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