Faculty Bibliography

BACKGROUND:Obesity and diabetes are major modifiable risk factors for pancreatic cancer. Interactions between genetic variants and diabetes/obesity have not previously been comprehensively investigated in pancreatic cancer at the genome-wide level. METHODS:We conducted a gene-environment interaction (GxE) analysis including 8,255 cases and 11,900 controls from four pancreatic cancer GWAS datasets (PanScan I-III and PanC4). Obesity (BMI=30 kg/m2) and diabetes (duration = 3 years) were the environmental variables of interest. Approximately 870,000 SNPs were analyzed. Case-control (CC), case-only (CO), and joint-effect test methods were used for SNP-level GxE analysis. As a complementary approach, gene-based GxE analysis was also performed. Age, sex, study site and principal components accounting for population substructure were included as covariates. Meta-analysis was applied to combine individual-GWAS summary statistics. RESULTS:No genome-wide significant interactions with diabetes or obesity were detected at the SNP level by the CC or CO approaches. The joint-effect test detected numerous genome-wide significant GxE signals in the GWAS main effects top hit regions but the significance diminished after adjusting for the GWAS top hits. In the gene-based analysis, a significant interaction of diabetes with variants in the FAM63A (family with sequence similarity 63 member A) gene (significance threshold P<1.25E-6) was observed in the meta-analysis (PGxE= 1.2E-6, PJoint= 4.2E-7). CONCLUSIONS:Our current analyses did not find significant GxE interactions at the SNP level but found one significant interaction with diabetes at the gene level. A larger sample size might unveil additional genetic factors via GxE scans. IMPACT/CONCLUSIONS:This study may contribute to discovering the mechanism of diabetes-associated pancreatic cancer.

PURPOSE/OBJECTIVE:Accurate life expectancy estimates are required to inform prostate cancer treatment decisions. However, few models are specific to the population served or easily implemented in a clinical setting. We sought to create life expectancy estimates specific to Veterans diagnosed with prostate cancer. MATERIALS AND METHODS/METHODS:Using national Veterans Health Administration electronic health records, we identified Veterans diagnosed with prostate cancer between 2000 and 2015. We abstracted demographics, comorbidities, oncologic staging, and treatment information. We fit Cox Proportional Hazards models to determine the impact of age, comorbidity, cancer risk, and race on survival. We stratified life expectancy estimates by age, comorbidity and cancer stage. RESULTS:Our analytic cohort included 145,678 patients. Survival modeling demonstrated the importance of age and comorbidity across all cancer risk categories. Life expectancy estimates generated from age and comorbidity data were predictive of overall survival (C-index 0.676, 95% CI 0.674-0.679) and visualized using Kaplan-Meier plots and heatmaps stratified by age and comorbidity. Separate life expectancy estimates were generated for patients with localized or advanced disease. These life expectancy estimates calibrate well across prostate cancer risk categories. CONCLUSIONS:Life expectancy estimates are essential to providing patient-centered prostate cancer care. We developed accessible life expectancy estimation tools for Veterans diagnosed with prostate cancer that can be used in routine clinical practice to inform medical-decision making.

OBJECTIVE:: 38.18]) as well as its severe form, critical limb ischemia (PAD cases with resting pain, ulcer, gangrene, or leg amputation) using Cox models. Over a median follow-up of 17.4 years, there were 316 cases of PAD including 119 critical limb ischemia cases. Log-transformed galectin-3 was associated with incident PAD (adjusted hazard ratio, 1.17 [1.05-1.31] per 1 SD increment) and critical limb ischemia (1.25 [1.05-1.49] per 1 SD increment). The association was slightly attenuated after further adjusting for hs-CRP (1.14 [1.02-1.27] and 1.22 [1.02-1.45], respectively). Log-transformed hs-CRP demonstrated robust associations with PAD and critical limb ischemia even after adjusting for galectin-3 (adjusted hazard ratio per 1 SD increment 1.34 [1.18-1.52] and 1.34 [1.09-1.65], respectively). The addition of galectin-3 and hs-CRP to traditional atherosclerotic predictors (C statistic of the base model 0.843 [0.815-0.871]) improved the risk prediction of PAD (ΔC statistics, 0.011 [0.002-0.020]). CONCLUSIONS:Galectin-3 and hs-CRP were independently associated with incident PAD in the general population, supporting the involvement of fibrosis and inflammation in the pathophysiology of PAD.

Biobanks have the potential to be robust resource for understanding potential cancer risks associated with gender-affirming interventions. In this narrative review, we synthesized the current published literature regarding the inclusion of TGD health data in cancer biorepositories and cancer research conducted on biospecimens. Of the 6986 initial results, 153 (2.2%) assessed the biological effects of gender-affirming interventions on TGD tissues. Within that category, only one paper examined transgender tissues in relation to cancer biobanks. Strategies are offered to address the inequities in TGD tissue-based research and diversify the field of biobanking as a whole.

