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

Sleep disruption and duration are associated with variants in genes involved in energy homeostasis in adults with HIV/AIDS

Aouizerat, B. E., Byun, E., Pullinger, C. R., Gay, C., Lerdal, A., & Lee, K. A. (2021). Sleep Medicine, 82, 84-95. 10.1016/j.sleep.2020.08.028
Abstract
Abstract
Objective: To determine whether selected genes and plasma markers involved in energy homeostasis are associated with sleep disruption or duration in adults with HIV/AIDS. Methods: A sample of 289 adults with HIV/AIDS wore a wrist actigraph for 72 h to estimate total sleep time (TST) and wake after sleep onset (WASO). Twenty-three single nucleotide polymorphisms (SNP) spanning 5 energy homeostasis genes (adiponectin [ADIPOQ], ghrelin [GHRL], leptin [LEP], peroxisome proliferator-activated receptor-alpha [PPARA], and -gamma [PPARG]) were genotyped using a custom array. Plasma markers of energy homeostasis (adiponectin, ghrelin, leptin) were measured by commercial multiplex assay. Results: After adjusting for demographic and clinical characteristics (race/ethnicity, gender, CD4 cell count, waist circumference, medications), both WASO and TST were associated with SNPs in ADIPOQ (rs182052), LEP (rs10244329, rs3828942), PPARA (rs135551, rs4253655), and PPARG (rs709151). Additional SNPs in ADIPOQ were associated with WASO (rs1501299, rs3821799, rs6773957) and TST (rs2241766). TST was also associated with SNPs in GHRL (rs26802), LEP (rs11760956), PPARA (rs135547, rs8138102, rs4253776), and PPARG (rs12490265, rs796313). Many covariate-adjusted associations involved a significant interaction with markers of HIV (viral load, years since diagnosis). Among plasma markers, higher adiponectin was associated with less WASO, higher ghrelin and glucose levels with shorter TST, and higher leptin with longer TST. Conclusions: Replication of SNPs in all five genes and three plasma markers of energy homeostasis were associated with objective sleep measures. HIV disease influenced many of the associations. Findings strengthen evidence for associations between energy homeostasis genetics and poor sleep, and provide direction for pharmacological intervention research.

TNFα promotes oral cancer growth, pain, and Schwann cell activation

Salvo, E., Tu, N. H., Scheff, N. N., Dubeykovskaya, Z. A., Chavan, S. A., Aouizerat, B. E., & Ye, Y. (2021). Scientific Reports, 11(1). 10.1038/s41598-021-81500-4
Abstract
Abstract
Oral cancer is very painful and impairs a patient’s ability to eat, talk, and drink. Mediators secreted from oral cancer can excite and sensitize sensory neurons inducing pain. Cancer mediators can also activate Schwann cells, the peripheral glia that regulates neuronal function and repair. The contribution of Schwann cells to oral cancer pain is unclear. We hypothesize that the oral cancer mediator TNFα activates Schwann cells, which further promotes cancer progression and pain. We demonstrate that TNFα is overexpressed in human oral cancer tissues and correlates with increased self-reported pain in patients. Antagonizing TNFα reduces oral cancer proliferation, cytokine production, and nociception in mice with oral cancer. Oral cancer or TNFα alone increases Schwann cell activation (measured by Schwann cell proliferation, migration, and activation markers), which can be inhibited by neutralizing TNFα. Cancer- or TNFα-activated Schwann cells release pro-nociceptive mediators such as TNFα and nerve growth factor (NGF). Activated Schwann cells induce nociceptive behaviors in mice, which is alleviated by blocking TNFα. Our study suggests that TNFα promotes cancer proliferation, progression, and nociception at least partially by activating Schwann cells. Inhibiting TNFα or Schwann cell activation might serve as therapeutic approaches for the treatment of oral cancer and associated pain.

Women's HIV disclosure to the dentist: Does frequent contact matter?

