Bio

Bio


I am a graduate of the Harvard School of Public Health with a dual-doctorate in molecular/genetic epidemiology and environmental health. I have extensive expertise in quantitative analysis, epidemiological study design, and causal inference in observational studies. However, I am best described as a genomic trauma specialist focusing on the relationship between molecular markers, environmental factors, and risk of chronic diseases. My current research is multifaceted. I am currently investigating the relationship between sex hormone levels and risk of uterine fibroids in the Study of Women's Health Across the Nation (SWAN). Additionally, I am characterizing chromosomal copy-number variations in relation to risk of cardiovascular outcomes in the Cardiovascular Health Study (CHS). I am also exploring gene-environment interactions within the Epidemiology of Endometrial Cancer Consortium (E2C2).

My career in biological research began at the British Columbia Cancer Agency under the guidance of Dr. Keith Humphries, a world renowned expert on the genetics of hematological disorders. It was in the Humphrie?s laboratory that I developed a strong foundation in molecular genetic techniques which served as a primer for the rest of my career. Subsequently, I became research laboratory manager for Dr. Immaculata De Vivo, a pioneer in molecular epidemiology at the Channing Division of Network Medicine at the Brigham and Women?s Hospital. Not only did I hone my expertise in molecular biology, but also received extensive training in the burgeoning field of molecular and genetic epidemiology.

I used a three-pronged paradigm in my research to combat cancer; understanding genetic and biological susceptibility, prevention by attenuating modifiable risk factors, and treatment of underlying causative factors. With respect to genetic susceptibility, my projects focused on functional characterization of polymorphisms which predisposed women to endometrial cancer. With respect to attenuating modifiable risk factors, we studied how smoking and other lifestyle choices affect cancer risk. With respect to treatment of underlying disease, I studied how a novel therapeutic molecule called dichloroacetate induces cell death in a panel of endometrial cancer cells.

My doctoral thesis focused on the effect of airborne particulate matter on telomere length, mediated through chronic inflammation and global DNA methylation. My interest in predictors of chronic disease is not limited to only to biological and environmental factors, but also social factors such as exposure to racism and early-life adversity in susceptible populations.

Professional Education


  • Master of Science, Harvard University (2011)
  • Bachelor of Science, Simon Fraser University (2001)
  • Doctor, Harvard University (2014)

Stanford Advisors


Research & Scholarship

Lab Affiliations


Publications

Journal Articles


  • Association Between Donor Leukocyte Telomere Length and Survival After Unrelated Allogeneic Hematopoietic Cell Transplantation for Severe Aplastic Anemia JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Gadalla, S. M., Wang, T., Haagenson, M., Spellman, S. R., Lee, S. J., Williams, K. M., Wong, J. Y., De Vivo, I., Savage, S. A. 2015; 313 (6): 594-602

    Abstract

    Telomeres protect chromosome ends and are markers of cellular aging and replicative capacity.To evaluate the association between recipient and donor pretransplant leukocyte telomere length with outcomes after unrelated donor allogeneic hematopoietic cell transplantation (HCT) for patients with severe aplastic anemia.The study included 330 patients (235 acquired, 85 Fanconi anemia, and 10 Diamond-Blackfan anemia) and their unrelated donors who had pre-HCT blood samples and clinical and outcome data available at the Center for International Blood and Marrow Transplant Research. Patients underwent HCT between 1989 and 2007 in 84 centers and were followed-up to March 2013.Recipient and donor pre-HCT leukocyte telomere length classified into long (third tertile) and short (first and second tertiles combined) based on donor telomere length distribution.Overall survival, neutrophil recovery, and acute and chronic graft-vs-host disease, as ascertained by transplant centers through regular patient follow-up.Longer donor leukocyte telomere length was associated with higher survival probability (5-year overall survival, 56%; number at risk, 57; cumulative deaths, 50) than shorter donor leukocyte telomere length (5-year overall survival, 40%; number at risk, 71; cumulative deaths, 128; P?=?.009). The association remained statistically significant after adjusting for donor age, disease subtype, Karnofsky performance score, graft type, HLA matching, prior aplastic anemia therapy, race/ethnicity, and calendar year of transplant (hazard ratio [HR], 0.61; 95% CI, 0.44-0.86). Similar results were noted in analyses stratified on severe aplastic anemia subtype, recipient age, HLA matching, calendar year of transplant, and conditioning regimen. There was no association between donor telomere length and neutrophil engraftment at 28 days (cumulative incidence, 86% vs 85%; HR, 0.94; 95% CI, 0.73-1.22), acute graft-vs-host disease grades III-IV at 100 days (cumulative incidence, 22% vs 28%; HR, 0.77; 95% CI, 0.48-1.23), or chronic graft-vs-host disease at 1-year (cumulative incidence, 28% vs 30%; HR, 0.81; 95% CI, 0.53-1.24) for long vs short, respectively. Pretransplant leukocyte telomere length in the recipients was not associated with posttransplant survival (HR, 0.91; 95% CI, 0.64-1.30).Longer donor leukocyte telomere length was associated with increased 5-year survival in patients who received HCT for severe aplastic anemia. Patient leukocyte telomere length was not associated with survival. The results of this observational study suggest that donor leukocyte telomere length may have a role in long-term posttransplant survival.

