Declining autozygosity over time: An exploration in over 1 million individuals from three diverse cohorts.

Previous studies have hypothesized that autozygosity is decreasing over generational time. However, these studies were limited to relatively small samples (n < 11,000) lacking in diversity, which may limit the generalizability of their findings. We present data that partially support this hypothesis from three large cohorts of diverse ancestries, two from the US (All of Us, n = 82,474; the Million Veteran Program, n = 622,497) and one from the UK (UK Biobank, n = 380,899). Our results from a mixed-effect meta-analysis demonstrate an overall trend of decreasing autozygosity over generational time (meta-analyzed slope = -0.029, SE = 0.009, p = 6.03e-4). On the basis of our estimates, we would predict FROH to decline 0.29% for every 20-year increase in birth year. We determined that a model including an ancestry-by-country interaction term fit the data best, indicating that ancestry differences in this trend differ by country. We found further evidence to suggest a difference between the US and UK cohorts by meta-analyzing within country, observing a significant negative estimate in the US cohorts (meta-analyzed slope = -0.058, SE = 0.015, p = 1.50e-4) but a non-significant estimate in the UK (meta-analyzed slope = -0.001, SE = 0.008, p = 0.945). The association between autozygosity and birth year was substantially attenuated when accounting for educational attainment and income (meta-analyzed slope = -0.011, SE = 0.008, p = 0.167), suggesting they may partially account for decreasing autozygosity over time. Overall, we demonstrate decreasing autozygosity over time in a large, modern sample and speculate that this trend can be attributed to increases in urbanization and panmixia and differences in sociodemographic processes lead to country-specific differences in the rate of decline.

Genome-wide association study identifies four pan-ancestry loci for suicidal ideation in the Million Veteran Program.

Suicidal ideation (SI) often precedes and predicts suicide attempt and death, is the most common suicidal phenotype and is over-represented in veterans. The genetic architecture of SI in the absence of suicide attempt (SA) is unknown, yet believed to have distinct and overlapping risk with other suicidal behaviors. We performed the first GWAS of SI without SA in the Million Veteran Program (MVP), identifying 99,814 SI cases from electronic health records without a history of SA or suicide death (SD) and 512,567 controls without SI, SA or SD. GWAS was performed separately in the four largest ancestry groups, controlling for sex, age and genetic substructure. Ancestry-specific results were combined via meta-analysis to identify pan-ancestry loci. Four genome-wide significant (GWS) loci were identified in the pan-ancestry meta-analysis with loci on chromosomes 6 and 9 associated with suicide attempt in an independent sample. Pan-ancestry gene-based analysis identified GWS associations with DRD2, DCC, FBXL19, BCL7C, CTF1, ANNK1, and EXD3. Gene-set analysis implicated synaptic and startle response pathways (q's<0.05). European ancestry (EA) analysis identified GWS loci on chromosomes 6 and 9, as well as GWS gene associations in EXD3, DRD2, and DCC. No other ancestry-specific GWS results were identified, underscoring the need to increase representation of diverse individuals. The genetic correlation of SI and SA within MVP was high (rG = 0.87; p = 1.09e-50), as well as with post-traumatic stress disorder (PTSD; rG = 0.78; p = 1.98e-95) and major depressive disorder (MDD; rG = 0.78; p = 8.33e-83). Conditional analysis on PTSD and MDD attenuated most pan-ancestry and EA GWS signals for SI without SA to nominal significance, with the exception of EXD3 which remained GWS. Our novel findings support a polygenic and complex architecture for SI without SA which is largely shared with SA and overlaps with psychiatric conditions frequently comorbid with suicidal behaviors.

A multi-population phenome-wide association study of genetically-predicted height in the Million Veteran Program.