Parish, C. L., Feaster, D. J., Pereyra, M. R., Alcaide, M. L., Weber, K. M., Cohen, M. H., Levin, S., Gustafson, D., Merenstein, D., Aouizerat, B. E., Donohue, J., Webster-Cyriaque, J., Wingood, G., Kempf, M. C., & Metsch, L. R. (2021). Journal of Public Health Dentistry, 81(1), 65-76. 10.1111/jphd.12403
Abstract
Abstract
Objectives: Research has shown inconsistent patterns of patients' HIV serostatus disclosure to their dentists. Common barriers to disclosure have included confidentiality concerns, fear of treatment refusal, and discrimination. This study evaluated the prevalence of HIV serostatus disclosure to the dentist, whether the frequency of dental care utilization is associated with disclosure, and reasons for nondisclosure among women living with HIV. Methods: We administered a cross-sectional oral health survey to 1,526 women living with HIV in the Women's Interagency HIV Study including questions regarding HIV serostatus disclosure to dentists. Logistic regression models were used to analyze the association between dental care utilization (at least annually versus less than annually) and HIV serostatus disclosure to dentists. Results: Overall, 83 percent of women reported that they disclosed their HIV serostatus to their dentist. The most common reasons for nondisclosure were: a) the dentist did not ask, b) believing that the dentist did not need to know, and c) not having a consistent dentist. In the multivariable logistic regression model, at least annual dental care utilization, compared to less than annual, led to a 59 percent reduction in the odds of HIV nondisclosure to the dentist. Discussion: Study findings highlight that dentists who see their patients infrequently should consider methods for overcoming barriers to HIV nondisclosure and the possibility that their patient's HIV serostatus is undisclosed. Educating women living with HIV about how disclosure to dentists is a critical component of their dental assessment and treatment, and how preventive dental treatment can improve overall health outcomes, is important.

African Mitochondrial DNA Haplogroup L2 Is Associated with Slower Decline of β-cell Function and Lower Incidence of Diabetes Mellitus in Non-Hispanic, Black Women Living with Human Immunodeficiency Virus

Sun, J., Brown, T. T., Tong, W., Samuels, D., Tien, P., Aissani, B., Aouizerat, B., Villacres, M., Kuniholm, M. H., Gustafson, D., Michel, K., Cohen, M., Schneider, M., Adimora, A. A., Ali, M. K., Bolivar, H., & Hulgan, T. (2020). Clinical Infectious Diseases, 71(8), E218-E225. 10.1093/cid/ciaa026
Abstract
Abstract
Background: Susceptibility to metabolic diseases may be influenced by mitochondrial genetic variability among people living with human immunodeficiency virus (HIV; PLWH), but remains unexplored in populations with African ancestry. We investigated the association between mitochondrial DNA (mtDNA) haplogroups and the homeostatic model assessments of β-cell function (HOMA-B) and insulin resistance (HOMA-IR), as well as incident diabetes mellitus (DM), among Black women living with or at risk for HIV. Methods: Women without DM who had fasting glucose (FG) and insulin (FI) data for ≥2 visits were included. Haplogroups were inferred from genotyping data using HaploGrep. HOMA-B and HOMA-IR were calculated using FG and FI data. Incident DM was defined by a combination of FG ≥ 126 mg/dL, the use of DM medication, a DM diagnosis, or hemoglobin A1c ≥ 6.5%. We compared HOMA-B, HOMA-IR, and incident DM by haplogroups and assessed the associations between HOMA-B and HOMA-IR and DM by haplogroup. Results: Of 1288 women (933 living with HIV and 355 living without HIV), PLWH had higher initial HOMA-B and HOMA-IR than people living without HIV. PLWH with haplogroup L2 had a slower decline in HOMA-B per year (Pinteraction =. 02) and a lower risk of incident DM (hazard ratio [HR], 0.51; 95% confidence interval [CI],. 32-.82) than PLWH with other haplogroups after adjustments for age, body mass index, combination antiretroviral therapy use, CD4 cell counts, and HIV RNA. The impact of HOMA-IR on incident DM was less significant in those with haplogroup L2, compared to non-L2 (HR, 1.28 [95% CI,. 70-2.38] vs 4.13 [95% CI, 3.28-5.22], respectively; Pinteraction <. 01), among PLWH. Conclusions: Mitochondrial genetic variation is associated with β-cell functions and incident DM in non-Hispanic, Black women with HIV and alters the relationship between insulin resistance and DM.