    View details for DOI 10.1001/jama.2015.7

    View details for Web of Science ID 000349070700019

    View details for PubMedID 25668263

  • The relationship between occupational metal exposure and arterial compliance. Journal of occupational and environmental medicine / American College of Occupational and Environmental Medicine Wong, J. Y., Fang, S. C., Grashow, R., Fan, T., Christiani, D. C. 2015; 57 (4): 355-60

    Abstract

    The objective of this study was to evaluate the relationship between cumulative occupational exposure to various metals and arterial compliance in welders.The observational follow-up study consisted of 25 subjects. Levels of nickel (Ni), lead, cadmium, manganese, and arsenic from toenails were assessed using mass spectrometry. Arterial compliance as reflected by augmentation index (AIx) was measured using SphygmoCor Px Pulse Wave Analysis System. Linear regression models were used to assess the associations.For every 1 unit increase in log-transformed toenail Ni, there was a statistically significant 5.68 (95% confidence interval, 1.38 to 9.98; P = 0.01) unit increase in AIx. No significant associations were found between AIx and lead, cadmium, manganese, and arsenic.Cumulative Ni exposure is associated with increased arterial stiffness in welders and may increase risk of adverse cardiovascular outcomes.

    View details for DOI 10.1097/JOM.0000000000000427

    View details for PubMedID 25738948

  • The Association Between Global DNA Methylation and Telomere Length in a Longitudinal Study of Boilermakers GENETIC EPIDEMIOLOGY Wong, J. Y., De Vivo, I., Lin, X., Grashow, R., Cavallari, J., Christiani, D. C. 2014; 38 (3): 254-264

    Abstract

    The objectives of this study were to determine if global DNA methylation, as reflected in LINE-1 and Alu elements, is associated with telomere length and whether it modifies the rate of telomeric change. A repeated-measures longitudinal study was performed with a panel of 87 boilermaker subjects. The follow-up period was 29 months. LINE-1 and Alu methylation was determined using pyrosequencing. Leukocyte relative telomere length was assessed via real-time qPCR. Linear-mixed models were used to estimate the association between DNA methylation and telomere length. A structural equation model (SEM) was used to explore the hypothesized relationship between DNA methylation, proxies of particulate matter exposure, and telomere length at baseline. There appeared to be a positive association between both LINE-1 and Alu methylation levels, and telomere length. For every incremental increase in LINE-1 methylation, there was a statistically significant 1.0 10(-1) (95% CI: 4.6 10(-2), 1.5 10(-1), P < 0.01) unit increase in relative telomere length, controlling for age at baseline, current and past smoking status, work history, BMI (log kg/m(2) ) and leukocyte differentials. Furthermore, for every incremental increase in Alu methylation, there was a statistically significant 6.2 10(-2) (95% CI: 1.0 10(-2), 1.1 10(-1), P = 0.02) unit increase in relative telomere length. The interaction between LINE-1 methylation and follow-up time was statistically significant with an estimate -9.8 10(-3) (95% CI: -1.8 10(-2), -1.9 10(-3), P = 0.02); suggesting that the rate of telomeric change was modified by the degree of LINE-1 methylation. No statistically significant association was found between the cumulative PM exposure construct, with global DNA methylation and telomere length at baseline.

