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DNA methylation-based telomere length is associated with HIV infection, physical frailty, cancer, and all-cause mortality

Liang, Xiaoyu; Aouizerat, Bradley E; So-Armah, Kaku; Cohen, Mardge H; Marconi, Vincent C; Xu, Ke; Justice, Amy C
Telomere length (TL) is an important indicator of cellular aging. Shorter TL is associated with several age-related diseases including coronary heart disease, heart failure, diabetes, osteoporosis, and cancer. Recently, a DNA methylation-based TL (DNAmTL) estimator has been developed as an alternative method for directly measuring TL. In this study, we examined the association of DNAmTL with cancer prevalence and mortality risk among people with and without HIV in the Veterans Aging Cohort Study Biomarker Cohort (VACS, N = 1917) and Women's Interagency HIV Study Cohort (WIHS, N = 481). We profiled DNAm in whole blood (VACS) or in peripheral blood mononuclear cells (WIHS) using an array-based method. Cancer prevalence was estimated from electronic medical records and cancer registry data. The VACS Index was used as a measure of physiologic frailty. Models were adjusted for self-reported race and ethnicity, batch, smoking status, alcohol consumption, and five cell types (CD4, CD8, NK, B cell, and monocyte). We found that people with HIV had shorter average DNAmTL than those without HIV infection [beta = -0.25, 95% confidence interval (-0.32, -0.18), p = 1.48E-12]. Greater value of VACS Index [beta = -0.002 (-0.003, -0.001), p = 2.82E-05] and higher cancer prevalence [beta = -0.07 (-0.10, -0.03), p = 1.37E-04 without adjusting age] were associated with shortened DNAmTL. In addition, one kilobase decrease in DNAmTL was associated with a 40% increase in mortality risk [hazard ratio: 0.60 (0.44, 0.82), p = 1.42E-03]. In summary, HIV infection, physiologic frailty, and cancer are associated with shortening DNAmTL, contributing to an increased risk of all-cause mortality.
PMID: 38629454
ISSN: 1474-9726
CID: 5657412

Computationally inferred cell-type specific epigenome-wide DNA methylation analysis unveils distinct methylation patterns among immune cells for HIV infection in three cohorts

Zhang, Xinyu; Hu, Ying; Vandenhoudt, Ral E; Yan, Chunhua; Marconi, Vincent C; Cohen, Mardge H; Wang, Zuoheng; Justice, Amy C; Aouizerat, Bradley E; Xu, Ke
BACKGROUND:Epigenome-wide association studies (EWAS) have identified CpG sites associated with HIV infection in blood cells in bulk, which offer limited knowledge of cell-type specific methylation patterns associated with HIV infection. In this study, we aim to identify differentially methylated CpG sites for HIV infection in immune cell types: CD4+ T-cells, CD8+ T-cells, B cells, Natural Killer (NK) cells, and monocytes. METHODS:Applying a computational deconvolution method, we performed a cell-type based EWAS for HIV infection in three independent cohorts (Ntotal = 1,382). DNA methylation in blood or in peripheral blood mononuclear cells (PBMCs) was profiled by an array-based method and then deconvoluted by Tensor Composition Analysis (TCA). The TCA-computed CpG methylation in each cell type was first benchmarked by bisulfite DNA methylation capture sequencing in a subset of the samples. Cell-type EWAS of HIV infection was performed in each cohort separately and a meta-EWAS was conducted followed by gene set enrichment analysis. RESULTS:The meta-analysis unveiled a total of 2,021 cell-type unique significant CpG sites for five inferred cell types. Among these inferred cell-type unique CpG sites, the concordance rate in the three cohorts ranged from 96% to 100% in each cell type. Cell-type level meta-EWAS unveiled distinct patterns of HIV-associated differential CpG methylation, where 74% of CpG sites were unique to individual cell types (false discovery rate, FDR <0.05). CD4+ T-cells had the largest number of unique HIV-associated CpG sites (N = 1,624) compared to any other cell type. Genes harboring significant CpG sites are involved in immunity and HIV pathogenesis (e.g. CD4+ T-cells: NLRC5, CX3CR1, B cells: IFI44L, NK cells: IL12R, monocytes: IRF7), and in oncogenesis (e.g. CD4+ T-cells: BCL family, PRDM16, monocytes: PRDM16, PDCD1LG2). HIV-associated CpG sites were enriched among genes involved in HIV pathogenesis and oncogenesis that were enriched among interferon-α and -γ, TNF-α, inflammatory response, and apoptotic pathways. CONCLUSION/CONCLUSIONS:Our findings uncovered computationally inferred cell-type specific modifications in the host epigenome for people with HIV that contribute to the growing body of evidence regarding HIV pathogenesis.
PMCID:10957090
PMID: 38466776
ISSN: 1553-7374
CID: 5645442

