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*

艾滋病毒-1是大流行病，HBV感染和HBV- HCC在东亚和撒哈拉以南非洲普遍存在，影响全球数百万人。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。我们的策略是识别不同影响感染率或发病过程的遗传变异，从而使用靶基因、基因组全关联研究（GWAS）和功能方法识别含有变异的基因。我们与南非和中国的研究人员建立了国际合作关系，以解决重要的公共卫生问题（即南非的艾滋病毒和中国的hbv相关肝癌）。在HIV疾病中的研究成果：1)APOL1是先天免疫系统的一员，受炎症细胞因子，特别是干扰素的上调。由于APOL1变异也会失调巨噬细胞分化，我们调查了440名非洲裔美国HIV感染者中APOL1与机会性感染的关系，并进行了一项包含4个HIV/AIDS队列的荟萃分析，其中包括2066名参与者。携带两个APOL1变异等位基因与机会性感染几率降低71%相关。在一项荟萃分析中，我们在三个HIV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。对成骨不全病因分类的亚组分析表明，成骨不全保护主要归因于对真菌感染的特异性保护（An等）。common Biol, 2021)。我们还发现，APOL1与脓毒症发生率增加25%相关，非裔美国人的脓毒症发生率不成比例（Chaudhary等人，clinj Amn Soc Nephrol, 2020）。这些研究表明APOL1变异等位基因在体内先天免疫和炎症中具有更广泛的作用。在与范德比尔特大学（Vanderbilt University）和英国国王学院（Kings College）的研究人员的合作研究中，我们正在调查APOL1基因型在接受治疗的艾滋病毒感染和普通COVID幸存者群体中的长期后果。我们发现，在目前居住在英国的接受过HIV治疗的非洲黑人中，西非患慢性肾脏疾病的风险最高。在2468名黑人参与者中，193名患有肾脏损害，87名患有晚期CKD或透析，126名患有蛋白尿，43名患有hiv /FSGS或动脉肾硬化。在调整了人口统计学特征、艾滋病毒和几种CKD危险因素并以东非血统为参照后，西非血统与肾脏损害和5期CKD的几率增加2倍以上相关（PR为2.23[1.23-4.04]）。西非血统（与东非/南非血统相比）也与hiv /FSGS或肾活检动脉肾硬化的诊断密切相关（PR 6.44 [2.42-17.14]） （Hong et al., ecclinicalmedicine, 2021）。这些结果表明，西非血统的艾滋病毒携带者患肾脏疾病的风险增加。随后的一项研究表明，25%的西非人存在APOL1高危基因型，但只有1%的东非人和3-5%的中非或南部非洲人存在APOL1高危基因型，这是西非人进行性CKD高发的原因，正如在与西非人有共同祖先的非洲裔美国人中所报道的那样（提交，2021年）。在尼日利亚进行的另一项研究中，我们发现APOL1高危状态因种族而异，并且与接受治疗的HIV感染患者肾功能下降和肾病范围蛋白尿密切相关（Wudil等人，KI, 2021）。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。我们首次进行了SOAT1基因变异和hbv相关HCC蛋白表达的研究。我们在221例活检证实的HCC患者和229例健康个体中对三种蛋白质编码区SOAT1变异进行了基因分型。V323V变异和单倍型TGA与HCC风险降低密切相关（风险降低42-60%）。通过免疫化学染色，我们发现肿瘤中SOAT1蛋白的表达与邻近组织相比显著升高（P < 0.001） （Chen等）。BMC癌症2021)。2)我们小组合作进行了一系列研究，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的失调RNA，确定了竞争的内源性RNA （ceRNA）网络，并研究HCC患者的潜在预后因素。本研究构建了一个丰富细胞周期、细胞分裂和细胞增殖通路的ceRNA网络和基因集。预后特征可能是预测HCC生存的独立工具（Liao et al., J Cancer, 2019）。3)通过整合来自TCGA和GEO数据集的HBV-HCC样本，我们进行了一项荟萃分析，以评估基因表达模式的变化。我们的分析显示，超过500个差异表达基因（DEG）在所有数据集中共享，表明大约8%的TCGA HBV-HCC差异表达基因在研究中被复制。确定的途径和基因对于靶向治疗的发展是无价的。4)我们正在寻找用于HCC诊断和预后的microRNA标志物。检测血清/血浆中的miRNA可能是早期HCC诊断和有效治疗的一种有前景的方法。我们正在使用RNA-seq技术系统地揭示来自南非的hbv相关HCC患者队列中的miRNA特征。我们预计在两个月内完成这项工程。5)人类APOBEC3家族的胞苷脱氨酶限制逆转录病毒和可移动的逆转录因子，但也会使宿主单链DNA发生超突变，这可能有助于致癌。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的强内源性诱变剂。APOBEC3B （A3B）缺失是一个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，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有关。我们发现，与无缺失相比，这种种系A3B缺失与HCC风险高2倍相关，与单拷贝或双拷贝缺失的风险高3-5倍相关。这一结果表明常见的A3B缺失是HCC的主要易感位点。我们进一步发现A3B缺失携带者发生肝硬化的风险高出2倍。亚洲是世界上HCC患病率最高的地区，由于A3B缺失的影响如此之大，携带率如此之高，因此将A3B纳入多基因HCC风险预测模型是有必要的。A3B可能通过与肿瘤抑制基因或癌基因等关键癌基因相互作用来改变HCC风险。我们还探讨了A3B缺失与肿瘤抑制基因TP53的关系。我们发现非A3B缺失携带者的TP53突变率高于双拷贝A3B缺失携带者（24% vs. 9%, p=0.02），提示A3B的存在可能导致TP53突变，而不存在A3B则降低了突变的几率，这与A3B的作用一致*TRUNCATED*

