Faculty Bibliography

BACKGROUND: United States Veterans are at excess risk for Type 2 diabetes and early mortality. Our objective is to determine the impact of prediabetes and related risk factors on the occurrence of diabetes and mortality in this at-risk population. METHODS: At the primary care practices of the VA New York Harbor (VA NYHHS) during 2004-2014, we identified 15,173 diabetes-free Veterans, among those who received 2 or more hemoglobin A1c tests (HbA1c). Among these participants, we identified 14,361 veterans with HbA1c values below the diabetic range (i.e., <6.5% HbA1c) and characterized these individuals with respect to selected risk factors. We followed these individuals through 2014 for incident diabetes and all-cause mortality. Cox proportional hazard regression was used to relate HbA1c levels, age, sex, race/ethnicity, anthropometric measures, and comorbid cardiovascular conditions (ischemic heart disease, cerebral vascular accident, congestive heart failure and peripheral vascular disease) to incident diabetes and all-cause mortality (Hazard Ratio [HR] and 95% confidence intervals). RESULTS: Among 8,145 Veterans with prediabetes (HbA1c 5.7-6.4%), 1,170 (14.4%) developed diabetes and 1,139 (14%) died during the course of follow-up. Compared to 5,292 normoglycemic Veterans (HbA1c: 5.0-5.6%), 4,207 prediabetics in the moderate risk group (HbA1c 5.7-5.9%) had a greater than 2-fold increased risk of incident diabetes (HR 2.46 [2.08-2.92]), and those 3,938 in the prediabetic high risk group (HbA1c 6.0-6.4%) had a greater than 5-fold risk (HR 5.70 [4.88-6.65]). Furthermore, all-cause mortality was increased in 924 participants with low glycemia (HbA1c <5.0%: HR 1.40 [1.17- 1.68]) and among those 812 in the diabetes risk range (HbA1c >6.5%:HR 1.44 [1.22-1.71]) compared with the normoglycemic group. Excess all-cause mortality was not observed among the prediabetic group, compared to the normoglycemic group. CONCLUSIONS: Among Veterans, prospective risk of transition to Type 2 diabetes ranged from 2.5-fold to 5.7-fold among prediabetics, depending on HbA1c level. Patients with HbA1c < 5.0 and those in the diabetic range had increased risks of all-cause mortality, while prediabetics showed no excess mortality. The higher risk population (HbA1c 6.0-6.4%) is an important group to target with diabetes prevention efforts

BACKGROUND: Prior studies of the mortality risk associated with glycosylated hemoglobin (A1c) have systematically excluded patients with key comorbidities, and thus may not reflect the true association of A1C with mortality. The objective of the study is to determine mortality risk after accounting for all comorbidities. Design: Retrospective, secondary data analysis from all 168 VA Medical Centers and 1,053 VA Community Based Outpatient Clinics; All patients who from 1/2008 to 12/2015 had >2 primary care visits, not more than 2 years apart, to a VA facility, who had no prevalent diabetes diagnosis before 1/2008, and who had at least 2 A1c measurements METHODS: The A1c level for each patient was defined as the max of the average of two consecutive A1c test results during the study period. The primary outcome was mortality within 6 months of the date of the latter of two consecutive A1c tests. Stratified covariate balancing was used to measure unconfounded impact of A1c on mortality rate, adjusting for the impact of comorbidities. RESULTS: 2,672,558 patients met the entry criteria. Average age was 62 (standard deviation = 14.6), 93% were male, and 71% White. 48% had 1 comorbidity; 19% had 2; 11% had 3; 7% had 4; and 15% had 5 or more. 0.7% had low A1c (<5.0%), 69.7% had normal A1c (5.0 to 5.7%); 26.7% had prediabetic A1C (5.7 to 6.4%), and 2.9% had A1c levels in diabetic range (A1c > 6.5%). The solid line in the Figure shows the 6-month mortality risk associated with unadjusted A1c levels; note that the Figure has deleted A1c levels with less than 1,000 unique patients. All diseases (e.g. cancer) affected both A1c levels and mortality rates. After stratification removed the impact of comorbidities (dashed line), risk of mortality associated with A1c levels dropped. The comorbidity-adjusted risk (e.g. risk at A1c of 4.6%) was lower than unadjusted normal levels (e.g. risk at A1c levels of 5.4%). Prior to adjustment, a change from normal (A1c = 5.4%) to diabetic (A1c = 7%) was associated with 8% higher mortality, while afterwards the same A1C was associated with only 3% higher mortality. CONCLUSIONS: A1c level is associated with mortality across the full range, with risk greatest for those with A1c >6.5% but most of the increase is accounted for by patients' comorbidities, so clinicians should focus on the progression of the underlying diseases and not simply on A1c test results among their patients at risk for diabetes. (Table Presented)

