Bradley E. Aouizerat

Abstract

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.

Abstract

Aims: The purpose of this study was to assess the levels of cardiovascular health (CVH) of Black and Latino adults with type 2 diabetes (T2D) and examine the association of individual and microsystem level factors with their CVH score. Methods: This was a cross-sectional design in 60 Black and Latino Adults aged 18–40 with T2D. Data were collected on sociodemographic, individual (sociodemographic, diabetes self-management, sleep disturbance, depressive symptoms, quality of life, and the inflammatory biomarkers IL-6 and hs-CRP) and microsystem factors (family functioning), and American Heart Association’s Life’s Simple 7 metrics of CVH. Factors significantly associated with the CVH score in the bivariate analyses were entered into a linear regression model. Results: The sample had a mean age 34 ± 5 years and was primarily female (75%) with a mean CVH score was 8.6 ± 2.2 (possible range of 0–14). The sample achieved these CVH factors at ideal levels: body mass index <25 kg/m2 (8%); blood pressure <120/80 (42%); hemoglobin A1c < 7% (57%); total cholesterol <200 mg/dL (83%); healthy diet (18%); never or former smoker > one year (95%); and physical activity (150 moderate-to-vigorous minutes/week; 45%). In the multivariable model, two factors were significantly associated with cardiovascular health: hs-CRP (B = −0.11621, p <.0001) and the general health scale (B = 0.45127, p =.0013). Conclusions: This sample had an intermediate level of CVH, with inflammation and general health associated with overall CVH score.

Abstract

Background: Cocaine-one of the most frequently abused illicit drugs among persons living with HIV [people living with HIV (PLWH)]-slows the decline of viral production after antiretroviral therapy and is associated with higher HIV viral load, more rapid HIV progression, and increased mortality. Setting: We examined the impact of cocaine use on the CD4+ T-cell HIV latent reservoir (HLR) in virally suppressed PLWH participating in a national, longitudinal cohort study of the natural and treated history of HIV in the United States. Methods: CD4+ T-cell genomic DNA from 434 women of diverse ancestry (ie, 75% Black, 14% Hispanic, 12% White) who self-reported cocaine use (ie, 160 cocaine users, 59 prior users, 215 non-users) was analyzed using the Intact Proviral HIV DNA Assay, measuring intact provirus per 106 CD4+ T cells. Findings: HIV latent reservoir size differed by cocaine use (ie, median [interquartile range]: 72 [14-193] for never users, 165 [63-387] for prior users, 184 [28-502] for current users), which was statistically significantly larger in both prior (P = 0.023) and current (P = 0.001) cocaine users compared with never users. Conclusions: Cocaine use may contribute to a larger replication competent HLR in CD4+ T cells among virologically suppressed women living with HIV. Our findings are important because women are underrepresented in HIV reservoir studies and in studies of the impact of cocaine use on outcomes among PLWH.

Abstract

Problem: Bacterial vaginosis (BV) disproportionally impacts Black and Hispanic women, placing them at risk for HIV, sexually transmitted infections and preterm birth. It is unknown whether there are differences by genetic ancestry in BV risk or whether polymorphisms associated with BV risk differ by ancestry. Methods: Women's Interagency HIV Study (WIHS) participants with longitudinal Nugent scores were dichotomized as having (n = 319, Nugent 7–10) or not having BV (n = 367, Nugent 0–3). Genetic ancestry was defined by clustering of principal components from ancestry informative markers and further stratified by BV status. 627 single nucleotide polymorphisms (SNPs) across 41 genes important in mucosal defense were identified in the WIHS GWAS. A logistic regression analysis was adjusted for nongenetic predictors of BV and self-reported race/ethnicity to assess associations between genetic ancestry and genotype. Results: Self-reported race and genetic ancestry were associated with BV risk after adjustment for behavioral factors. Polymorphisms in mucosal defense genes including syndecans, cytokines and toll-like receptors (TLRs) were associated with BV in all ancestral groups. Conclusions: The common association of syndecan, cytokine and TLR genes and the importance of immune function and inflammatory pathways in BV, suggests these should be targeted for further research on BV pathogenesis and therapeutics.

Abstract

Methylation quantitative trait loci (meQTLs) quantify the effects of genetic variants on DNA methylation levels. However, most published studies utilize bulk methylation datasets composed of different cell types and limit our understanding of cell-type-specific methylation regulation. We propose a hierarchical Bayesian interaction (HBI) model to infer cell-type-specific meQTLs, which integrates a large-scale bulk methylation data and a small-scale cell-type-specific methylation data. Through simulations, we show that HBI enhances the estimation of cell-type-specific meQTLs. In real data analyses, we demonstrate that HBI can further improve the functional annotation of genetic variants and identify biologically relevant cell types for complex traits.

Abstract

Background: Pre-diabetes mellitus (DM) is associated with proteinuria, a risk factor for chronic kidney disease. While people with human immunodeficiency virus (HIV; PWH) have a higher risk of proteinuria than people without HIV (PWOH), it is unknown whether incident proteinuria differs by HIV serostatus among prediabetic persons. Methods: The urine protein-to-creatinine ratio was measured at semiannual visits among men in the Multicenter AIDS Cohort Study since April 2006. Men with pre-DM on or after April 2006 and no prevalent proteinuria or use of antidiabetic medications were included. Pre-DM was defined as a fasting glucose level of 100-125 mg/dL confirmed within a year by a repeated fasting glucose or hemoglobin A1c measurement of 5.7%-6.4%. Incident proteinuria was defined as a urine protein-to-creatinine ratio (UPCR) >200 mg/g, confirmed within a year. We used Poisson regression models to determine whether incident proteinuria in participants with pre-DM differed by HIV serostatus and, among PWH, whether HIV-specific factors were related to incident proteinuria. Results: Between 2006 and 2019, among 1276 men with pre-DM, proteinuria developed in 128 of 613 PWH (21%) and 50 of 663 PWOH (8%) over a median 10-year follow-up. After multivariable adjustment, the incidence of proteinuria in PWH with pre-DM was 3.3 times (95% confidence interval, 2.3-4.8 times) greater than in PWOH (P <. 01). Among PWH, current CD4 cell count <50/μL (P <. 01) and current use of protease inhibitors (P =. 03) were associated with incident proteinuria, while lamivudine and integrase inhibitor use were associated with a lower risk. Conclusions: Among men with pre-DM, the risk of incident proteinuria was 3 times higher in PWH. Strategies to preserve renal function are needed in this population.