项目成果

Impacts of the SOAT1 genetic variants and protein expression on HBV-related hepatocellular carcinoma.

• DOI: 10.1186/s12885-021-08245-1
• 发表时间: 2021-05-26
• 期刊: BMC cancer
• 影响因子: 3.8
• 作者: Chen Y;Yang X;Chen Y;Chen G;Winkler CA;An P;Lyu J
• 通讯作者: Lyu J

The evolving story of apolipoprotein L1 nephropathy: the end of the beginning.

• DOI: 10.1038/s41581-022-00538-3
• 发表时间: 2022-05
• 期刊: Nature reviews. Nephrology
• 作者: Daneshpajouhnejad P;Kopp JB;Winkler CA;Rosenberg AZ
• 通讯作者: Rosenberg AZ

Circulating microRNA's as a diagnostic tool for hepatocellular carcinoma in a hyper endemic HIV setting, KwaZulu-Natal, South Africa: a case control study protocol focusing on viral etiology.

• DOI: 10.1186/s12885-017-3915-z
• 发表时间: 2017-12-28
• 期刊: BMC cancer
• 影响因子: 3.8
• 作者: Sartorius K;Sartorius B;Kramvis A;Singh E;Turchinovich A;Burwinkel B;Madiba T;Winkler CA
• 通讯作者: Winkler CA

Genetics of focal segmental glomerulosclerosis and human immunodeficiency virus-associated collapsing glomerulopathy: the role of MYH9 genetic variation.

• DOI: 10.1016/j.semnephrol.2010.01.003
• 发表时间: 2010-03
• 期刊: SEMINARS IN NEPHROLOGY
• 影响因子: 3.3
• 作者: Winkler, Cheryl A.;Nelson, George;Oleksyk, Taras K.;Nava, M. Berenice;Kopp, Jeffrey B.
• 通讯作者: Kopp, Jeffrey B.

Host and Viral Genetic Variation in HBV-Related Hepatocellular Carcinoma.

• DOI: 10.3389/fgene.2018.00261
• 发表时间: 2018
• 期刊: Frontiers in genetics
• 影响因子: 3.7
• 作者: An P;Xu J;Yu Y;Winkler CA
• 通讯作者: Winkler CA