Importance/UNASSIGNED:Prospective studies are needed to examine the temporal relationship between oral human papillomavirus (HPV) detection and risk of head and neck squamous cell carcinoma (HNSCC). Moreover, the oral cavity contains a wide spectrum of α-, β-, and γ-HPV types, but their association with risk of HNSCC is unknown. Objective/UNASSIGNED:To prospectively examine associations between α-, β-, and γ-HPV detection in the oral cavity and incident HNSCC. Design/UNASSIGNED:A nested case-control study was carried out among 96 650 participants, cancer free at baseline, with available mouthwash samples in 2 prospective cohort studies: (1) the American Cancer Society Cancer Prevention Study II Nutrition Cohort and (2) the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Incident cases of HNSCC (n = 132) were identified during an average 3.9 years of follow-up in both cohorts. Three controls per case (n = 396) were selected through incidence density sampling and matched on age, sex, race/ethnicity, and time since mouthwash collection. Methods/UNASSIGNED:Through a next-generation sequencing assay, DNA from α-, β-, and γ-HPV types were detected. Conditional logistic regression models were used to estimate odds ratios (ORs) and 95% CIs, adjusting for smoking history, alcohol consumption, and detection of HPV-16 for β- and γ-HPVs. Main Outcomes and Measures/UNASSIGNED:Incident HNSCC, which includes cancers of the oropharynx, oral cavity, and larynx. Results/UNASSIGNED:A total of 132 participants developed HNSCC during the follow-up period (103 men and 29 women; average age at baseline, 66.5 years). Oral HPV-16 detection was associated with incident HNSCC (OR, 7.1; 95% CI, 2.2-22.6), with positive association for oropharyngeal SCC (OR, 22.4; 95% CI, 1.8-276.7), but not for oral cavity (OR, 4.5; 95% CI, 0.6-34.7) or laryngeal SCCs (OR, 0.11; 95% CI, 0.01-834.80). Detection of β1-HPV-5 and β2-HPV-38 types, as well as γ-11 and γ-12 species, had ORs for HNSCC that ranged from 2.64 to 5.45 (P < .01 for all comparisons). Detection of β1-HPV-5 type was associated with oropharyngeal (OR, 7.42; 95% CI, 0.98-56.82; P = .054), oral cavity (OR, 5.34; 95% CI, 1.51-18.80; P = .01), and laryngeal SCCs (OR, 2.71; 95% CI, 1.00-7.43; P = .05), whereas γ11- and γ12-HPV species were associated with both oral cavity (OR, 7.47; 95% CI, 1.21-46.17; P = .03; and OR, 6.71; 95% CI, 1.47-30.75; P = .01, respectively) and laryngeal SCCs (OR, 7.49; 95% CI, 1.10-51.04; P = .04 and OR, 5.31; 95% CI, 1.13-24.95; P = .03, respectively). Conclusions and Relevance/UNASSIGNED:This study demonstrates that HPV-16 detection precedes the incidence of oropharyngeal SCC. Associations of other HPVs, including γ11- and γ12-HPV species and β1-HPV-5 type suggest a broader role for HPVs in HNSCC etiology.

