Bradley E. Aouizerat

Faculty

Bradley E. Aouizerat headshot

Bradley E. Aouizerat

PhD

Professor, College of Dentistry

Bradley E. Aouizerat's additional information

BS, Microbiology/ Molecular Genetics - University of California at Los Angeles
PhD, Microbiology/ Molecular Genetics/lmmunology - University of California at Los Angeles
MAS, Master of Advance Science Research in Clinical - University of California at San Francisco

Oral-systemic health

American Heart Association
American Liver Foundation
American Pain Society
American Society for Human Genetics
International Association for the Study of Pain

Faculty Honors Awards

Excellence in Research Mentoring Faculty Teaching Award (2013)
Excellence in Research Mentoring Faculty Teaching Award (Nominee) (2012)
Excellence in Research Mentoring Faculty Teaching Award (Nominee) (2011)
Most Dedicated Mentor Award, PMCTR Fellowship Program (2009)
Early Career Investigator Award, Bayer Healthcare International (2006)
Multidisciplinary Clinical Research Scholar, Roadmap K12 (2006)
Early Career Faculty Award, Hellman Family (2005)
Faculty Mentorship Award Nominee (2005)
Young Investigator Award, National Hemophilia Foundation (2005)
National Liver Scholar Award, American Liver Foundation (2004)
Irvine H. Page Young Investigator Award (Finalist), American Heart Association (2004)
Faculty Mentorship Award Nominee (2004)
Sam and Rose Gilbert Fellowship, UCLA (1998)
Warsaw Fellowship (1998)

Publications

A Genome-Wide Association Study Identifies a Candidate Gene Associated With Atazanavir Exposure Measured in Hair

Tamraz, B., Huang, Y., French, A. L., Kassaye, S., Anastos, K., Nowicki, M. J., Gange, S., Gustafson, D. R., Bacchetti, P., Greenblatt, R. M., Hysi, P. G., & Aouizerat, B. E. (2018). Clinical Pharmacology and Therapeutics, 104(5), 949-956. 10.1002/cpt.1014
Abstract
Abstract
Hair provides a direct measure of long-term exposure of atazanavir (ATV). We report the results of the first genome-wide association study (GWAS) of ATV exposure measured in hair in an observational cohort representative of US women living with HIV; the Women's Interagency HIV Study. Approximately 14.1 million single nucleotide polymorphisms (SNPs) were analyzed in linear regression-based GWAS, with replication, adjusted for nongenetic predictors collected under conditions of actual use of ATV in 398 participants. Lastly, the PharmGKB database was used to identify pharmacogene associations with ATV exposure. The rs73208473, within intron 1 of SORCS2, resulted in a 0.46-fold decrease in ATV exposure, with the strongest association (P = 1.71×10−8) in GWAS. A priori pharmacogene screening did not identify additional variants statistically significantly associated with ATV exposure, including those previously published in ATV plasma candidate pharmacogene studies. The findings demonstrate the potential value of pharmacogenomic GWAS in ethnically diverse populations under conditions of actual use.

HIV and symptoms of depression are independently associated with impaired glucocorticoid signaling