The replication-competent HIV reservoir is a genetically restricted, younger subset of the overall pool of HIV proviruses persisting during therapy, which is highly genetically stable over time

Shahid, Aniqa; MacLennan, Signe; Jones, Bradley R; Sudderuddin, Hanwei; Dang, Zhong; Cobarrubias, Kyle; Duncan, Maggie C; Kinloch, Natalie N; Dapp, Michael J; Archin, Nancie M; Fischl, Margaret A; Ofotokun, Igho; Adimora, Adaora; Gange, Stephen; Aouizerat, Bradley; Kuniholm, Mark H; Kassaye, Seble; Mullins, James I; Goldstein, Harris; Joy, Jeffrey B; Anastos, Kathryn; Brumme, Zabrina L; ,
Within-host HIV populations continually diversify during untreated infection, and this diversity persists within infected cell reservoirs during antiretroviral therapy (ART). Achieving a better understanding of on-ART proviral evolutionary dynamics, and a better appreciation of how the overall persisting pool of (largely genetically defective) proviruses differs from the much smaller replication-competent HIV reservoir, is critical to HIV cure efforts. We reconstructed within-host HIV evolutionary histories in blood from seven participants of the Women's Interagency HIV Study who experienced HIV seroconversion, and used these data to characterize the diversity, lineage origins, and ages of proviral env-gp120 sequences sampled longitudinally up to 12 years on ART. We also studied HIV sequences emerging from the reservoir in two participants. We observed that proviral clonality generally increased over time on ART, with clones frequently persisting long term. While on-ART proviral integration dates generally spanned the duration of untreated infection, HIV emerging in plasma was exclusively younger (i.e., dated to the years immediately pre-ART). The genetic and age distributions of distinct proviral sequences remained stable during ART in all but one participant, in whom there was evidence that younger proviruses had been preferentially eliminated after 12 years on ART. Analysis of the gag region in three participants corroborated our env-gp120-based observations, indicating that our observations are not influenced by the HIV region studied. Our results underscore the remarkable genetic stability of the distinct proviral sequences that persist in blood during ART. Our results also suggest that the replication-competent HIV reservoir is a genetically restricted, younger subset of this overall proviral pool.IMPORTANCECharacterizing the genetically diverse HIV sequences that persist in the reservoir despite antiretroviral therapy (ART) is critical to cure efforts. Our observations confirm that proviruses persisting in blood on ART, which are largely genetically defective, broadly reflect the extent of within-host HIV evolution pre-ART. Moreover, on-ART clonal expansion is not appreciably accompanied by the loss of distinct proviral lineages. In fact, on-ART proviral genetic composition remained stable in all but one participant, in whom, after 12 years on ART, proviruses dating to around near ART initiation had been preferentially eliminated. We also identified recombinant proviruses between parental sequence fragments of different ages. Though rare, such sequences suggest that reservoir cells can be superinfected with HIV from another infection era. Overall, our finding that the replication-competent reservoir in blood is a genetically restricted, younger subset of all persisting proviruses suggests that HIV cure strategies will need to eliminate a reservoir that differs in key respects from the overall proviral pool.
PMID: 38214547
ISSN: 1098-5514
CID: 5634722

Substance Use Over Time Among Sexual and Gender Minority People: Differences at the Intersection of Sex and Gender

Flentje, Annesa; Sunder, Gowri; Ceja, Alexis; Lisha, Nadra E; Neilands, Torsten B; Aouizerat, Bradley E; Lubensky, Micah E; Capriotti, Matthew R; Dastur, Zubin; Lunn, Mitchell R; Obedin-Maliver, Juno
PMID: 38206680
ISSN: 2325-8306
CID: 5631322

Longitudinal associations between microRNAs and weight in the diabetes prevention program