Abstract

Objective: 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: 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: 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: 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.

Abstract

The Diabetes Prevention Program (DPP) randomized controlled trial demonstrated that metformin treatment reduced progression to type 2 diabetes (T2D) by 31% compared to placebo in adults with prediabetes. Circulating micro-ribonucleic acids (miRs) are promising biomarkers of T2D risk, but little is known about their associations with metformin regimens for T2D risk reduction. We compared the change in 24 circulating miRs from baseline to 2 years in a subset from DPP metformin intervention (n = 50) and placebo (n = 50) groups using Wilcoxon signed rank tests. Spearman correlations were used to evaluate associations between miR change and baseline clinical characteristics. Multiple linear regression was used to adjust for covariates. The sample was 73% female, 17% Black, 13% Hispanic, and 50 ± 11 years. Participants were obese, normotensive, prediabetic, and dyslipidemic. Change in 12 miR levels from baseline to 2 years was significantly different in the metformin group compared with placebo after adjusting for multiple comparisons: six (let-7c-5p, miR-151a-3p, miR-17-5p, miR-20b-5p, miR-29b-3p, and miR-93-5p) were significantly upregulated and six (miR-130b-3p, miR-22-3p, miR-222-3p, miR-320a-3p, miR-320c, miR-92a-3p) were significantly downregulated in the metformin group. These miRs help to explain how metformin is linked to T2D risk reduction, which may lead to novel biomarkers, therapeutics, and precision health strategies.

Abstract

Head and neck squamous cell carcinoma (HNSCC) is painful, and perineural invasion (PNI) has been associated with the worst pain. Pain due to HNSCC is diverse and may vary based on clinicopathological factors. This study aims to characterize different pain patterns linked with PNI, its influence on daily functioning, and gain insights into molecular changes and pathways associated with PNI-related pain in HNSCC patients. We conducted a cross-sectional study across 3 medical centers (n = 114), assessing pain phenotypes and their impact on daily functioning using 2 self-reported pain questionnaires, given to patients prior to their cancer surgery. Furthermore, we conducted RNA-seq analysis utilizing the The Cancer Genome Atlas dataset of HNSCC tumor from patients (n = 192) to identify genes relevant to both PNI and pain. Upon adjusting for demographic and clinicopathological variables using linear regression models, we found that PNI independently predicted function-evoked pain according to the University of Calfornia San Francisco Oral Cancer Pain Questionnaire, as well as the worst pain intensity reported in the Brief Pain Inventory. Distinct pain patterns were observed to be associated with daily activities in varying manners. Our molecular analyses revealed significant disruptions in pathways associated with the extracellular matrix structure and organization. The top differentially expressed genes linked to the extracellular matrix are implicated in cancer development, pain, and neurodegenerative diseases. Our data underscore the importance of properly categorizing pain phenotypes in future studies aiming to uncover mechanistic underpinnings of pain. Additionally, we have compiled a list of genes of interest that could serve as targets for both cancer and cancer pain management. Perspective: PNI independently predicts function-evoked pain. Different pain phenotypes affect daily activities differently. We identified a list of candidate genes involved in the extracellular matrix structure and function that can be targeted for both cancer and cancer pain control.

Abstract

Objective: This epigenomics sub-study embedded within a randomized controlled trial examined whether an evidenced-based behavioral intervention model that decreased stimulant use altered leukocyte DNA methylation (DNAm). Methods: Sexual minority men with HIV who use methamphetamine were randomized to a five-session positive affect intervention (n = 32) or an attention-control condition (n = 21), both delivered during three months of contingency management for stimulant abstinence. All participants exhibited sustained HIV virologic control – an HIV viral load less than 40 copies/mL at baseline and six months post-randomization. The Illumina EPIC BeadChip measured leukocyte methylation of cytosine-phosphate-guanosine (CpG) sites mapping onto five a priori candidate genes of interest (i.e., ADRB2, BDNF, FKBP5, NR3C1, OXTR). Functional DNAm pathways and soluble markers of immune dysfunction were secondary outcomes. Results: Compared to the attention-control condition, the positive affect intervention significantly decreased methylation of CpG sites on genes that regulate β2 adrenergic and oxytocin receptors. There was an inconsistent pattern for the direction of the intervention effects on methylation of CpG sites on genes for glucocorticoid receptors and brain-derived neurotrophic factor. Pathway analyses adjusting for the false discovery rate (padj < 0.05) revealed significant intervention-related alterations in DNAm of Reactome pathways corresponding to neural function as well as dopamine, glutamate, and serotonin release. Positive affect intervention effects on DNAm were accompanied by significant reductions in the self-reported frequency of stimulant use. Conclusions: There is an epigenetic signature of an evidence-based behavioral intervention model that reduced stimulant use, which will guide the identification of biomarkers for treatment responses.