Bekhbat, M., Mehta, C. C., Kelly, S. D., Vester, A., Ofotokun, I., Felger, J., Wingood, G., Anastos, K., Gustafson, D. R., Kassaye, S., Milam, J., Aouizerat, B., Weber, K., Golub, E. T., Moore, M. F., Diclemente, R., Fischl, M., Kempf, M. C., Maki, P., & Neigh, G. N. (2018). Psychoneuroendocrinology, 96, 118-125. 10.1016/j.psyneuen.2018.06.013
Abstract
Abstract
Chronic inflammation caused by HIV infection may lead to deficient glucocorticoid (GC) signaling predisposing people living with HIV to depression and other psychiatric disorders linked to GC resistance. We hypothesized that comorbid HIV and depressive symptoms in women would synergistically associate with deficits in GC signaling. This cross-sectional study used samples obtained from the Women's Interagency HIV Study (WIHS). The Centers for Epidemiological Studies (CES-D) was used to define depression in four groups of women from the Women's Interagency HIV Study (WIHS): 1) HIV-negative, non-depressed (n = 37); 2) HIV-negative, depressed (n = 34); 3) HIV-positive, non-depressed (n = 38); and 4) HIV-positive, depressed (n = 38). To assess changes in GC signaling from peripheral blood mononuclear cells (PBMCs), we examined baseline and dexamethasone (Dex)-stimulated changes in the expression of the GC receptor (GR, gene: Nr3c1) and its negative regulator Fkbp5 via quantitative RT-PCR. GR sensitivity was evaluated in vitro by assessing the Dex inhibition of lipopolysaccharide (LPS)-stimulated IL-6 and TNF-α levels. Depressive symptoms and HIV serostatus were independently associated with elevated baseline expression of Fkbp5 and Nr3c1. Depressive symptoms, but not HIV status, was independently associated with reduced LPS-induced release of IL-6. Counter to predictions, there was no interactive association of depressive symptoms and HIV on any outcome. Comorbid depressive symptoms with HIV infection were associated with a gene expression and cytokine profile similar to that of healthy control women, a finding that may indicate further disruptions in disease adaptation.

In Children With Nonalcoholic Fatty Liver Disease, Zone 1 Steatosis Is Associated With Advanced Fibrosis

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Abstract
Abstract
Background & Aims: Focal zone 1 steatosis, although rare in adults with nonalcoholic fatty liver disease (NAFLD), does occur in children with NAFLD. We investigated whether focal zone 1 steatosis and focal zone 3 steatosis are distinct subphenotypes of pediatric NAFLD. We aimed to determine associations between the zonality of steatosis and demographic, clinical, and histologic features in children with NAFLD. Methods: We performed a cross-sectional study of baseline data from 813 children (age <18 years; mean age, 12.8 ± 2.7 years). The subjects had biopsy-proven NAFLD and were enrolled in the Nonalcoholic Steatohepatitis Clinical Research Network. Liver histology was reviewed using the Nonalcoholic Steatohepatitis Clinical Research Network scoring system. Results: Zone 1 steatosis was present in 18% of children with NAFLD (n = 146) and zone 3 steatosis was present in 32% (n = 244). Children with zone 1 steatosis were significantly younger (10 vs 14 years; P <.001) and a significantly higher proportion had any fibrosis (81% vs 51%; P <.001) or advanced fibrosis (13% vs 5%; P <.001) compared with children with zone 3 steatosis. In contrast, children with zone 3 steatosis were significantly more likely to have steatohepatitis (30% vs 6% in children with zone 1 steatosis; P <.001). Conclusions: Children with zone 1 or zone 3 distribution of steatosis have an important subphenotype of pediatric NAFLD. Children with zone 1 steatosis are more likely to have advanced fibrosis and children with zone 3 steatosis are more likely to have steatohepatitis. To achieve a comprehensive understanding of pediatric NAFLD, studies of pathophysiology, natural history, and response to treatment should account for the zonality of steatosis.

Knowing something versus feeling different: the effects and non-effects of genetic ancestry on racial identity

Shim, J. K., Rab Alam, S., & Aouizerat, B. E. (2018). New Genetics and Society, 37(1), 44-66. 10.1080/14636778.2018.1430560
Abstract
Abstract
Since the completion of the Human Genome Project, there have been pitched debates about its implications and the research it enables. One prominent thread of concern focuses on the role of post-genomic science on technically enabling and generating interest in genetic ancestry testing (GAT). Critical analyses of GAT have pointed to multiple issues, raising the alarm on consumers’ experiences with such technologies. This paper describes the results of a pilot study in which we tracked women’s experiences receiving their genetic ancestry results, and their understandings of, reactions to, and valuing of this information over time. Overwhelmingly, our participants reported a curious combination of anticipation and satisfaction yet no discernable impact on their sense of self or racial identity. We elaborate on the effects and non-effects of GAT for the women in our study, and how we make sense of their simultaneous experiences of ‘knowing something’ but not ‘feeling different.’.

