Faculty Bibliography

BACKGROUND:The United Arab Emirates (UAE) is faced with a rapidly increasing burden of non-communicable diseases including obesity, diabetes, and cardiovascular disease. The UAE Healthy Future study is a prospective cohort designed to identify associations between risk factors and these diseases amongst Emiratis. The study will enroll 20,000 UAE nationals aged ≥18 years. Environmental and genetic risk factors will be characterized and participants will be followed for future disease events. As this was the first time a prospective cohort study was being planned in the UAE, a pilot study was conducted in 2015 with the primary aim of establishing the feasibility of conducting the study. Other objectives were to evaluate the implementation of the main study protocols, and to build adequate capacity to conduct advanced clinical laboratory analyses. METHODS:Seven hundred sixty nine UAE nationals aged ≥18 years were invited to participate voluntarily in the pilot study. Participants signed an informed consent, completed a detailed questionnaire, provided random blood, urine, and mouthwash samples and were assessed for a series of clinical measures. All specimens were transported to the New York University Abu Dhabi laboratories where samples were processed and analyzed for routine chemistry and hematology. Plasma, serum, and a small whole blood sample for DNA extraction were aliquoted and stored at -80 °C for future analyses. RESULTS:Overall, 517 Emirati men and women agreed to participate (68% response rate). Of the total participants, 495 (95.0%), 430 (82.2%), and 492 (94.4%), completed the questionnaire, physical measurements, and provided biological samples, respectively. CONCLUSIONS:The pilot study demonstrated the feasibility of recruitment and completion of the study protocols for the first large-scale cohort study designed to identify emerging risk factors for the major non-communicable diseases in the region.

BACKGROUND: Daily aspirin use has been recommended for secondary prevention of cardiovascular disease, but its use for primary prevention remains controversial. METHODS: We followed 440,277 men and women from the NIH-AARP Diet and Health Study (ages 50-71) and the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (ages 55-74) for mortality for 13 years on average. Frequency of aspirin use was ascertained through self-report, and cause of death by death certificates. We calculated multivariate hazard ratios (HRs) and 95% confidence intervals (CI) for mortality using Cox proportional hazards models for each cohort and combined by meta-analysis. RESULTS: We found a consistent U-shaped relationship between aspirin use and mortality in both studies, with differential risk patterns for cardiovascular mortality by disease history. Among individuals with a history of cardiovascular disease, daily aspirin use was associated with reduced cardiovascular mortality [HR=0.78 (95% CI 0.74-0.82)]. However, among those without a previous history, we observed no protection for daily aspirin users [HR=1.06 (1.02-1.11)], and elevated risk of cardiovascular mortality for those taking aspirin twice daily or more [HR=1.29 (1.19-1.39)]. Elevated risk persisted even among participants who lived beyond 5 years of follow-up and used aspirin without other nonsteroidal anti-inflammatory drugs [HR=1.31 (1.17-1.47)]. CONCLUSIONS: Results from these two large population-based U.S. cohorts confirm the utility of daily aspirin use for secondary prevention of cardiovascular mortality; however, our data suggest that caution should be exercised in more frequent use, particularly among individuals without a history of cardiovascular disease.

OBJECTIVE: A history of periodontal disease and the presence of circulating antibodies to selected oral pathogens have been associated with increased risk of pancreatic cancer; however, direct relationships of oral microbes with pancreatic cancer have not been evaluated in prospective studies. We examine the relationship of oral microbiota with subsequent risk of pancreatic cancer in a large nested case-control study. DESIGN: We selected 361 incident adenocarcinoma of pancreas and 371 matched controls from two prospective cohort studies, the American Cancer Society Cancer Prevention Study II and the National Cancer Institute Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. From pre-diagnostic oral wash samples, we characterised the composition of the oral microbiota using bacterial 16S ribosomal RNA (16S rRNA) gene sequencing. The associations between oral microbiota and risk of pancreatic cancer, controlling for the random effect of cohorts and other covariates, were examined using traditional and L1-penalised least absolute shrinkage and selection operator logistic regression. RESULTS: Carriage of oral pathogens, Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans, were associated with higher risk of pancreatic cancer (adjusted OR for presence vs absence=1.60 and 95% CI 1.15 to 2.22; OR=2.20 and 95% CI 1.16 to 4.18, respectively). Phylum Fusobacteria and its genus Leptotrichia were associated with decreased pancreatic cancer risk (OR per per cent increase of relative abundance=0.94 and 95% CI 0.89 to 0.99; OR=0.87 and 95% CI 0.79 to 0.95, respectively). Risks related to these phylotypes remained after exclusion of cases that developed within 2 years of sample collection, reducing the likelihood of reverse causation in this prospective study. CONCLUSIONS: This study provides supportive evidence that oral microbiota may play a role in the aetiology of pancreatic cancer.