Association of HLA genotype with T-cell activation in human immunodeficiency virus (HIV) and HIV/ hepatitis c virus-coinfected women

Kovacs, A. A., Kono, N., Wang, C. H., Wang, D., Frederick, T., Operskalski, E., Tien, P. C., French, A. L., Minkoff, H., Kassaye, S., Golub, E. T., Aouizerat, B. E., Kuniholm, M. H., & Millstein, J. (2020). Journal of Infectious Diseases, 221(7), 1156-1166. 10.1093/infdis/jiz589
Abstract
Abstract
BACKGROUND: Global immune activation and HLA alleles are each associated with the pathogenesis of human immunodeficiency virus (HIV) and hepatitis C virus .METHODS: We evaluated the relationship between 44 HLA class I and 28 class II alleles and percentages of activated CD8 (CD8+CD38+DR+) and CD4 (CD4+CD38+DR+) T cells in 586 women who were naive to highly active antiretroviral therapy. We used linear generalized estimating equation regression models, adjusting for race/ethnicity, age, HIV load, and hepatitis C virus infection and controlling for multiplicity using a false discovery rate threshold of 0.10.RESULTS: Ten HLA alleles were associated with CD8 and/or CD4 T-cell activation. Lower percentages of activated CD8 and/or CD4 T cells were associated with protective alleles B*57:03 (CD8 T cells, -6.6% [P = .002]; CD4 T cells, -2.7% [P = .007]), C*18:01 (CD8 T cells, -6.6%; P < .0008) and DRB1*13:01 (CD4 T cells, -2.7%; P < .0004), and higher percentages were found with B*18:01 (CD8 T cells, 6.2%; P < .0003), a detrimental allele. Other alleles/allele groups associated with activation included C*12:03, group DQA1*01:00, DQB1*03:01, DQB1*03:02, DQB1*06:02, and DQB1*06:03.CONCLUSION: These findings suggest that a person's HLA type may play a role in modulating T-cell activation independent of viral load and sheds light on the relationship between HLA, T-cell activation, immune control, and HIV pathogenesis.

Comparison of methylation capture sequencing and Infinium MethylationEPIC array in peripheral blood mononuclear cells

Shu, C., Zhang, X., Aouizerat, B. E., & Xu, K. (2020). Epigenetics and Chromatin, 13(1). 10.1186/s13072-020-00372-6
Abstract
Abstract
Background: Epigenome-wide association studies (EWAS) have been widely applied to identify methylation CpG sites associated with human disease. To date, the Infinium MethylationEPIC array (EPIC) is commonly used for high-throughput DNA methylation profiling. However, the EPIC array covers only 30% of the human methylome. Methylation Capture bisulfite sequencing (MC-seq) captures target regions of methylome and has advantages of extensive coverage in the methylome at an affordable price. Methods: Epigenome-wide DNA methylation in four peripheral blood mononuclear cell samples was profiled by using SureSelectXT Methyl-Seq for MC-seq and EPIC platforms separately. CpG site-based reproducibility of MC-seq was assessed with DNA sample inputs ranging in quantity of high (> 1000 ng), medium (300–1000 ng), and low (150 ng–300 ng). To compare the performance of MC-seq and the EPIC arrays, we conducted a Pearson correlation and methylation value difference at each CpG site that was detected by both MC-seq and EPIC. We compared the percentage and counts in each CpG island and gene annotation between MC-seq and the EPIC array. Results: After quality control, an average of 3,708,550 CpG sites per sample were detected by MC-seq with DNA quantity > 1000 ng. Reproducibility of DNA methylation in MC-seq-detected CpG sites was high among samples with high, medium, and low DNA inputs (r > 0.96). The EPIC array captured an average of 846,464 CpG sites per sample. Compared with the EPIC array, MC-seq detected more CpGs in coding regions and CpG islands. Among the 472,540 CpG sites captured by both platforms, methylation of a majority of CpG sites was highly correlated in the same sample (r: 0.98–0.99). However, methylation for a small proportion of CpGs (N = 235) differed significantly between the two platforms, with differences in beta values of greater than 0.5. Conclusions: Our results show that MC-seq is an efficient and reliable platform for methylome profiling with a broader coverage of the methylome than the array-based platform. Although methylation measurements in majority of CpGs are highly correlated, a number of CpG sites show large discrepancy between the two platforms, which warrants further investigation and needs cautious interpretation.