Machine learning for detection of lymphedema among breast cancer survivors

Fu, M., Wang, Y., LI, C., Qiu, Z., Axelrod, D., Guth, A. A., Scagliola, J., Conley, Y. P., Aouizerat, B., Qiu, J. M., Yu, G., Van Cleave, J., Haber, J., & Cheung, Y. K. (2018). MHealth, 4. 10.21037/mhealth.2018.04.02
Abstract
Abstract
Background: In the digital era when mHealth has emerged as an important venue for health care, the application of computer science, such as machine learning, has proven to be a powerful tool for health care in detecting or predicting various medical conditions by providing improved accuracy over conventional statistical or expert-based systems. Symptoms are often indicators for abnormal changes in body functioning due to illness or side effects from medical treatment. Real-time symptom report refers to the report of symptoms that patients are experiencing at the time of reporting. The use of machine learning integrating real-time patient-centered symptom report and real-time clinical analytics to develop real-time precision prediction may improve early detection of lymphedema and long term clinical decision support for breast cancer survivors who face lifelong risk of lymphedema. Lymphedema, which is associated with more than 20 distressing symptoms, is one of the most distressing and dreaded late adverse effects from breast cancer treatment. Currently there is no cure for lymphedema, but early detection can help patients to receive timely intervention to effectively manage lymphedema. Because lymphedema can occur immediately after cancer surgery or as late as 20 years after surgery, real-time detection of lymphedema using machine learning is paramount to achieve timely detection that can reduce the risk of lymphedema progression to chronic or severe stages. This study appraised the accuracy, sensitivity, and specificity to detect lymphedema status using machine learning algorithms based on real-time symptom report.Methods: A web-based study was conducted to collect patients' real-time report of symptoms using a mHealth system. Data regarding demographic and clinical information, lymphedema status, and symptom features were collected. A total of 355 patients from 45 states in the US completed the study. Statistical and machine learning procedures were performed for data analysis. The performance of five renowned classification algorithms of machine learning were compared: Decision Tree of C4.5, Decision Tree of C5.0, gradient boosting model (GBM), artificial neural network (ANN), and support vector machine (SVM). Each classification algorithm has certain user-definable hyper parameters. Five-fold cross validation was used to optimize these hyper parameters and to choose the parameters that led to the highest average cross validation accuracy.Results: Using machine leaning procedures comparing different algorithms is feasible. The ANN achieved the best performance for detecting lymphedema with accuracy of 93.75%, sensitivity of 95.65%, and specificity of 91.03%.Conclusions: A well-trained ANN classifier using real-time symptom report can provide highly accurate detection of lymphedema. Such detection accuracy is significantly higher than that achievable by current and often used clinical methods such as bio-impedance analysis. Use of a well-trained classification algorithm to detect lymphedema based on symptom features is a highly promising tool that may improve lymphedema outcomes.

Machine learning selected smoking-associated DNA methylation signatures that predict HIV prognosis and mortality

Zhang, X., Hu, Y., Aouizerat, B. E., Peng, G., Marconi, V. C., Corley, M. J., Hulgan, T., Bryant, K. J., Zhao, H., Krystal, J. H., Justice, A. C., & Xu, K. (2018). Clinical Epigenetics, 10(1). 10.1186/s13148-018-0591-z
Abstract
Abstract
Background: The effects of tobacco smoking on epigenome-wide methylation signatures in white blood cells (WBCs) collected from persons living with HIV may have important implications for their immune-related outcomes, including frailty and mortality. The application of a machine learning approach to the analysis of CpG methylation in the epigenome enables the selection of phenotypically relevant features from high-dimensional data. Using this approach, we now report that a set of smoking-associated DNA-methylated CpGs predicts HIV prognosis and mortality in an HIV-positive veteran population. Results: We first identified 137 epigenome-wide significant CpGs for smoking in WBCs from 1137 HIV-positive individuals (p < 1.70E-07). To examine whether smoking-associated CpGs were predictive of HIV frailty and mortality, we applied ensemble-based machine learning to build a model in a training sample employing 408,583 CpGs. A set of 698 CpGs was selected and predictive of high HIV frailty in a testing sample [(area under curve (AUC) = 0.73, 95%CI 0.63~0.83)] and was replicated in an independent sample [(AUC = 0.78, 95%CI 0.73~0.83)]. We further found an association of a DNA methylation index constructed from the 698 CpGs that were associated with a 5-year survival rate [HR = 1.46; 95%CI 1.06~2.02, p = 0.02]. Interestingly, the 698 CpGs located on 445 genes were enriched on the integrin signaling pathway (p = 9.55E-05, false discovery rate = 0.036), which is responsible for the regulation of the cell cycle, differentiation, and adhesion. Conclusion: We demonstrated that smoking-associated DNA methylation features in white blood cells predict HIV infection-related clinical outcomes in a population living with HIV.