Bacteria may play a role in esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (ESCC), although evidence is limited to cross-sectional studies. In this study, we examined the relationship of oral microbiota with EAC and ESCC risk in a prospective study nested in two cohorts. Oral bacteria were assessed using 16S rRNA gene sequencing in prediagnostic mouthwash samples from n = 81/160 EAC and n = 25/50 ESCC cases/matched controls. Findings were largely consistent across both cohorts. Metagenome content was predicted using PiCRUST. We examined associations between centered log-ratio transformed taxon or functional pathway abundances and risk using conditional logistic regression adjusting for BMI, smoking, and alcohol. We found the periodontal pathogen Tannerella forsythia to be associated with higher risk of EAC. Furthermore, we found that depletion of the commensal genus Neisseria and the species Streptococcus pneumoniae was associated with lower EAC risk. Bacterial biosynthesis of carotenoids was also associated with protection against EAC. Finally, the abundance of the periodontal pathogen Porphyromonas gingivalis trended with higher risk of ESCC. Overall, our findings have potential implications for the early detection and prevention of EAC and ESCC. Cancer Res; 77(23); 6777-87. ©2017 AACR.

Aims/UNASSIGNED:The transformation of the United Arab Emirates (UAE) from a semi-nomadic to a high income society has been accompanied by increasing rates of obesity and Type 2 diabetes mellitus. We examined if the AGE-RAGE (receptor for advanced glycation endproducts) axis is associated with obesity and diabetes mellitus in the pilot phase of the UAE Healthy Futures Study (UAEHFS). Methods/UNASSIGNED:517 Emirati subjects were enrolled and plasma/serum levels of AGE, carboxy methyl lysine (CML)-AGE, soluble (s)RAGE and endogenous secretory (es)RAGE were measured along with weight, height, waist and hip circumference (WC/HC), blood pressure, HbA1c, Vitamin D levels and routine chemistries. The relationship between the AGE-RAGE axis and obesity and diabetes mellitus was tested using proportional odds models and linear regression. Results/UNASSIGNED:After covariate adjustment, AGE levels were significantly associated with diabetes status. Levels of sRAGE and esRAGE were associated with BMI and levels of sRAGE were associated with WC/HC. Conclusions/UNASSIGNED:The AGE-RAGE axis is associated with diabetes status and obesity in this Arab population. Prospective serial analysis of this axis may identify predictive biomarkers of obesity and cardiometabolic dysfunction in the UAEHFS.