Depression and psychosocial stress are associated with subclinical carotid atherosclerosis among women living with hiv

Levy, M. E., Anastos, K., Levine, S. R., Plankey, M., Castel, A. D., Molock, S., Sen, S., Asch, F. M., Milam, J., Aouizerat, B., Weber, K. M., Golub, E. T., Kaplan, R. C., & Kassaye, S. (2020). Journal of the American Heart Association, 9(13). 10.1161/JAHA.120.016425
Abstract
Abstract
BACKGROUND: To identify reasons for increased atherosclerotic risk among women living with HIV (WLWH), we evaluated the associations between psychosocial risk factors (depressive symptoms, perceived stress, and posttraumatic stress disorder symptoms) and subclinical atherosclerosis among WLWH and HIV-negative women. METHODS AND RESULTS: Carotid artery focal plaque (localized intima-media thickness >1.5 mm) was measured using B-mode ultrasound imaging in 2004–2005 and 2010–2012 in the Women’s Interagency HIV Study. We created psychosocial risk groups using latent class analysis and defined prevalent plaque at the final measurement. We also examined repeated semiannual depression measures with respect to focal plaque formation throughout follow-up. The associations between latent class and prevalent plaque, and between depressive symptom persistence and plaque formation, were assessed separately by HIV status using multivariable logistic regression. Among 700 women (median age 47 years), 2 latent classes were identified: high (n=163) and low (n=537) psychosocial risk, with corresponding prevalence of depression (65%/13%), high stress (96%/12%), and probable posttraumatic stress disorder (46%/2%). Among WLWH, plaque prevalence was 23% and 11% in high versus low psychosocial risk classes (adjusted odds ratio [aOR], 2.12; 95% CI, 1.11–4.05) compared with 9% and 9% among HIV-negative women (aOR, 1.07; 95% CI, 0.24–4.84), respectively. New plaque formation occurred among 17% and 9% of WLWH who reported high depressive symptoms at ≥45% versus <45% of visits (aOR, 1.96; 95% CI, 1.06–3.64), compared with 9% and 7% among HIV-negative women (aOR, 0.82; 95% CI, 0.16–4.16), respectively. CONCLUSIONS: Psychosocial factors were independent atherosclerotic risk factors among WLWH. Research is needed to determine whether interventions for depression and psychosocial stress can mitigate the increased risk of atherosclerosis for WLWH.

A disintegrin and metalloproteinase domain 17-epidermal growth factor receptor signaling contributes to oral cancer pain

Scheff, N. N., Ye, Y., Conley, Z. R., Quan, J. W., Ronald Lam, Y. V., Klares, R., Singh, K., Schmidt, B. L., & Aouizerat, B. E. (2020). Pain, 161(10), 2330-2343. 10.1097/j.pain.0000000000001926
Abstract
Abstract
Cancer cells secrete pronociceptive mediators that sensitize adjacent sensory neurons and cause pain. Identification and characterization of these mediators could pinpoint novel targets for cancer pain treatment. In this study, we identified candidate genes in cancer cell lines that encode for secreted or cell surface proteins that may drive nociception. To undertake this work, we used an acute cancer pain mouse model, transcriptomic analysis of publicly available human tumor-derived cell line data, and a literature review. Cancer cell line supernatants were assigned a phenotype based on evoked nociceptive behavior in an acute cancer pain mouse model. We compared gene expression data from nociceptive and nonnociceptive cell lines. Our analyses revealed differentially expressed genes and pathways; many of the identified genes were not previously associated with cancer pain signaling. Epidermal growth factor receptor (EGFR) and disintegrin metalloprotease domain 17 (ADAM17) were identified as potential targets among the differentially expressed genes. We found that the nociceptive cell lines contained significantly more ADAM17 protein in the cell culture supernatant compared to nonnociceptive cell lines. Cytoplasmic EGFR was present in almost all (.90%) tongue primary afferent neurons in mice. Monoclonal antibody against EGFR, cetuximab, inhibited cell line supernatant-induced nociceptive behavior in an acute oral cancer pain mouse model. We infer from these data that ADAM17-EGFR signaling is involved in cancer mediator-induced nociception. The differentially expressed genes and their secreted protein products may serve as candidate therapeutic targets for oral cancer pain and warrant further evaluation.