BACKGROUND: Height has been associated with many clinical traits but whether such associations are causal versus secondary to confounding remains unclear in many cases. To systematically examine this question, we performed a Mendelian Randomization-Phenome-wide association study (MR-PheWAS) using clinical and genetic data from a national healthcare system biobank. METHODS AND FINDINGS: Analyses were performed using data from the US Veterans Affairs (VA) Million Veteran Program in non-Hispanic White (EA, n = 222,300) and non-Hispanic Black (AA, n = 58,151) adults in the US. We estimated height genetic risk based on 3290 height-associated variants from a recent European-ancestry genome-wide meta-analysis. We compared associations of measured and genetically-predicted height with phenome-wide traits derived from the VA electronic health record, adjusting for age, sex, and genetic principal components. We found 345 clinical traits associated with measured height in EA and an additional 17 in AA. Of these, 127 were associated with genetically-predicted height at phenome-wide significance in EA and 2 in AA. These associations were largely independent from body mass index. We confirmed several previously described MR associations between height and cardiovascular disease traits such as hypertension, hyperlipidemia, coronary heart disease (CHD), and atrial fibrillation, and further uncovered MR associations with venous circulatory disorders and peripheral neuropathy in the presence and absence of diabetes. As a number of traits associated with genetically-predicted height frequently co-occur with CHD, we evaluated effect modification by CHD status of genetically-predicted height associations with risk factors for and complications of CHD. We found modification of effects of MR associations by CHD status for atrial fibrillation/flutter but not for hypertension, hyperlipidemia, or venous circulatory disorders. CONCLUSIONS: We conclude that height may be an unrecognized but biologically plausible risk factor for several common conditions in adults. However, more studies are needed to reliably exclude horizontal pleiotropy as a driving force behind at least some of the MR associations observed in this study.

Modeling the longitudinal changes of ancestry diversity in the Million Veteran Program.

BACKGROUND: The Million Veteran Program (MVP) participants represent 100 years of US history, including significant social and demographic changes over time. Our study assessed two aspects of the MVP: (i) longitudinal changes in population diversity and (ii) how these changes can be accounted for in genome-wide association studies (GWAS). To investigate these aspects, we divided MVP participants into five birth cohorts (N-range = 123,888 [born from 1943 to 1947] to 136,699 [born from 1948 to 1953]). RESULTS: Ancestry groups were defined by (i) HARE (harmonized ancestry and race/ethnicity) and (ii) a random-forest clustering approach using the 1000 Genomes Project and the Human Genome Diversity Project (1kGP + HGDP) reference panels (77 world populations representing six continental groups). In these groups, we performed GWASs of height, a trait potentially affected by population stratification. Birth cohorts demonstrate important trends in ancestry diversity over time. More recent HARE-assigned Europeans, Africans, and Hispanics had lower European ancestry proportions than older birth cohorts (0.010 < Cohen's d < 0.259, p < 7.80 × 10-4). Conversely, HARE-assigned East Asians showed an increase in European ancestry proportion over time. In GWAS of height using HARE assignments, genomic inflation due to population stratification was prevalent across all birth cohorts (linkage disequilibrium score regression intercept = 1.08 ± 0.042). The 1kGP + HGDP-based ancestry assignment significantly reduced the population stratification (mean intercept reduction = 0.045 ± 0.007, p < 0.05) confounding in the GWAS statistics. CONCLUSIONS: This study provides a characterization of ancestry diversity of the MVP cohort over time and compares two strategies to infer genetically defined ancestry groups by assessing differences in controlling population stratification in genome-wide association studies.

Genome-Wide Genetic Analysis of Dropout in a Controlled Exercise Intervention in Sedentary Adults With Overweight or Obesity and Cardiometabolic Disease.

BACKGROUND: Despite the benefits of exercise, many individuals are unable or unwilling to adopt an exercise intervention. PURPOSE: The purpose of this analysis was to identify putative genetic variants associated with dropout from exercise training interventions among individuals in the STRRIDE trials. METHODS: We used a genome-wide association study approach to identify genetic variants in 603 participants initiating a supervised exercise intervention. Exercise intervention dropout occurred when a subject withdrew from further participation in the study or was otherwise lost to follow-up. RESULTS: Exercise intervention dropout was associated with a cluster of single-nucleotide polymorphisms with the top candidate being rs722069 (T/C, risk allele = C) (unadjusted p = 2.2 × 10-7, odds ratio = 2.23) contained within a linkage disequilibrium block on chromosome 16. In Genotype-Tissue Expression, rs722069 is an expression quantitative trait locus of the EARS2, COG7, and DCTN5 genes in skeletal muscle tissue. In subsets of the STRRIDE genetic cohort with available muscle gene expression (n = 37) and metabolic data (n = 82), at baseline the C allele was associated with lesser muscle expression of EARS2 (p < .002) and COG7 (p = .074) as well as lesser muscle concentrations of C2- and C3-acylcarnitines (p = .026). CONCLUSIONS: Our observations imply that exercise intervention dropout is genetically moderated through alterations in gene expression and metabolic pathways in skeletal muscle. Individual genetic traits may allow the development of a biomarker-based approach for identifying individuals who may benefit from more intensive counseling and other interventions to optimize exercise intervention adoption. CLINICAL TRIAL INFORMATION: STRRIDE I = NCT00200993; STRRIDE AT/RT = NCT00275145; STRRIDE-PD = NCT00962962.

