Faculty Bibliography

Benzene, formaldehyde (FA), and trichloroethylene (TCE) are ubiquitous chemicals in workplaces and the general environment. Benzene is an established myeloid leukemogen and probable lymphomagen. FA is classified as a myeloid leukemogen but has not been associated with non-Hodgkin lymphoma (NHL), whereas TCE has been associated with NHL but not myeloid leukemia. Epidemiologic associations between FA and myeloid leukemia, and between benzene, TCE and NHL are, however, still debated. Previously, we showed that these chemicals are associated with hematotoxicity in cross-sectional studies of factory workers in China, which included extensive personal monitoring and biological sample collection. Here, we compare and contrast patterns of hematotoxicity, monosomy 7 in myeloid progenitor cells, and B-cell activation biomarkers across these studies to further evaluate possible mechanisms of action and consistency of effects with observed hematologic cancer risks. Workers exposed to benzene or FA, but not TCE, showed declines in cell types derived from myeloid progenitor cells, including granulocytes and platelets. Alterations in lymphoid cell types, including B-cells and CD4+ T cells, and B-cell activation markers were apparent in workers exposed to benzene or TCE. Given that alterations in myeloid and lymphoid cell types are associated with hematological malignancies, our data provide biologic insight into the epidemiological evidence linking benzene and FA exposure with myeloid leukemia risk, and TCE and benzene exposure with NHL risk.

Higher body mass index (BMI) is a well-established risk factor for colorectal cancer (CRC), but is inconsistently associated with CRC survival. In 6 prospective studies participating in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), 2,249 non-Hispanic white CRC cases were followed for a median 4.5 years after diagnosis, during which 777 died, 554 from CRC-related causes. Associations between pre-diagnosis BMI and survival (overall and CRC-specific) were evaluated using Cox regression models adjusted for age at diagnosis, sex, study, and smoking status (current/former/never). The association between BMI category and CRC survival varied by cancer stage at diagnosis (I-IV) for both all-cause (P-interaction=0.03) and CRC-specific mortality (P-interaction=0.04). Compared to normal BMI (18.5-24.9 kg/m2 ), overweight (BMI 25.0-29.9) was associated with increased mortality among those with stage I disease, and decreased mortality among those with stages II-IV disease. Similarly, obesity (BMI >/=30) was associated with increased mortality among those with stages I-II disease, and decreased mortality among those with stages III-IV disease. These results suggest the relationship between BMI and survival after CRC diagnosis differs by stage at diagnosis, and may emphasize the importance of adequate metabolic reserves for colorectal cancer survival in patients with late-stage disease

BACKGROUND AND AIMS: Investigation of microbe-metabolite relationships in the gut is needed to understand and potentially reduce colorectal cancer (CRC) risk. METHODS: Microbiota and metabolomics profiling were performed on lyophilized feces from 42 CRC cases and 89 matched controls. Multivariable logistic regression was used to identify statistically independent associations with CRC. First principal coordinate-component pair (PCo1-PC1) and false discovery rate (0.05)-corrected P-values were calculated for 116,000 Pearson correlations between 530 metabolites and 220 microbes in a sex*case/control meta-analysis. RESULTS: Overall microbe-metabolite PCo1-PC1 was more strongly correlated in cases than in controls (Rho 0.606 vs 0.201, P = 0.01). CRC was independently associated with lower levels of Clostridia, Lachnospiraceae, p-aminobenzoate and conjugated linoleate, and with higher levels of Fusobacterium, Porphyromonas, p-hydroxy-benzaldehyde, and palmitoyl-sphingomyelin. Through postulated effects on cell shedding (palmitoyl-sphingomyelin), inflammation (conjugated linoleate), and innate immunity (p-aminobenzoate), metabolites mediated the CRC association with Fusobacterium and Porphyromonas by 29% and 34%, respectively. Overall, palmitoyl-sphingomyelin correlated directly with abundances of Enterobacteriaceae (Gammaproteobacteria), three Actinobacteria and five Firmicutes. Only Parabacteroides correlated inversely with palmitoyl-sphingomyelin. Other lipids correlated inversely with Alcaligenaceae (Betaproteobacteria). Six Bonferroni-significant correlations were found, including low indolepropionate and threnoylvaline with Actinobacteria and high erythronate and an uncharacterized metabolite with Enterobacteriaceae. CONCLUSIONS: Feces from CRC cases had very strong microbe-metabolite correlations that were predominated by Enterobacteriaceae and Actinobacteria. Metabolites mediated a direct CRC association with Fusobacterium and Porphyromonas, but not an inverse association with Clostridia and Lachnospiraceae. This study identifies complex microbe-metabolite networks that may provide insights on neoplasia and targets for intervention.