Oral health–related quality of life and unmet dental needs among women living with HIV

Parish, C. L., Feaster, D. J., Pereyra, M. R., Alcaide, M. L., Weber, K. M., Cohen, M., Levin, S., Gustafson, D., Merenstein, D., Aouizerat, B. E., Donohue, J., Webster-Cyriaque, J., Wingood, G., Kempf, M. C., & Metsch, L. R. (2020). Journal of the American Dental Association, 151(7), 527-535. 10.1016/j.adaj.2020.04.013
Abstract
Abstract
Background: Oral health–related quality of life (OHRQoL) is a multidimensional, perception-based measure of how oral health affects social and physical functioning and self-image. OHRQoL is important for assessing women living with HIV (WLWH) who may have unmet dental needs and experience disparities that impact dental care accessibility. Methods: In 2016, the authors conducted an assessment of OHRQoL among a national sample of 1,526 WLWH in the Women's Interagency HIV Study using the Oral Health Impact Profile instrument, which assesses the frequency of 14 oral health impact items. OHRQoL was measured using multivariable linear regression with a negative binomial distribution to assess the association between report of a recent unmet dental need and OHRQoL. Results: “Fair or poor” oral health condition was reported by 37.8% (n = 576) of WLWH. Multivariable linear regression showed that unmet dental needs had the strongest positive association with poor OHRQoL (difference in Oral Health Impact Profile mean, 2.675; P <.001) compared with not having unmet needs. The frequency of dental care utilization was not associated with higher OHRQoL. Older age, fair or poor dental condition, smoking, symptoms of anxiety and loneliness, and poor OHRQoL were also associated with worse OHRQoL. Conclusion: Self-perceived impact of oral health on social and physical function and self-image, as measured by OHRQoL, may be an easily assessable but underrecognized aspect of OHRQoL, particularly among women aging with HIV. Practical Implications: Dentists should implement OHRQoL assessments in their management of the care of patients with HIV to identify those who do have significant oral health impacts.

The role of DNA methylation and histone modification in periodontal disease: A systematic review

Khouly, I., Braun, R. S., Ordway, M., Aouizerat, B. E., Ghassib, I., Larsson, L., & Asa’ad, F. (2020). International Journal of Molecular Sciences, 21(17), 1-37. 10.3390/ijms21176217
Abstract
Abstract
Despite a number of reports in the literature on the role of epigenetic mechanisms in periodontal disease, a thorough assessment of the published studies is warranted to better comprehend the evidence on the relationship between epigenetic changes and periodontal disease and its treatment. Therefore, the aim of this systematic review is to identify and synthesize the evidence for an association between DNA methylation/histone modification and periodontal disease and its treatment in human adults. A systematic search was independently conducted to identify articles meeting the inclusion criteria. DNA methylation and histone modifications associated with periodontal diseases, gene expression, epigenetic changes after periodontal therapy, and the association between epigenetics and clinical parameters were evaluated. Sixteen studies were identified. All included studies examined DNA modifications in relation to periodontitis, and none of the studies examined histone modifications. Substantial variation regarding the reporting of sample sizes and patient characteristics, statistical analyses, and methodology, was found. There was some evidence, albeit inconsistent, for an association between DNA methylation and periodontal disease. IL6, IL6R, IFNG, PTGS2, SOCS1, and TNF were identified as candidate genes that have been assessed for DNA methylation in periodontitis. While several included studies found associations between methylation levels and periodontal disease risk, there is insufficient evidence to support or refute an association between DNA methylation and periodontal disease/therapy in human adults. Further research must be conducted to identify reproducible epigenetic markers and determine the extent to which DNA methylation can be applied as a clinical biomarker.