Flowers, Elena; Stroebel, Benjamin; Lewis, Kimberly A; Aouizerat, Bradley E; Gadgil, Meghana; Kanaya, Alka M; Zhang, Li; Gong, Xingyue
OBJECTIVE/UNASSIGNED:Circulating microRNAs show cross-sectional associations with overweight and obesity. Few studies provided data to differentiate between a snapshot perspective on these associations versus how microRNAs characterize prodromal risk from disease pathology and complications. This study assessed longitudinal relationships between circulating microRNAs and weight at multiple time-points in the Diabetes Prevention Program trial. RESEARCH DESIGN AND METHODS/UNASSIGNED:A subset of participants (n=150) from the Diabetes Prevention Program were included. MicroRNAs were measured from banked plasma using a Fireplex Assay. We used generalized linear mixed models to evaluate relationships between microRNAs and changes in weight at baseline, year-1, and year-2. Logistic regression was used to evaluate whether microRNAs at baseline were associated with weight change after 2 years. RESULTS/UNASSIGNED:In fully adjusted models that included relevant covariates, seven miRs (i.e., miR-126, miR-15a, miR-192, miR-23a, and miR-27a) were statistically associated with weight over 2 years. MiR-197 and miR-320a remained significant after adjustment for multiple comparisons. Baseline levels of let-7f, miR-17, and miR-320c were significantly associated with 3% weight loss after 2 years in fully adjusted models. DISCUSSION/UNASSIGNED:This study provided evidence for longitudinal relationships between circulating microRNAs and weight. Because microRNAs characterize the combined effects of genetic determinants and responses to behavioral determinants, they may provide insights about the etiology of overweight and obesity in the context or risk for common, complex diseases. Additional studies are needed to validate the potential genes and biological pathways that might be targeted by these microRNA biomarkers and have mechanistic implications for weight loss and disease prevention.
PMID: 39359416
ISSN: 1664-2392
CID: 5706632

Single-Cell Molecular Profiling of Head and Neck Squamous Cell Carcinoma Reveals Five Dysregulated Signaling Pathways Associated With Circulating Tumor Cells

Stucky, Andres; Viet, Chi T; Aouizerat, Bradley E; Ye, Yi; Doan, Coleen; Mundluru, Tarun; Sedhiazadeh, Parish; Sinha, Uttam K; Chen, Xuelian; Zhang, Xi; Li, Shengwen Calvin; Cai, Jin; Zhong, Jiang F
OBJECTIVES/OBJECTIVE:To determine the dysregulated signaling pathways of head and neck squamous cell carcinoma associated with circulating tumor cells (CTCs) via single-cell molecular characterization. INTRODUCTION/BACKGROUND:Head and neck squamous cell carcinoma (HNSCC) has a significant global burden and is a disease with poor survival. Despite trials exploring new treatment modalities to improve disease control rates, the 5 year survival rate remains low at only 60%. Most cancer malignancies are reported to progress to a fatal phase due to the metastatic activity derived from treatment-resistant cancer cells, regarded as one of the most significant obstacles to develope effective cancer treatment options. However, the molecular profiles of cancer cells have not been thoroughly studied. METHODS:Here, we examined in-situ HNSCC tumors and pairwisely followed up with the downstream circulating tumor cells (CTCs)-based on the surrogate biomarkers to detect metastasis that is established in other cancers - not yet being fully adopted in HNSCC treatment algorithms. RESULTS:Specifically, we revealed metastatic HNSCC patients have complex CTCs that could be defined through gene expression and mutational gene profiling derived from completed single-cell RNASeq (scRNASeq) that served to confirm molecular pathways inherent in these CTCs. To enhance the reliability of our findings, we cross-validated those molecular profiles with results from previously published studies. CONCLUSION/CONCLUSIONS:Thus, we identified 5 dysregulated signaling pathways in CTCs to derive HNSCC biomarker panels for screening HNSCC in situ tumors.
PMCID:11179551
PMID: 38869038
ISSN: 1526-2359
CID: 5669692

Reply to: Genetic differentiation at probe SNPs leads to spurious results in meQTL discovery [Letter]

Cheng, Youshu; Li, Boyang; Zhang, Xinyu; Aouizerat, Bradley E; Zhao, Hongyu; Xu, Ke
PMCID:10739901
PMID: 38129596
ISSN: 2399-3642
CID: 5611782

Co-occurrence of injection drug use and hepatitis C increases epigenetic age acceleration that contributes to all-cause mortality among people living with HIV

Liang, Xiaoyu; Justice, Amy C; Marconi, Vincent C; Aouizerat, Bradley E; Xu, Ke
Co-occurrence of injection drug use (IDU) and hepatitis C virus infection (HCV) is common in people living with HIV (PLWH) and leads to significantly increased mortality. Epigenetic clocks derived from DNA methylation (DNAm) are associated with disease progression and all-cause mortality. In this study, we hypothesized that epigenetic age mediates the relationships between the co-occurrence of IDU and HCV with mortality risk among PLWH. We tested this hypothesis in the Veterans Aging Cohort Study (n = 927) by using four established epigenetic clocks of DNAm age (i.e., Horvath, Hannum, Pheno, Grim). Compared to individuals without IDU and HCV (IDU-HCV-), participants with IDU and HCV (IDU+HCV+) showed a 2.23-fold greater risk of mortality estimated using a Cox proportional hazards model (hazard ratio: 2.23; 95% confidence interval: 1.62-3.09; p = 1.09E-06). IDU+HCV+ was associated with a significantly increased epigenetic age acceleration (EAA) measured by 3 out of 4 epigenetic clocks, adjusting for demographic and clinical variables (Hannum: p = 8.90E-04, Pheno: p = 2.34E-03, Grim: p = 3.33E-11). Furthermore, we found that epigenetic age partially mediated the relationship between IDU+HCV+ and all-cause mortality, up to a 13.67% mediation proportion. Our results suggest that comorbid IDU with HCV increases EAA in PLWH that partially mediates the increased mortality risk.
PMCID:10190198
PMID: 37191953
ISSN: 1559-2308
CID: 5503552