BACKGROUND: Colorectal cancer is a heterogeneous disease arising from at least two precursors-the conventional adenoma (CA) and the serrated polyp. We and others have previously shown a relationship between the human gut microbiota and colorectal cancer; however, its relationship to the different early precursors of colorectal cancer is understudied. We tested, for the first time, the relationship of the gut microbiota to specific colorectal polyp types. RESULTS: Gut microbiota were assessed in 540 colonoscopy-screened adults by 16S rRNA gene sequencing of stool samples. Participants were categorized as CA cases (n = 144), serrated polyp cases (n = 73), or polyp-free controls (n = 323). CA cases were further classified as proximal (n = 87) or distal (n = 55) and as non-advanced (n = 121) or advanced (n = 22). Serrated polyp cases were further classified as hyperplastic polyp (HP; n = 40) or sessile serrated adenoma (SSA; n = 33). We compared gut microbiota diversity, overall composition, and normalized taxon abundance among these groups. CA cases had lower species richness in stool than controls (p = 0.03); in particular, this association was strongest for advanced CA cases (p = 0.004). In relation to overall microbiota composition, only distal or advanced CA cases differed significantly from controls (p = 0.02 and p = 0.002). In taxon-based analysis, stool of CA cases was depleted in a network of Clostridia operational taxonomic units from families Ruminococcaceae, Clostridiaceae, and Lachnospiraceae, and enriched in the classes Bacilli and Gammaproteobacteria, order Enterobacteriales, and genera Actinomyces and Streptococcus (all q < 0.10). SSA and HP cases did not differ in diversity or composition from controls, though sample size for these groups was small. Few taxa were differentially abundant between HP cases or SSA cases and controls; among them, class Erysipelotrichi was depleted in SSA cases. CONCLUSIONS: Our results indicate that gut microbes may play a role in the early stages of colorectal carcinogenesis through the development of CAs. Findings may have implications for developing colorectal cancer prevention therapies targeting early microbial drivers of colorectal carcinogenesis.

The relationship between occupational benzene exposure and levels of immune markers measured using a multiplex panel was studied. Personal benzene exposure was monitored in workers using a 3 M organic vapor passive monitoring badge before phlebotomy. The differences in marker concentrations between benzene exposed vs. unexposed workers, and the exposure-response trends were evaluated. BCA-1 (45% reduction overall) and IL-17A (38% reduction overall) were significantly reduced in both lower and higher exposed workers compared to unexposed workers. Occupational exposure to benzene was associated with a range of immune perturbations, including alterations in markers that regulate B-cell chemotaxis and regulation of cytotoxic T-cell activity

Genome-wide association studies (GWAS) have identified many genetic susceptibility loci for colorectal cancer (CRC). However, variants in these loci explain only a small proportion of familial aggregation, and there are likely additional variants that are associated with CRC susceptibility. Genome-wide studies of gene-environment interactions may identify variants that are not detected in GWAS of marginal gene effects. To study this, we conducted a genome-wide analysis for interaction between genetic variants and alcohol consumption and cigarette smoking using data from the Colon Cancer Family Registry (CCFR) and the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). Interactions were tested using logistic regression. We identified interaction between CRC risk and alcohol consumption and variants in the 9q22.32/HIATL1 (Pinteraction = 1.76x10-8; permuted p-value 3.51x10-8) region. Compared to non-/occasional drinking light to moderate alcohol consumption was associated with a lower risk of colorectal cancer among individuals with rs9409565 CT genotype (OR, 0.82 [95% CI, 0.74-0.91]; P = 2.1x10-4) and TT genotypes (OR,0.62 [95% CI, 0.51-0.75]; P = 1.3x10-6) but not associated among those with the CC genotype (p = 0.059). No genome-wide statistically significant interactions were observed for smoking. If replicated our suggestive finding of a genome-wide significant interaction between genetic variants and alcohol consumption might contribute to understanding colorectal cancer etiology and identifying subpopulations with differential susceptibility to the effect of alcohol on CRC risk.

Genome-wide association studies (GWAS) have identified many common single nucleotide polymorphisms (SNPs) associated with colorectal cancer risk. These SNPs may tag correlated variants with biological importance. Fine-mapping around GWAS loci can facilitate detection of functional candidates and additional independent risk variants. We analyzed 11,900 cases and 14,311 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium and the Colon Cancer Family Registry. To fine-map genomic regions containing all known common risk variants, we imputed high-density genetic data from the 1000 Genomes Project. We tested single-variant associations with colorectal tumor risk for all variants spanning genomic regions 250-kb upstream or downstream of 31 GWAS-identified SNPs (index SNPs). We queried the University of California, Santa Cruz Genome Browser to examine evidence for biological function. Index SNPs did not show the strongest association signals with colorectal tumor risk in their respective genomic regions. Bioinformatics analysis of SNPs showing smaller P-values in each region revealed 21 functional candidates in 12 loci (5q31.1, 8q24, 11q13.4, 11q23, 12p13.32, 12q24.21, 14q22.2, 15q13, 18q21, 19q13.1, 20p12.3, and 20q13.33). We did not observe evidence of additional independent association signals in GWAS-identified regions. Our results support the utility of integrating data from comprehensive fine-mapping with expanding publicly available genomic databases to help clarify GWAS associations and identify functional candidates that warrant more onerous laboratory follow-up. Such efforts may aid the eventual discovery of disease-causing variant(s).