    View details for DOI 10.1002/gepi.21796

    View details for Web of Science ID 000332700300008

    View details for PubMedID 24616077

  • The Relationship between Inflammatory Biomarkers and Telomere Length in an Occupational Prospective Cohort Study PLOS ONE Wong, J. Y., De Vivo, I., Lin, X., Fang, S. C., Christiani, D. C. 2014; 9 (1)

    Abstract

    Chronic inflammation from recurring trauma is an underlying pathophysiological basis of numerous diseases. Furthermore, it may result in cell death, scarring, fibrosis, and loss of tissue function. In states of inflammation, subsequent increases in oxidative stress and cellular division may lead to the accelerated erosion of telomeres, crucial genomic structures which protect chromosomes from decay. However, the association between plasma inflammatory marker concentrations and telomere length has been inconsistent in previous studies.The purpose of this study was to determine the longitudinal association between telomere length and plasma inflammatory biomarker concentrations including: CRP, SAA, sICAM-1, sVCAM-1, VEGF, TNF-?, IL-1?, IL-2, IL-6, IL-8, and IL-10.The longitudinal study population consisted of 87 subjects. The follow-up period was approximately 2 years. Plasma inflammatory biomarker concentrations were assessed using highly sensitive electrochemiluminescent assays. Leukocyte relative telomere length was assessed using Real-Time qPCR. Linear mixed effects regression models were used to analyze the association between repeated-measurements of relative telomere length as the outcome and each inflammatory biomarker concentration as continuous exposures separately. The analyses controlled for major potential confounders and white blood cell differentials.At any follow-up time, each incremental ng/mL increase in plasma CRP concentration was associated with a decrease in telomere length of -2.610? (95%CI: -4.310?, -8.210?, p?=?0.004) units. Similarly, the estimate for the negative linear association between SAA and telomere length was -2.610? (95%CI:-4.510?, -6.110?, p?=?0.011). No statistically significant associations were observed between telomere length and plasma concentrations of pro-inflammatory interleukins, TNF-?, and VEGF.Findings from this study suggest that increased systemic inflammation, consistent with vascular injury, is associated with decreased leukocyte telomere length.

    View details for DOI 10.1371/journal.pone.0087348

    View details for Web of Science ID 000330507300174

    View details for PubMedID 24475279

  • Cumulative PM2.5 Exposure and Telomere Length in Workers Exposed to Welding Fumes. Journal of toxicology and environmental health. Part A Wong, J. Y., De Vivo, I., Lin, X., Christiani, D. C. 2014; 77 (8): 441-455

    Abstract

    Telomeres are genomic structures that reflect both mitotic history and biochemical trauma to the genome. Metals inherent in fine particulate matter (PM2.5) were shown to be genotoxic via oxidative damage. However, few studies investigated the induction time of cumulative PM2.5 exposure on telomere length in a longitudinal setting. Therefore, the purpose of this study was to assess the association between occupational PM2.5 exposure in various time windows and telomere length. The study population consisted of 48 boilermakers and the follow-up period was 8 yr. The main exposures were cumulative occupational PM2.5 in the month, year, and career prior to each blood draw, assessed via work history questionnaires and area air measures. Repeated telomere length measurements from leukocytes were assessed via real-time qualitative polymerase chain reaction (qPCR). Analysis was performed using linear mixed models controlling for confounders and white blood cell differentials. Cumulative PM2.5 exposure was treated continuously and categorized into quartiles, in separate analyses. At any follow-up time, for each milligram per cubic meter per hour increase in cumulative PM2.5 exposure in the prior month, there was a statistically significant decrease in relative telomere length of -0.04 units. When categorizing the exposure into quartiles, there was a significant negative association between telomere length and highest quartile of cumulative PM2.5 exposure in the prior month (-0.16). These findings suggest that genomic trauma to leukocyte telomeres was more consistent with recent occupational PM2.5 exposure, as opposed to cumulative exposure extending into the distant past.