Background: The two most common types of esophageal cancer, esophageal adenocarcinoma (EAC) and squamous cell carcinoma (ESCC), are highly fatal. The human microbiota have been suggested to play a role in esophageal cancer etiology, although the evidence is limited to small, cross-sectional studies. We hypothesized that the oral microbiota, which shape the esophageal microbiota, may be causative agents in esophageal carcinogenesis. Methods: We conducted a prospective study nested in two large U.S. cohorts: ACS CPS-II and NCI-PLCO. Oral bacteria were assessed in pre-diagnostic mouth-wash samples collected from cases and controls (n=81/160 EAC and n=25/50 ESCC cases/matched controls), using 16S rRNA gene sequencing. We compared overall microbial composition between cases and controls using permutational multivariate analysis of variance (PERMANOVA) of UniFrac distances, and we examined associations between centered log-ratio transformed taxon abundances and cancer risk using conditional logistic regression. Metagenome functional content was predicted from taxonomic composition using PiCRUST. Results: Overall microbial composition did not differ between EAC cases and matched controls or ESCC cases and matched controls, adjusting for matching factors (age, sex, race, cohort, time to diagnosis/selection), BMI, smoking, and alcohol intake (all p>0.40). The periodontal pathogens Tannerella forsythia and Porphyromonas gingivalis were nominally associated with increased risk for EAC (OR [95% CI] = 1.21 [1.01, 1.46], p=0.04) and ESCC (OR [95% CI] = 1.3 [0.96, 1.77], p=0.09), respectively. Conversely, genus Neisseria, previously shown to be depleted by cigarette smoking, was associated with protection against EAC (OR [95% CI] = 0.88 [0.8, 0.97], p=0.01). Other species associated with EAC risk (p<0.05) included Corynebacterium durum, Prevotella nanceiensis, and Streptococcus pneumoniae (inversely associated with EAC), and Actinomyces cardiffensis, Selenomonas oral taxon 134, and Veillonella oral taxon 917 (positively associated with EAC). Other species associated with ESCC risk (p<0.05) included Aggregatibacter paraphrophilus (inversely associated with ESCC) and Prevotella nanceiensis, Bergeyella oral taxon 322, and Neisseria weaveri (positively associated with ESCC). Analysis of inferred metagenomes revealed that bacterial carotenoid biosynthesis was associated with protection against EAC (OR [95% CI] = 0.84 [0.7, 1.0], p=0.05). Conclusions: Our findings from this prospective study suggest that specific bacterial pathogens may play a causal role in esophageal cancer, while members of the healthy oral microbiota may protect against carcinogenesis. Unique microbial profiles may contribute to each of the distinct esophageal cancer types, EAC and ESCC. Oral microbiota manipulation may be a future strategy for preventing this highly fatal disease

Circadian disruption has been linked to carcinogenesis in animal models, but the evidence in humans is inconclusive. Genetic variation in circadian rhythm genes provides a tool to investigate such associations. We examined associations of genetic variation in nine core circadian rhythm genes and six melatonin pathway genes with risk of colorectal, lung, ovarian and prostate cancers using data from the Genetic Associations and Mechanisms in Oncology (GAME-ON) network. The major results for prostate cancer were replicated in the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial, and for colorectal cancer in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). The total number of cancer cases and controls was 15,838/18,159 for colorectal, 14,818/14,227 for prostate, 12,537/17,285 for lung and 4,369/9,123 for ovary. For each cancer site, we conducted gene-based and pathway-based analyses by applying the summary-based Adaptive Rank Truncated Product method (sARTP) on the summary association statistics for each SNP within the candidate gene regions. Aggregate genetic variation in circadian rhythm and melatonin pathways were significantly associated with the risk of prostate cancer in data combining GAME-ON and PLCO, after Bonferroni correction (Ppathway <0.00625). The two most significant genes were NPAS2 (Pgene =0.0062) and AANAT (Pgene =0.00078); the latter being significant after Bonferroni correction. For colorectal cancer, we observed a suggestive association with the circadian rhythm pathway in GAME-ON (Ppathway =0.021); this association was not confirmed in GECCO (Ppathway =0.76) or the combined data (Ppathway =0.17). No association was observed for ovarian and lung cancer. These findings support a potential role for circadian rhythm and melatonin pathways in prostate carcinogenesis. Further functional studies are needed to better understand the underlying biologic mechanisms