Minority stress and leukocyte gene expression in sexual minority men living with treated HIV infection

Flentje, A., Kober, K. M., Carrico, A. W., Neilands, T. B., Flowers, E., Heck, N. C., & Aouizerat, B. E. (2018). Brain, Behavior, and Immunity, 70, 335-345. 10.1016/j.bbi.2018.03.016
Abstract
Abstract
Sexual minority (i.e., non-heterosexual) individuals experience poorer mental and physical health, accounted for in part by the additional burden of sexual minority stress occurring from being situated in a culture favoring heteronormativity. Informed by previous research, the purpose of this study was to identify the relationship between sexual minority stress and leukocyte gene expression related to inflammation, cancer, immune function, and cardiovascular function. Sexual minority men living with HIV who were on anti-retroviral medication, had viral load < 200 copies/mL, and had biologically confirmed, recent methamphetamine use completed minority stress measures and submitted blood samples for RNA sequencing on leukocytes. Differential gene expression and pathway analyses were conducted comparing those with clinically elevated minority stress (n = 18) and those who did not meet the clinical cutoff (n = 20), covarying reactive urine toxicology results for very recent stimulant use. In total, 90 differentially expressed genes and 138 gene set pathways evidencing 2-directional perturbation were observed at false discovery rate (FDR) < 0.10. Of these, 41 of the differentially expressed genes and 35 of the 2-directionally perturbed pathways were identified as functionally related to hypothesized mechanisms of inflammation, cancer, immune function, and cardiovascular function. The neuroactive-ligand receptor pathway (implicated in cancer development) was identified using signaling pathway impact analysis. Our results suggest several potential biological pathways for future work investigating the relationship between sexual minority stress and health.

Racial differences in human papilloma virus types amongst United States women with HIV and cervical precancer

Keller, M. J., Burk, R. D., Massad, L. S., Eltoum, I. E., Hessol, N. A., Anastos, K., Xie, X., Minkoff, H., Xue, X., Reimers, L. L., Kuniholm, M., D’Souza, G., Colie, C., Aouizerat, B., Palefsky, J. M., & Strickler, H. D. (2018). AIDS, 32(18), 2821-2826. 10.1097/QAD.0000000000002005
Abstract
Abstract
Objective:Recent studies reported a lower human papillomavirus 16 (HPV16) prevalence in cervical precancer among African American than Caucasian women in the general population. We assessed this relationship in women with HIV.Design:Women living with or at risk for HIV in the Women's Interagency HIV Study were followed semi-annually with Pap tests, colposcopy/histology (if indicated), and collection of cervicovaginal lavage samples for HPV testing by PCR. Racial and ethnic groups were defined using genomic Ancestry Informative Markers (AIMs).Results:Among 175 cases of cervical intraepithelial neoplasia 3 or worse (CIN-3+), 154 were diagnosed in women with HIV. African American (27%) and Hispanic (37%) cases were significantly less likely than Caucasian (62%) women to test positive for HPV16 (P=0.01). In multivariate logistic regression models, these associations remained significant for African Americans (odds ratio=0.13; 95% confidence interval (CI) 0.04-0.44; P=0.001) but not Hispanics, after controlling for HIV status, CD4+ count, history of AIDS, age, smoking, and sexual behavior. Limiting the analysis to women with HIV did not change the findings.Conclusion:HPV16 prevalence is lower in African American compared with Caucasian women with HIV and cervical precancer, independent of immune status. Future studies to determine why these racial differences exist are warranted, and whether there are similar associations between race and invasive cervical cancer in women with HIV. Further, HPV types not covered by quadrivalent and bivalent vaccines may play an especially important role in cervical precancer among HIV-positive African American women, a possible advantage to using nonavalent HPV vaccine in this population.