Regular participation in exercise can provide a myriad of health benefits. Although individuals recognize these benefits, many are unable or unwilling to adopt an exercise intervention once initiated. The purpose of this analysis was to identify genetic variants associated with dropout from an exercise training intervention. We found exercise intervention dropout to be genetically moderated through changes in gene expression and metabolic pathways in muscle. Thus, individual genetic traits may allow for the development of a biomarker-based targeted approach for identifying individuals who may benefit from more intensive counseling and interventions to optimize the adoption of an exercise intervention program.

Military exposures and Gulf War illness in veterans with and without posttraumatic stress disorder.

Gulf War illness (GWI) is a chronic multisymptom disorder of unknown etiology that is believed to be caused by neurotoxicant exposure experienced during deployment to the Gulf War. Posttraumatic stress disorder (PTSD) covaries with GWI and is believed to play a role in GWI symptoms. The present study examined the association between self-reported military exposures and GWI, stratified by PTSD status, in veterans from the Gulf War Era Cohort and Biorepository who were deployed to the Persian Gulf during the war. Participants self-reported current GWI and PTSD symptoms as well as military exposures (e.g., pyridostigmine [PB] pills, pesticides/insecticides, combat, chemical attacks, and oil well fires) experienced during the Gulf War. Deployed veterans' (N = 921) GWI status was ascertained using the Centers for Disease Control and Prevention definition. Individuals who met the GWI criteria were stratified by PTSD status, yielding three groups: GWI-, GWI+/PTSD-, and GWI+/PTSD+. Multivariable logistic regression, adjusted for covariates, was used to examine associations between GWI/PTSD groups and military exposures. Apart from insect bait use, the GWI+/PTSD+ group had higher odds of reporting military exposures than the GWI+/PTSD- group, adjusted odds ratio (aOR) = 2.15, 95% CI [1.30, 3.56]-aOR = 6.91, 95% CI [3.39, 14.08]. Except for PB pills, the GWI+/PTSD- group had a higher likelihood of reporting military exposures than the GWI- group, aOR = 2.03, 95% CI [1.26, 3.26]-aOR = 4.01, 95% CI [1.57, 10.25]. These findings are consistent with roles for both PTSD and military exposures in the etiology of GWI.

Genotyping Array Design and Data Quality Control in the Million Veteran Program.

The Million Veteran Program (MVP), initiated by the Department of Veterans Affairs (VA), aims to collect biosamples with consent from at least one million veterans. Presently, blood samples have been collected from over 800,000 enrolled participants. The size and diversity of the MVP cohort, as well as the availability of extensive VA electronic health records, make it a promising resource for precision medicine. MVP is conducting array-based genotyping to provide a genome-wide scan of the entire cohort, in parallel with whole-genome sequencing, methylation, and other 'omics assays. Here, we present the design and performance of the MVP 1.0 custom Axiom array, which was designed and developed as a single assay to be used across the multi-ethnic MVP cohort. A unified genetic quality-control analysis was developed and conducted on an initial tranche of 485,856 individuals, leading to a high-quality dataset of 459,777 unique individuals. 668,418 genetic markers passed quality control and showed high-quality genotypes not only on common variants but also on rare variants. We confirmed that, with non-European individuals making up nearly 30%, MVP's substantial ancestral diversity surpasses that of other large biobanks. We also demonstrated the quality of the MVP dataset by replicating established genetic associations with height in European Americans and African Americans ancestries. This current dataset has been made available to approved MVP researchers for genome-wide association studies and other downstream analyses. Further data releases will be available for analysis as recruitment at the VA continues and the cohort expands both in size and diversity.

A genome-wide association study of suicide attempts in the million veterans program identifies evidence of pan-ancestry and ancestry-specific risk loci.