OBJECTIVE:To evaluate whether the incidence of infectious diseases increases the long-term risk for incident end-stage renal disease (ESRD) in the general population. PATIENTS AND METHODS:In 10,290 participants of the Atherosclerosis Risk in Communities Study who attended visit 4 (1996-1998), we evaluated the association of incident hospitalization with major infections (pneumonia, urinary tract infection, bloodstream infection, and cellulitis and osteomyelitis) with subsequent risk for ESRD through September 30, 2015. Hospitalization with major infection was entered into multivariable Cox models as a time-varying exposure to estimate the hazard ratios. RESULTS:. During a median follow-up of 17.4 years, there were 2642 incident hospitalizations with major infection and 281 cases of ESRD (132 cases after hospitalization with major infection). The risk for ESRD was higher following major infection compared with while free of major infection (crude incidence rate, 10.9 vs 1.0 per 1000 person-years). In multivariable time-varying Cox analysis, hospitalization with major infection was associated with a 3.3-fold increased risk for ESRD (hazard ratio, 3.34; 95% CI, 2.56-4.37). The association was similar across pneumonia, urinary tract infection, bloodstream infection, and cellulitis and osteomyelitis, and remained significant across subgroups of age, sex, race, diabetes, history of cardiovascular disease, and chronic kidney disease. CONCLUSION:Hospitalization with major infection was independently and robustly associated with subsequent risk for ESRD. Whether preventive approaches against infection have beneficial effects on kidney outcomes may deserve future investigations.

BACKGROUND AND PURPOSE/OBJECTIVE:Liver enzymes (aspartate aminotransferase [AST], alanine aminotransferase [ALT], and gamma-glutamyl transpeptidase [GGT]) are glutamate-regulatory enzymes, and higher glutamate levels correlated with worse prognosis of patients with neurotrauma. However, less is known about the association between liver enzymes and incidence of stroke. We evaluated the association between serum levels of AST, ALT, and GGT and incidence of stroke in the Atherosclerosis Risk in Communities (ARIC) study cohort from 1990 to 1992 through December 31, 2016. METHODS:We included 12,588 ARIC participants without prevalent stroke and with data on liver enzymes ALT, AST, and GGT at baseline. We used multivariable Cox regression models to examine the associations between liver enzymes levels at baseline and stroke risk (overall, ischemic stroke, and intracerebral hemorrhage [ICH]) through December 31, 2016, adjusting for potential confounders. RESULTS:During a median follow-up time of 24.2 years, we observed 1,012 incident strokes (922ischemic strokes and 90 ICH). In age, sex, and race-center adjusted models, the hazard ratios (HRs; 95% confidence intervals [CIs]) for the highest compared to lowest GGT quartile were 1.94 (95% CI, 1.64 to 2.30) for all incident stroke and 2.01 (95% CI, 1.68 to 2.41) for ischemic stroke, with the results supporting a dose-response association (P for linear trend <0.001). Levels of AST were associated with increased risk of ICH, but the association was significant only when comparing the third quartile with the lowest quartile (adjusted HR, 1.82; 95% CI, 1.06 to 3.13). CONCLUSIONS:Elevated levels of GGT (within normal levels), independent of liver disease, are associated with higher risk of incident stroke overall and ischemic stroke, but not ICH.

The 2017 American College of Cardiology/American Heart Association guideline defines hypertension as a blood pressure ≥130/80 mm Hg, whereas the 2018 European Society of Cardiology (ESC) and 2019 National Institute for Health and Care Excellence (NICE) guidelines use a ≥140/90 mm Hg threshold. Our objective was to study the associations between isolated diastolic hypertension (IDH), diagnosed using these 2 blood pressure thresholds, and cardiovascular disease (CVD) in a large cohort of UK adults. We analyzed data from UK Biobank, which enrolled participants between 2006 and 2010 with follow-up through March 2019. We excluded persons with systolic hypertension or baseline CVD. We defined incident CVD as a composite of nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. We used Cox regression to quantify associations between IDH and CVD, as well as the individual outcomes included in the composite outcome. We studied 151 831 participants with normal systolic blood pressure (mean age 54 years, 40% male). Overall, 24.5% had IDH by the American College of Cardiology/American Heart Association definition compared with 6% by the ESC/NICE definition. Compared with normal diastolic blood pressure, IDH by the American College of Cardiology/American Heart Association definition was not significantly associated with CVD risk (hazard ratio, 1.08 [95% CI, 0.98-1.18]) whereas IDH by the ESC/NICE definition was significantly associated with a modest increase in CVD (hazard ratio, 1.15 [95% CI, 1.04-1.29]). Similar results were found by sex and among participants not taking baseline antihypertensives. Furthermore, neither IDH definition was associated with the individual outcomes of nonfatal myocardial infarction or stroke. In conclusion, the proportion of UK Biobank participants with IDH was significantly higher by the American College of Cardiology/American Heart Association definition compared with the ESC/NICE definitions; however, only the ESC/NICE definition was statistically associated with increased CVD risk.