BACKGROUND: The oral fungal microbiome (mycobiome) is not well characterized, particularly in relation to oral diseases such as periodontal disease. We aimed to describe and compare the oral mycobiome of subjects with and without periodontal disease. RESULTS: We characterized the oral mycobiome in 30 adult subjects (15 with periodontal disease, 15 with good oral health) by sequencing the taxonomically informative pan-fungal internal transcribed spacer (ITS) gene in DNA extracted from oral wash samples. We observed at least 81 genera and 154 fungal species across all samples. Candida and Aspergillus were the most frequently observed genera (isolated from 100% of participants), followed by Penicillium (97%), Schizophyllum (93%), Rhodotorula (90%), and Gibberella (83%). Candida and Aspergillus were also the most highly abundant genera in the samples (median relative abundance = 21% and 44%, respectively). Aspergillus niger was the most highly abundant species in the samples (median relative abundance = 44%). We did not observe significant differences in overall oral mycobiome diversity or composition between participants with periodontal disease and participants with good oral health, nor did we observe significant differences in phylum through species level taxon relative abundance or carriage between the two groups. Genus Candida, previously associated with periodontal disease in culture-based studies, had higher median relative abundance in participants with periodontal disease (33.2%) compared to participants with oral health (2.2%), though the difference was not significant (p = 0.52). Additionally, within the periodontal disease group, median relative abundance of Candida increased with increasing number of permanent teeth lost (1-2 teeth lost: 3.2%; 3-4 teeth lost: 16.6%; >/=5 teeth lost: 73.9%; p = 0.11), though sample size was small for this analysis. CONCLUSIONS: In this first study comprehensively characterizing the oral mycobiome of adults with periodontal disease or good oral health, we observed trends of higher Candida abundance in participants with periodontal disease, and participants with greater tooth loss. Small sample size may have limited the power to detect significant associations. Larger studies including subgingival samples may further establish the core oral mycobiome in health, and relate it to periodontal disease.

Higher carbohydrate intake, glycaemic index (GI), and glycaemic load (GL) are hypothesised to increase cancer risk through metabolic dysregulation of the glucose-insulin axis and adiposity-related mechanisms, but epidemiological evidence is inconsistent. This prospective cohort study investigates carbohydrate quantity and quality in relation to risk of adiposity-related cancers, which represent the most commonly diagnosed preventable cancers in the USA. In exploratory analyses, associations with three site-specific cancers: breast, prostate and colorectal cancers were also examined. The study sample consisted of 3184 adults from the Framingham Offspring cohort. Dietary data were collected in 1991-1995 using a FFQ along with lifestyle and medical information. From 1991 to 2013, 565 incident adiposity-related cancers, including 124 breast, 157 prostate and sixty-eight colorectal cancers, were identified. Cox proportional hazards models were used to evaluate the role of carbohydrate nutrition in cancer risk. GI and GL were not associated with risk of adiposity-related cancers or any of the site-specific cancers. Total carbohydrate intake was not associated with risk of adiposity-related cancers combined or prostate and colorectal cancers. However, carbohydrate consumption in the highest v. lowest quintile was associated with 41 % lower breast cancer risk (hazard ratio (HR) 0.59; 95 % CI 0.36, 0.97). High-, medium- and low-GI foods were not associated with risk of adiposity-related cancers or prostate and colorectal cancers. In exploratory analyses, low-GI foods, were associated with 49 % lower breast cancer risk (HR 0.51; 95 % CI 0.32, 0.83). In this cohort of Caucasian American adults, associations between carbohydrate nutrition and cancer varied by cancer site. Healthier low-GI carbohydrate foods may prevent adiposity-related cancers among women, but these findings require confirmation in a larger sample.

PURPOSE: Results from previous sero-epidemiologic studies of Trichomonas vaginalis infection and prostate cancer (PCa) support a positive association between this sexually transmitted infection and aggressive PCa. However, findings from previous studies are not entirely consistent, and only one has investigated the possible relation between T. vaginalis seropositivity and PCa in African-American men who are at highest risk of both infection and PCa. Therefore, we examined this possible relation in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, including separate analyses for aggressive PCa and African-American men. METHODS: We included a sample of participants from a previous nested case-control study of PCa, as well as all additional Caucasian, aggressive, and African-American cases diagnosed since the previous study (total n = 438 Gleason 7 Caucasian cases, 487 more advanced Caucasian cases (>/=Gleason 8 or stage III/IV), 201 African-American cases, and 1216 controls). We tested baseline sera for T. vaginalis antibodies. RESULTS: No associations were observed for risk of Gleason 7 (odds ratio (OR) = 0.87, 95% confidence interval (CI) 0.55-1.37) or more advanced (OR = 0.90, 95% CI 0.58-1.38) PCa in Caucasian men, or for risk of any PCa (OR = 1.06, 95% CI 0.67-1.68) in African-American men. CONCLUSIONS: Our findings do not support an association between T. vaginalis infection and PCa.