To identify pan-ancestry and ancestry-specific loci associated with attempting suicide among veterans, we conducted a genome-wide association study (GWAS) of suicide attempts within a large, multi-ancestry cohort of U.S. veterans enrolled in the Million Veterans Program (MVP). Cases were defined as veterans with a documented history of suicide attempts in the electronic health record (EHR; N = 14,089) and controls were defined as veterans with no documented history of suicidal thoughts or behaviors in the EHR (N = 395,064). GWAS was performed separately in each ancestry group, controlling for sex, age and genetic substructure. Pan-ancestry risk loci were identified through meta-analysis and included two genome-wide significant loci on chromosomes 20 (p = 3.64 × 10-9) and 1 (p = 3.69 × 10-8). A strong pan-ancestry signal at the Dopamine Receptor D2 locus (p = 1.77 × 10-7) was also identified and subsequently replicated in a large, independent international civilian cohort (p = 7.97 × 10-4). Additionally, ancestry-specific genome-wide significant loci were also detected in African-Americans, European-Americans, Asian-Americans, and Hispanic-Americans. Pathway analyses suggested over-representation of many biological pathways with high clinical significance, including oxytocin signaling, glutamatergic synapse, cortisol synthesis and secretion, dopaminergic synapse, and circadian rhythm. These findings confirm that the genetic architecture underlying suicide attempt risk is complex and includes both pan-ancestry and ancestry-specific risk loci. Moreover, pathway analyses suggested many commonly impacted biological pathways that could inform development of improved therapeutics for suicide prevention.

Associations between neighborhood socioeconomic cluster and hypertension, diabetes, myocardial infarction, and coronary artery disease within a cohort of cardiac catheterization patients.

BACKGROUND: Neighborhood-level socioeconomic status (SES) is associated with health outcomes, including cardiovascular disease and diabetes, but these associations are rarely studied across large, diverse populations. METHODS: We used Ward's Hierarchical clustering to define eight neighborhood clusters across North Carolina using 11 census-based indicators of SES, race, housing, and urbanicity and assigned 6992 cardiac catheterization patients at Duke University Hospital from 2001 to 2010 to clusters. We examined associations between clusters and coronary artery disease index > 23 (CAD), history of myocardial infarction, hypertension, and diabetes using logistic regression adjusted for age, race, sex, body mass index, region of North Carolina, distance to Duke University Hospital, and smoking status. RESULTS: Four clusters were urban, three rural, and one suburban higher-middle-SES (referent). We observed greater odds of myocardial infarction in all six clusters with lower or middle-SES. Odds of CAD were elevated in the rural cluster that was low-SES and plurality Black (OR 1.16, 95% CI 0.94-1.43) and in the rural cluster that was majority American Indian (OR 1.31, 95% CI 0.91-1.90). Odds of diabetes and hypertension were elevated in two urban and one rural low- and lower-middle SES clusters with large Black populations. CONCLUSIONS: We observed higher prevalence of cardiovascular disease and diabetes in neighborhoods that were predominantly rural, low-SES, and non-White, highlighting the importance of public health and healthcare system outreach into these communities to promote cardiometabolic health and prevent and manage hypertension, diabetes and coronary artery disease.

Longitudinal assessment of colonoscopy adverse events in the prospective Cooperative Studies Program no. 380 colorectal cancer screening and surveillance cohort.

BACKGROUND AND AIMS: Data are limited regarding colonoscopy risk during long-term, programmatic colorectal cancer screening and follow-up. We aimed to describe adverse events during follow-up in a colonoscopy screening program after the baseline examination and examine factors associated with increased risk. METHODS: Cooperative Studies Program no. 380 includes 3121 asymptomatic veterans aged 50 to 75 years who underwent screening colonoscopy between 1994 and 1997. Periprocedure adverse events requiring significant intervention were defined as major events (other events were minor) and were tracked during follow-up for at least 10 years. Multivariable odds ratios (ORs) were calculated for factors associated with risk of follow-up adverse events. RESULTS: Of 3727 follow-up examinations in 1983 participants, adverse events occurred in 105 examinations (2.8%) in 93 individuals, including 22 major and 87 minor events (examinations may have had >1 event). Incidence of major events (per 1000 examinations) remained relatively stable over time, with 6.1 events at examination 2, 4.8 at examination 3, and 7.2 at examination 4. Examinations with major events included 1 perforation, 3 GI bleeds requiring intervention, and 17 cardiopulmonary events. History of prior colonoscopic adverse events was associated with increased risk of events (major or minor) during follow-up (OR, 2.7; 95% confidence interval, 1.6-4.6). CONCLUSIONS: Long-term programmatic screening and surveillance was safe, as major events were rare during follow-up. However, serious cardiopulmonary events were the most common major events. These results highlight the need for detailed assessments of comorbid conditions during routine clinical practice, which could help inform individual decisions regarding the utility of ongoing colonoscopy follow-up.