    View details for DOI 10.1080/15287394.2013.875497

    View details for PubMedID 24627998

  • The association between leukocyte telomere length and cigarette smoking, dietary and physical variables, and risk of prostate cancer AGING CELL Mirabello, L., Huang, W., Wong, J. Y., Chatterjee, N., Reding, D., Crawford, E. D., De Vivo, I., Hayes, R. B., Savage, S. A. 2009; 8 (4): 405-413

    Abstract

    Telomeres consist of nucleotide repeats and a protein complex at chromosome ends that are essential to maintaining chromosomal integrity. Several studies have suggested that subjects with shorter telomeres are at increased risk of bladder and lung cancer. In comparison to normal tissues, telomeres are shorter in high-grade intraepithelial neoplasia and prostate cancer. We examined prostate cancer risk associated with relative telomere length as determined by quantitative PCR on prediagnostic buffy coat DNA isolated from 612 advanced prostate cancer cases and 1049 age-matched, cancer-free controls from the PLCO Cancer Screening Trial. Telomere length was analyzed as both a continuous and a categorical variable with adjustment for potential confounders. Statistically significant inverse correlations between telomere length, age and smoking status were observed in cases and controls. Telomere length was not associated with prostate cancer risk (at the median, OR = 0.85, 95% CI: 0.67, 1.08); associations were similar when telomere length was evaluated as a continuous variable or by quartiles. The relationships between telomere length and inflammation-related factors, diet, exercise, body mass index, and other lifestyle variables were explored since many of these have previously been associated with shorter telomeres. Healthy lifestyle factors (i.e., lower BMI, more exercise, tobacco abstinence, diets high in fruit and vegetables) tended to be associated with greater telomere length. This study found no statistically significant association between leukocyte telomere length and advanced prostate cancer risk. However, correlations of telomere length with healthy lifestyles were noted, suggesting the role of these factors in telomere biology maintenance and potentially impacting overall health status.

    View details for DOI 10.1111/j.1474-9726.2009.00485.x

    View details for Web of Science ID 000268213300006

    View details for PubMedID 19493248

  • Dichloroacetate induces apoptosis in endometrial cancer cells GYNECOLOGIC ONCOLOGY Wong, J. Y., Huggins, G. S., Debidda, M., Munshi, N. C., De Vivo, I. 2008; 109 (3): 394-402

    Abstract

    A recent landmark study demonstrated that Dichloroacetate (DCA) treatment promoted apoptosis in lung, breast, and glioblastoma cancer cell lines by shifting metabolism from aerobic glycolysis to glucose oxidation coupled with NFAT-Kv1.5 axis remodeling. The objective of this study was to determine whether DCA induces apoptosis in endometrial cancer cells and to assess apoptotic mechanism.A panel of endometrial cancer cell lines with varying degrees of differentiation was treated with DCA and analyzed for apoptosis via flow cytometry. Biological correlates such as gene expression, intracellular Ca(2+), and mitochondrial membrane potential were examined to assess apoptotic mechanism.Initiation of apoptosis was observed in five low to moderately invasive cancer cell lines including Ishikawa, RL95-2, KLE, AN3CA, and SKUT1B while treatment had no effect on non-cancerous 293T cells. Two highly invasive endometrial adenocarcinoma cell lines, HEC1A and HEC1B, were found to be resistant to DCA-induced apoptosis. Apoptotic responding cell lines had a significant increase in early and late apoptotis, a decrease in mitochondrial membrane potential, and decreased Survivin transcript abundance, which are consistent with a mitochondrial-regulated mechanism. DCA treatment decreased intracellular calcium levels in most apoptotic responding cell lines which suggests a contribution from the NFAT-Kv1.5-mediated pathway. DCA treatment increased p53 upregulated modulator of apoptosis (PUMA) transcripts in cell lines with an apoptotic response, suggesting involvement of a p53-PUMA-mediated mechanism.Dichloroacetate effectively sensitizes most endometrial cancer cell lines to apoptosis via mitochondrial, NFAT-Kv1.5, and PUMA-mediated mechanisms. Further investigation of the cancer therapeutic potential of DCA is warranted.