Oral microbiome dysbiosis is associated with oral disease and potentially with systemic diseases; however, the determinants of these microbial imbalances are largely unknown. In a study of 1204 US adults, we assessed the relationship of cigarette smoking with the oral microbiome. 16S rRNA gene sequencing was performed on DNA from oral wash samples, sequences were clustered into operational taxonomic units (OTUs) using QIIME and metagenomic content was inferred using PICRUSt. Overall oral microbiome composition differed between current and non-current (former and never) smokers (P<0.001). Current smokers had lower relative abundance of the phylum Proteobacteria (4.6%) compared with never smokers (11.7%) (false discovery rate q=5.2 x 10-7), with no difference between former and never smokers; the depletion of Proteobacteria in current smokers was also observed at class, genus and OTU levels. Taxa not belonging to Proteobacteria were also associated with smoking: the genera Capnocytophaga, Peptostreptococcus and Leptotrichia were depleted, while Atopobium and Streptococcus were enriched, in current compared with never smokers. Functional analysis from inferred metagenomes showed that bacterial genera depleted by smoking were related to carbohydrate and energy metabolism, and to xenobiotic metabolism. Our findings demonstrate that smoking alters the oral microbiome, potentially leading to shifts in functional pathways with implications for smoking-related diseases.The ISME Journal advance online publication, 25 March 2016; doi:10.1038/ismej.2016.37.

BACKGROUND: In developing medical research, particularly in regions where medical research is largely unfamiliar, it is important to understand public perceptions and attitudes towards medical research. In preparation for starting the first cohort study in the United Arab Emirates, the Abu Dhabi Cohort Study (ADCS), we sought to understand how we could improve the quality of the research process for participants and increase public trust and awareness of research. METHODS: We conducted six focus groups (FG), consisting of Emirati men and women aged above 18 years to resemble the target population for the ADCS. Sampling was purposive and convenient. Data collection was an iterative process until saturation was reached with no new themes identified. Text from each FG was analyzed separately by identifying emerging issues and organizing related concepts into categories or themes. A coding tree was developed, consisting of the main concepts, themes, subthemes and corresponding quotes. Both themes and main ideas were identified using inductive analysis. RESULTS: Forty-two participants enrolled at 3 academic centers (New York University Abu Dhabi, UAE University, Zayed University) and the Abu Dhabi blood bank. Focus group participants described lack of awareness of research as a challenge to participation in clinical research studies. Altruism, personal relevance of the research, and the use of role models were commonly identified motivators. Participants were generally satisfied with the informed consent process for the ADCS, but would be disappointed if not provided test results or study outcomes. Fear of a breach in confidentiality was a frequently expressed concern. CONCLUSIONS: Participants join research studies for varied, complex reasons, notably altruism and personal relevance. Based on these insights, we propose specific actions to enhance participant recruitment, retention and satisfaction in the ADCS. We identified opportunities to improve the research experience through improved study materials and communication to participants and the broader community.