Recent stimulant use and leukocyte gene expression in methamphetamine users with treated HIV infection

Carrico, A. W., Flentje, A., Kober, K., Lee, S., Hunt, P., Riley, E. D., Shoptaw, S., Flowers, E., Dilworth, S. E., Pahwa, S., & Aouizerat, B. E. (2018). Brain, Behavior, and Immunity, 71, 108-115. 10.1016/j.bbi.2018.04.004
Abstract
Abstract
Stimulant use may accelerate HIV disease progression through biological and behavioral pathways. However, scant research with treated HIV-positive persons has examined stimulant-associated alterations in pathophysiologic processes relevant to HIV pathogenesis. In a sample of 55 HIV-positive, methamphetamine-using sexual minority men with a viral load less than 200 copies/mL, we conducted RNA sequencing to examine patterns of leukocyte gene expression in participants who had a urine sample that was reactive for stimulants (n = 27) as compared to those who tested non-reactive (n = 28). Results indicated differential expression of 32 genes and perturbation of 168 pathways in recent stimulant users. We observed statistically significant differential expression of single genes previously associated with HIV latency, cell cycle regulation, and immune activation in recent stimulant users (false discovery rate p < 0.10). Pathway analyses indicated enrichment for genes associated with inflammation, innate immune activation, neuroendocrine hormone regulation, and neurotransmitter synthesis. Recent stimulant users displayed concurrent elevations in plasma levels of tumor necrosis factor – alpha (TNF-α) but not interleukin 6 (IL-6). Further research is needed to examine the bio-behavioral mechanisms whereby stimulant use may contribute to HIV persistence and disease progression.

Alterations in opioid inhibition cause widespread nociception but do not affect anxiety-like behavior in oral cancer mice

Ye, Y., Bernabé, D. G., Salvo, E., Viet, C. T., Ono, K., Dolan, J. C., Janal, M., Aouizerat, B. E., Miaskowski, C., & Schmidt, B. L. (2017). Neuroscience, 363, 50-61. 10.1016/j.neuroscience.2017.06.038
Abstract
Abstract
Widespread pain and anxiety are commonly reported in cancer patients. We hypothesize that cancer is accompanied by attenuation of endogenous opioid-mediated inhibition, which subsequently causes widespread pain and anxiety. To test this hypothesis we used a mouse model of oral squamous cell carcinoma (SCC) in the tongue. We found that mice with tongue SCC exhibited widespread nociceptive behaviors in addition to behaviors associated with local nociception that we reported previously. Tongue SCC mice exhibited a pattern of reduced opioid receptor expression in the spinal cord; intrathecal administration of respective mu (MOR), delta (DOR), and kappa (KOR) opioid receptor agonists reduced widespread nociception in mice, except for the fail flick assay following administration of the MOR agonist. We infer from these findings that opioid receptors contribute to widespread nociception in oral cancer mice. Despite significant nociception, mice with tongue SCC did not differ from sham mice in anxiety-like behaviors as measured by the open field assay and elevated maze. No significant differences in c-Fos staining were found in anxiety-associated brain regions in cancer relative to control mice. No correlation was found between nociceptive and anxiety-like behaviors. Moreover, opioid receptor agonists did not yield a statistically significant effect on behaviors measured in the open field and elevated maze in cancer mice. Lastly, we used an acute cancer pain model (injection of cancer supernatant into the mouse tongue) to test whether adaptation to chronic pain is responsible for the absence of greater anxiety-like behavior in cancer mice. No changes in anxiety-like behavior were observed in mice with acute cancer pain.