    View details for DOI 10.1016/j.ygyno.2008.01.038

    View details for Web of Science ID 000256892900015

    View details for PubMedID 18423823

  • Telomere length, cigarette smoking, and bladder cancer risk in men and women CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION McGrath, M., Wong, J. Y., Michaud, D., Hunter, D. J., De Vivo, I. 2007; 16 (4): 815-819

    Abstract

    Truncated telomeres are among the defining characteristics of most carcinomas. Given the role of telomeres in tumorigenesis, we reasoned that constitutionally short telomeres might be associated with an increased risk of bladder cancer. Using quantitative real-time PCR, we measured relative telomere length in bladder cancer cases and healthy controls and evaluated the association between telomere length, cigarette smoking, and bladder cancer risk in a case-control study nested within the Health Professionals Follow-up Study and a case-control study nested within the Nurses' Health Study. Telomeres were significantly shorter in bladder cancer cases (n = 184) than in controls (n = 192). The mean relative telomere length in cases was 0.23 (SD, 0.16) versus 0.27 (SD, 0.15) in controls (P = 0.001). The adjusted odds ratio for bladder cancer was 1.88 (95% confidence interval, 1.05, 3.36) for individuals in the quartile with the shortest telomeres as compared with individuals in the quartile with the longest telomeres (P(trend) = 0.006). We observed a statistically significant difference in telomere length among men and women (P < 0.001); however, the interaction between gender, telomere length, and bladder cancer risk was not significant. We also observed a significant difference in telomere length across categories of pack-years of smoking (P = 0.01). These findings suggest that truncated telomeres are associated with an increased risk of bladder cancer.

    View details for DOI 10.1158/1055-9965.EPI-06-0961

    View details for Web of Science ID 000245732600026

    View details for PubMedID 17416776

  • GATA5 activation of the progesterone receptor gene promoter in breast cancer cells is influenced by the+331G/A polymorphism CANCER RESEARCH Huggins, G. S., Wong, J. Y., Hankinson, S. E., De Vivo, I. 2006; 66 (3): 1384-1390

    Abstract

    Previously, a modest association was observed between the progesterone receptor +331G/A gene variant and breast cancer risk. Here, in a larger sample of breast cancer cases and controls (n = 1,322/n = 1,953) nested in the Nurses' Health Study cohort, we confirm a significant association (odds ratio, 1.41; 95% confidence interval, 1.10-1.79) and suggest a molecular model. The association of the +331G/A variant with breast cancer was particularly strong among obese women (body mass index > 30; odds ratio, 2.87; 95% confidence interval, 1.40-5.90). To help understand the molecular mechanism by which this variant may predispose women to breast cancer, we identified nearby transcription factor binding sites. This search predicted a binding site for the GATA family of transcriptional regulators adjacent to this hPR polymorphism. Importantly, we found GATA3, GATA4, and GATA6 are expressed in normal breast tissue and two breast cancer cell lines, whereas GATA5 is minimally expressed in normal mammary tissue and more strongly expressed in two breast cancer cell lines. This finding was relevant because GATA5 bound the site adjacent to the +331G/A polymorphism, and activated the hPR (-711 to +822)-luciferase reporter plasmid in breast cancer cells. Overexpression of GATA5 increased expression of the endogenous hPR transcript, and GATA5 more strongly activated an hPR promoter construct encoding the PR-B isoform. Finally, hPR promoter constructs including the +331A were more strongly activated by GATA5 than constructs including +331G. Our findings suggest that GATA5 interacts with the +331G/A polymorphism to stimulate hPR-B expression in mammary cells, which may contribute to breast cancer susceptibility.

    View details for DOI 10.1158/0008-5472.CAN-05-2715

    View details for Web of Science ID 000235095900020

    View details for PubMedID 16452193

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