BACKGROUND: Menopausal hormone therapy (MHT) use has been consistently associated with a decreased risk of colorectal cancer (CRC) in women. Our aim was to use a genome-wide gene-environment interaction analysis to identify genetic modifiers of CRC risk associated with use of MHT. METHODS: We included 10 835 postmenopausal women (5419 cases and 5416 controls) from 10 studies. We evaluated use of any MHT, oestrogen-only (E-only) and combined oestrogen-progestogen (E+P) hormone preparations. To test for multiplicative interactions, we applied the empirical Bayes (EB) test as well as the Wald test in conventional case-control logistic regression as primary tests. The Cocktail test was used as secondary test. RESULTS: The EB test identified a significant interaction between rs964293 at 20q13.2/CYP24A1 and E+P (interaction OR (95% CIs)=0.61 (0.52-0.72), P=4.8 x 10-9). The secondary analysis also identified this interaction (Cocktail test OR=0.64 (0.52-0.78), P=1.2 x 10-5 (alpha threshold=3.1 x 10-4). The ORs for association between E+P and CRC risk by rs964293 genotype were as follows: C/C, 0.96 (0.61-1.50); A/C, 0.61 (0.39-0.95) and A/A, 0.40 (0.22-0.73), respectively. CONCLUSIONS: Our results indicate that rs964293 modifies the association between E+P and CRC risk. The variant is located near CYP24A1, which encodes an enzyme involved in vitamin D metabolism. This novel finding offers additional insight into downstream pathways of CRC etiopathogenesis.British Journal of Cancer advance online publication, 14 January 2016; doi:10.1038/bjc.2015.443 www.bjcancer.com.

BACKGROUND: Because a significant number of patients with prostate cancer (PCa) are diagnosed with disease unlikely to cause harm, genetic markers associated with clinically aggressive PCa have potential clinical utility. Since cell cycle checkpoint dysregulation is crucial for the development and progression of cancer, we tested the hypothesis that common germ-line variants within cell cycle genes were associated with aggressive PCa. METHODS: Via a two-stage design, 364 common sequence variants in 88 genes were tested. The initial stage consisted of 258 aggressive PCa patients and 442 controls, and the second stage added 384 aggressive PCa Patients and 463 controls. European-American and African-American samples were analyzed separately. In the first stage, SNPs were typed by Illumina Goldengate assay while in the second stage SNPs were typed by Pyrosequencing assays. Genotype frequencies between cases and controls were compared using logistical regression analysis with additive, dominant and recessive models. RESULTS: Eleven variants within 10 genes (CCNC, CCND3, CCNG1, CCNT2, CDK6, MDM2, SKP2, WEE1, YWHAB, YWHAH) in the European-American population and nine variants in 7 genes (CCNG1, CDK2, CDK5, MDM2, RB1, SMAD3, TERF2) in the African-American population were found to be associated with aggressive PCa using at least one model. Of particular interest, CCNC (rs3380812) was associated with risk in European-American cohorts from both institutions. CDK2 (rs1045435) and CDK5 (rs2069459) were associated with risk in the African-American cohorts from both institutions. Lastly, variants within MDM2 and CCNG1 were protective for aggressive PCa in both ethnic groups. CONCLUSIONS: This study confirms that polymorphisms within cell cycle genes are associated with clinically aggressive PCa. Validation of these markers in additional populations is necessary, but these markers may help identify patients at risk for potentially lethal carcinoma. Prostate (c) 2015 Wiley Periodicals, Inc.

BACKGROUND: Long-term exposure to ambient particulate matter (PM) air pollution is associated with increased cardiovascular disease (CVD); however, the impact of PM on clinical risk factors for CVD in healthy subjects is unclear. We examined the relationship of PM with levels of circulating lipids and blood pressure in the Third National Health and Nutrition Examination Survey (NHANES III), a large nationally-representative US survey. METHODS: This study was based on 11,623 adult participants of NHANES III (1988-1994; median age 41.0). Serum lipids and blood pressure were measured during the NHANES III examination. Average exposure for 1988-1994 to particulate matter <10microm in aerodynamic diameter (PM10) at the residences of participants was estimated based on measurements from U.S. Environmental Protection Agency monitors. Multivariate linear regression was used to estimate the associations of PM10 with lipids and blood pressure. RESULTS: An interquartile range width (IQRw) increase in PM10 exposure (11.1 microg/m) in the study population was associated with 2.42 percent greater serum triglycerides (95% confidence interval [CI]: 1.09-3.76); multivariate adjusted means of triglycerides according to increasing quartiles of PM10 were 137.6, 142.5, 142.6, and 148.9 mg/dL, respectively. An IQRw increase in PM10 was associated with 1.43 percent greater total cholesterol (95% CI: 1.21-1.66). These relationships with triglycerides and total cholesterol did not differ by age or region. Associations of PM10 with blood pressure were modest. CONCLUSIONS: Findings from this large diverse study indicate that greater long-term PM10 exposure is associated with elevated serum triglycerides and total cholesterol, potentially mediating air pollution-related effects on CVD.

