOBEC3B (A3B) deletion, a 29.5-kb DNA germline deletion that fuses the coding region of APOBEC3A with the 3'UTR of APOBCE3B, 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 of 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. A3B may modify HCC risk by interacting with key cancer genes including tumor suppressor genes or oncogenes. We also 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 that A3B presence may cause TP53 mutation, and that its absence reduces the chance of mutation, consistent with the A3B role *TRUNCATED*

项目摘要 HIV-1 是一种流行病，而 HBV 感染和 HBV-HCC 在东亚和撒哈拉以南非洲地区很流行，影响了全球数百万人。我们的目标是确定导致这些传染病发生和发展的遗传因素。我们的策略是识别对感染率或发病过程有不同影响的遗传变异，从而利用目标基因、全基因组关联研究 (GWAS) 和功能方法识别包含变异的基因。我们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（即南非的艾滋病毒和中国的乙型肝炎相关肝癌。在艾滋病毒疾病方面的成就：1）APOL1 是先天免疫系统的成员，炎症细胞因子，特别是干扰素上调。由于 APOL1 变异也会导致巨噬细胞分化失调，因此我们在 440 名 HIV 感染者中调查了 APOL1 与 HIV 感染者机会性感染的关系，并对 4 个 HIV/AIDS 队列的 2066 名参与者进行了荟萃分析。携带两个 APOL1 变异等位基因与机会性感染几率降低 71% 相关。我们通过荟萃分析在三个艾滋病毒前瞻性队列中验证了这一发现。 通过结合所有四个队列的全球测试，13% 的非裔美国人携带两个 APOL1 变异等位基因，与机会性感染几率降低 50% 相关。 OI 病因类别的亚组分析表明，OI 保护主要归因于对真菌感染的特定保护（An et al. Commun Biol, 2021）。我们还发现 APOL1 与败血症事件风险增加 25% 相关，这不成比例地影响非裔美国人（Chaudhary 等人，Clin J Amn Soc Nephrol，2020）。这些研究表明 APOL1 变异等位基因在先天免疫和体内炎症中发挥更广泛的作用。在与英国范德比尔特大学和国王学院的研究人员合作进行的研究中，我们正在调查 APOL1 基因型对治疗的 HIV 感染者和普通 COVID 幸存者人群的长期影响。我们发现，在目前居住在英国的接受艾滋病毒感染治疗的非洲黑人中，西非患慢性肾病的风险最高。在 2468 名黑人参与者中，193 名患有肾功能不全，87 名患有晚期 CKD 或正在进行透析，126 名患有蛋白尿，43 名患有 HIVAN/FSGS 或动脉肾硬化。调整人口特征、HIV 和一些 CKD 危险因素并以东非血统为参考后，西非血统与肾功能不全和 5 期 CKD 的几率增加 2 倍以上相关 (PR 2.23 [1.23-4.04]) 。西非血统（与东非/南非血统相比）也与肾活检诊断出 HIVAN/FSGS 或动脉肾硬化密切相关 (PR 6.44 [2.42-17.14]) (Hong et al., eClinicalMedicine, 2021)。这些结果表明，西非血统的艾滋病毒感染者患肾脏疾病的风险增加。随后的一项研究表明，APOL1 高风险基因型存在于 25% 的西非人中，但只有 1% 的东非人，以及 3-5% 的中非或南部非洲人，是西非人进行性 CKD 高患病率的原因，正如与西非人有共同血统的非裔美国人所报道的那样（2021 年提交）。在尼日利亚进行的另一项研究中，我们发现 APOL1 高风险状态因种族而异，并且与接受治疗的 HIV 感染者的肾功能下降和肾病范围蛋白尿密切相关（Wudil 等人，KI，2021）。在HBV相关肝癌方面取得的成就：1）最近的一项蛋白质组学研究报道了脂质代谢酶甾醇O-酰基转移酶（SOAT1）参与HCC的进展。我们首次研究了 HBV 相关 HCC 中的 SOAT1 基因变异和蛋白表达。我们对 221 名活检证实的 HCC 患者和 229 名健康个体的三个蛋白质编码区 SOAT1 变体进行了基因分型。 V323V 变体和单倍型 TGA 与 HCC 风险降低密切相关（风险降低 42-60%）。使用免疫化学染色，我们发现肿瘤中SOAT1的蛋白表达与邻近组织相比显着增加（P < 0.001）（Chen et al. BMC Cancer 2021）。 2) 我们小组合作开展了一系列研究，以确定 HCC 预后的生物标志物。研究小组利用 TCGA 中肿瘤和邻近肝组织之间失调的 RNA 确定了竞争性内源性 RNA (ceRNA) 网络，并研究了 HCC 患者的潜在预后因素。本研究构建了富含细胞周期、细胞分裂和细胞增殖途径的 ceRNA 网络和基因集。预后特征可能为预测 HCC 生存提供独立工具（Liao 等人，J Cancer，2019）。 3) 我们通过整合 TCGA 和 GEO 数据集中的 HBV-HCC 样本进行了荟萃分析，以评估基因表达模式的变化。我们的分析显示，所有数据集中共有超过 500 个差异表达基因 (DEG)，这表明 TCGA HBV-HCC 中大约 8% 的差异表达基因在各个研究中重复。已确定的途径和基因对于靶向治疗的开发具有无价的价值。 4) 我们正在鉴定用于 HCC 诊断和预后的 microRNA 标记。检测血清/血浆中的 miRNA 可能是早期 HCC 诊断的一种有前途的方法，从而实现有效的治疗。我们正在使用 RNA 测序技术系统地揭示来自南非的一组 HBV 相关 HCC 患者的 miRNA 特征。我们预计该项目将在 2 个月内完成。 5) 人类 APOBEC3 家族的胞苷脱氨酶限制逆转录病毒和移动逆转录元件，但也会使宿主单链 (ss)DNA 发生超突变，从而可能导致癌变。我们之前在 A3-VIf 通路的 A3G、A3B、A3F 和 CUL5 中发现了几个影响 HIV-1 感染或进展的遗传变异。 A3B/A3A 最近被认为是多种癌症中强内源性诱变剂。 APOBEC3B (A3B) 缺失是一种 29.5 kb DNA 种系缺失，将 APOBEC3A 的编码区与 APOBCE3B 的 3'UTR 融合，在亚洲人中很常见，但在其他人群中很少见，并且与乳腺癌风险升高相关。我们发现，与不删除相比，种系 A3B 删除与 HCC 风险高出 2 倍相关，而一或两个拷贝删除的风险则高出 3-5 倍。该结果表明常见的A3B缺失是HCC的主要易感位点。我们进一步发现A3B缺失携带者患肝硬化的风险高出2倍。由于 A3B 缺失的影响如此强烈，并且在亚洲（亚洲是世界上 HCC 患病率最高的地区）携带率如此之高，因此有必要将 A3B 纳入多基因 HCC 风险预测模型中。 A3B 可能通过与肿瘤抑制基因或癌基因等关键癌症基因相互作用来改变 HCC 风险。我们还探讨了A3B缺失与抑癌基因TP53之间的关系。我们发现，与两拷贝 A3B 缺失携带者相比，非 A3B 缺失携带者的 TP53 突变率更高（24% vs. 9%，p=0.02），表明 A3B 的存在可能导致 TP53 突变，而 A3B 缺失则可能导致 TP53 突变。减少突变的机会，与 A3B 角色一致*截断*