Variations in Genes Encoding Human Papillomavirus Binding Receptors and Susceptibility to Cervical Precancer

Mukherjee, Amrita; Ye, Yuanfan; Wiener, Howard W; Kuniholm, Mark H; Minkoff, Howard; Michel, Kate; Palefsky, Joel; D'Souza, Gypsyamber; Rahangdale, Lisa; Butler, Kenneth R; Kempf, Mirjam-Colette; Sudenga, Staci L; Aouizerat, Bradley E; Ojesina, Akinyemi I; Shrestha, Sadeep
BACKGROUND:Cervical cancer oncogenesis starts with human papillomavirus (HPV) cell entry after binding to host cell surface receptors; however, the mechanism is not fully known. We examined polymorphisms in receptor genes hypothesized to be necessary for HPV cell entry and assessed their associations with clinical progression to precancer. METHODS:African American women (N = 1,728) from the MACS/WIHS Combined Cohort Study were included. Two case-control study designs were used-cases with histology-based precancer (CIN3+) and controls without; and cases with cytology-based precancer [high-grade squamous intraepithelial lesions (HSIL)] and controls without. SNPs in candidate genes (SDC1, SDC2, SDC3, SDC4, GPC1, GPC2, GPC3, GPC4, GPC5, GPC6, and ITGA6) were genotyped using an Illumina Omni2.5-quad beadchip. Logistic regression was used to assess the associations in all participants and by HPV genotypes, after adjusting for age, human immunodeficiency virus serostatus, CD4 T cells, and three principal components for ancestry. RESULTS:Minor alleles in SNPs rs77122854 (SDC3), rs73971695, rs79336862 (ITGA6), rs57528020, rs201337456, rs11987725 (SDC2), rs115880588, rs115738853, and rs9301825 (GPC5) were associated with increased odds of both CIN3+ and HSIL, whereas, rs35927186 (GPC5) was found to decrease the odds for both outcomes (P value ≤ 0.01). Among those infected with Alpha-9 HPV types, rs722377 (SDC3), rs16860468, rs2356798 (ITGA6), rs11987725 (SDC2), and rs3848051 (GPC5) were associated with increased odds of both precancer outcomes. CONCLUSIONS:Polymorphisms in genes that encode binding receptors for HPV cell entry may play a role in cervical precancer progression. IMPACT:Our findings are hypothesis generating and support further exploration of mechanisms of HPV entry genes that may help prevent progression to cervical precancer.
PMCID:10472094
PMID: 37410084
ISSN: 1538-7755
CID: 5620072

MicroRNA biomarkers target genes and pathways associated with type 2 diabetes

Kariuki, Dorian; Aouizerat, Bradley E; Asam, Kesava; Kanaya, Alka M; Zhang, Li; Florez, Jose C; Flowers, Elena
AIMS/HYPOTHESIS/OBJECTIVE:Our prior analysis of the Diabetes Prevention Program study identified a subset of five miRNAs that predict incident type 2 diabetes. The purpose of this study was to identify mRNAs and biological pathways targeted by these five miRNAs to elucidate potential mechanisms of risk and responses to the tested interventions. METHODS:Using experimentally validated data from miRTarBase version 8.0 and R (2021), we identified mRNAs with strong evidence to be regulated by individual or combinations of the five predictor miRNAs. Overrepresentation of the mRNA targets was assessed in pathways from the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway annotation database. RESULTS:The five miRNAs targeted 167 pathways and 122 mRNAs. Nine of the pathways have known associations with type 2 diabetes: Insulin signaling, Insulin resistance, Diabetic cardiomyopathy, Type 2 diabetes, AGE-RAGE signaling in diabetic complications, HIF-1 signaling, TGF-beta signaling, PI3K/Akt signaling, and Adipocytokine signaling pathways. Vascular endothelial growth factor A (VEGFA) has prior genetic associations with risk for type 2 diabetes and was the most commonly targeted mRNA for this set of miRNAs. CONCLUSIONS/INTERPRETATION/CONCLUSIONS:These findings show that miRNA predictors of incident type 2 diabetes target mRNAs and pathways known to underlie risk for type 2 diabetes. Future studies should evaluate miRNAs as potential therapeutic targets for preventing and treating type 2 diabetes.
PMID: 37543292
ISSN: 1872-8227
CID: 5619012