Genome-wide association studies have identified several germline single nucleotide polymorphisms (SNPs) significantly associated with colorectal cancer (CRC) incidence. Common germline genetic variation may also be related to CRC survival. We used a discovery-based approach to identify SNPs related to survival outcomes after CRC diagnosis. Genome-wide genotyping arrays were conducted for 3494 individuals with invasive CRC enrolled in six prospective cohort studies (median study-specific follow-up=4.2-8.1 years). In pooled analyses, we used Cox regression to assess SNP-specific associations with CRC-specific and overall survival, with additional analyses stratified by stage at diagnosis. Top findings were followed-up in independent studies. A P-value threshold of P<5x10-8 in analyses combining discovery and follow-up studies was required for genome-wide significance. Among individuals with distant-metastatic CRC, several SNPs at 6p12.1, nearest the ELOVL5 gene, were statistically significantly associated with poorer survival, with the strongest associations noted for rs209489 [hazard ratio (HR)=1.8, P=7.6x10-10 and HR=1.8, P=3.7x10-9 for CRC-specific and overall survival, respectively). No SNPs were statistically significantly associated with survival among all cases combined or in cases without distant-metastases. SNPs in 6p12.1/ELOVL5 were associated with survival outcomes in individuals with distant-metastatic CRC, and merit further follow-up for functional significance. Findings from this genome-wide association study highlight the potential importance of genetic variation in CRC prognosis and provide clues to genomic regions of potential interest.

BACKGROUND: Outdoor fine particulate matter (PM2.5) has been identified as a global health threat, but the number of large U.S. prospective cohort studies with individual participant data remains limited, especially at lower recent exposures. OBJECTIVES: To test the relationship between long-term exposure PM2.5 and death risk from all non-accidental causes, cardiovascular (CVD), and respiratory diseases in 517,041 men and women enrolled in the National Institutes of Health-AARP cohort. METHODS: Individual participant data were linked with residence PM2.5 exposure estimates across the continental U.S for a 2000-2009 follow up period when matching census-tract level PM2.5 exposure data were available. Participants enrolled ranged from 50-71 yrs. of age, residing in 6 U.S. States and 2 cities. Cox Proportional Hazard models yielded Hazard Ratio (HR) estimates per 10 microg/m3 of PM2.5 exposure. RESULTS: PM2.5 exposure was significantly associated with total mortality (HR= 1.03, 95% CI =1.00, 1.05) and CVD mortality (HR=1.10, 95% CI=1.05, 1.15), but the association with respiratory mortality was not statistically significant (HR=1.05, 95% CI=0.98,1.13). A significant association was found with respiratory mortality only among never smokers (HR=1.27; 95% CI: 1.03, 1.56). Associations with 10 microg/m3 PM2.5 exposures in yearly participant residential annual mean, or in metropolitan area-wide mean, were consistent with baseline exposure model results. Associations with PM2.5 were similar when adjusted for ozone exposures. Analyses of California residents alone also yielded statistically significant PM2.5 mortality HR's for total and CVD mortality. CONCLUSIONS: Long-term exposure to PM2.5 air pollution was associated with an increased risk of total and CVD mortality, providing an independent test of the PM2.5 - mortality relationship in a new large U.S. prospective cohort experiencing lower post-2000 PM2.5 exposure levels.