项目成果

Evidence for selection at HIV host susceptibility genes in a West Central African human population.

中西部非洲人群中艾滋病毒宿主易感性基因选择的证据。

• 发表时间: 2012-12-06
• 影响因子: 3.4
• 作者: Zhao, Kai;Ishida, Yasuko;Oleksyk, Taras K;Winkler, Cheryl A;Roca, Alfred L
• 通讯作者: Roca, Alfred L

Telomerase reverse transcriptase promoter mutations in hepatitis B virus-associated hepatocellular carcinoma.

乙型肝炎病毒相关肝细胞癌中的端粒酶逆转录酶启动子突变。

• 发表时间: 2016-05-10
• 作者: Yang, Xunjun;Guo, Xiuchan;Chen, Yao;Chen, Guorong;Ma, Yin;Huang, Kate;Zhang, Yuning;Zhao, Qiongya;Winkler, Cheryl A;An, Ping;Lyu, Jianxin
• 通讯作者: Lyu, Jianxin

Impact of rural versus urban setting on kidney markers: a cross-sectional study in South-Kivu, DRCongo.

农村与城市环境对肾脏标志物的影响：刚果民主共和国南基伍省的一项横断面研究。

• 发表时间: 2021
• 影响因子: 2.3
• 作者: Masimango, Mannix Imani;Hermans, Michel P;Malembaka, Espoir Bwenge;Wallemacq, Pierre;Sumaili, Ernest Kiswaya;Fillée, Catherine;D'Hoore, William;Winkler, Cheryl A;Limou, Sophie;Jadoul, Michel
• 通讯作者: Jadoul, Michel

A common HLA-DPA1 variant is a major determinant of hepatitis B virus clearance in Han Chinese.

常见的 HLA-DPA1 变异是汉族人乙型肝炎病毒清除的主要决定因素。

• DOI: 10.1093/infdis/jiq154
• 发表时间: 2011-04-01
• 期刊: The Journal of infectious diseases
• 作者: P. An;C. Winkler;Li Guan;S. O’Brien;Z. Zeng
• 通讯作者: Z. Zeng

Accounting for multiple comparisons in a genome-wide association study (GWAS).

考虑全基因组关联研究 (GWAS) 中的多重比较。

• 发表时间: 2010
• 影响因子: 4.4
• 作者: Johnson, Randall C;Nelson, George W;Troyer, Jennifer L;Lautenberger, James A;Kessing, Bailey D;Winkler, Cheryl A;O'Brien, Stephen J
• 通讯作者: O'Brien, Stephen J