Exposures to low-levels of fine particulate matter are associated with acute changes in heart rate variability, cardiac repolarization, and circulating blood lipids in coronary artery disease patients.

Exposure to air pollution is a major risk factor for cardiovascular disease, disease risk factors, and mortality. Specifically, particulate matter (PM), and to some extent ozone, are contributors to these effects. In addition, exposures to these pollutants may be especially dangerous for susceptible populations. In this repeated-visit panel study, cardiovascular markers were collected from thirteen male participants with stable coronary artery disease. For 0-4 days prior to the health measurement collections, daily concentrations of fine PM (PM2.5) and ozone were obtained from local central monitoring stations located near the participant's homes. Then, single (PM2.5) and two-pollutant (PM2.5 and ozone) models were used to assess whether there were short-term changes in cardiovascular health markers. Per interquartile range increase in PM2.5, there were decrements in several heart rate variability metrics, including the standard deviation of the normal-to-normal intervals (lag 3, -5.8%, 95% confidence interval (CI) = -11.5, 0.3) and root-mean squared of successive differences (five day moving average, -8.1%, 95% CI = -15.0, -0.7). In addition, increases in PM2.5 were also associated with changes in P complexity (lag 1, 4.4%, 95% CI = 0.5, 8.5), QRS complexity (lag 1, 4.9%, 95% CI = 1.4, 8.5), total cholesterol (five day moving average, -2.1%, 95% CI = -4.1, -0.1), and high-density lipoprotein cholesterol (lag 2, -1.6%, 95% CI = -3.1, -0.1). Comparisons to our previously published work on ozone were conducted. We found that ozone affected inflammation and endothelial function, whereas PM2.5 influenced heart rate variability, repolarization, and lipids. All the health changes from these two studies were found at concentrations below the United States Environmental Protection Agency's National Ambient Air Quality Standards. Our results imply clear differences in the cardiovascular outcomes observed with exposure to the two ubiquitous air pollutants PM2.5 and ozone; this observation suggests different mechanisms of toxicity for these exposures.

Ten or More Cumulative Lifetime Adenomas Are Associated with Increased Risk for Advanced Neoplasia and Colorectal Cancer.

BACKGROUND: Colorectal cancer (CRC) screening guidelines recommend frequent colonoscopies and consideration of genetic testing in individuals with ≥10 cumulative adenomas. However, it is unclear how these guidelines apply to routine practice. AIMS: We estimated the proportion of participants found to have ≥10 cumulative adenomas in a screening population and described their outcomes of advanced neoplasia (AN), CRC, and extra-colonic malignancy. METHODS: We performed a secondary analysis of VA CSP#380, which includes 3121 veterans aged 50-75 who were followed up to 10 years after screening colonoscopy. We calculated the cumulative risk of ≥10 cumulative adenomas by Kaplan-Meier method. We compared baseline risk factors in those with and without ≥10 cumulative adenomas as well as the risk for AN (adenoma ≥1 cm, villous adenoma or high-grade dysplasia, or CRC) and extra-colonic malignancy by multivariate logistic regression. RESULTS: The cumulative risk of ≥10 cumulative adenomas over 10.5 years was 6.51% (95% CI 4.38%-9.62%). Age 60-69 or 70-75 at baseline colonoscopy was the only factors associated with the finding of ≥10 cumulative adenomas. Compared to those with 0-9 cumulative adenomas, participants with ≥10 cumulative adenomas were more likely to have had AN (OR 17.03; 95% CI 9.41-30.84), including CRC (OR 7.00; 95% CI 2.84-17.28), but not extra-colonic malignancies. CONCLUSIONS: Approximately 6.5% of participants in this screening population were found to have ≥10 cumulative adenomas over 10.5 years, which was uncommon before age 60. These participants were found to have AN and CRC significantly more often compared to those with lower cumulative adenomas.

Genome-wide analysis identifies novel susceptibility loci for myocardial infarction.

AIMS: While most patients with myocardial infarction (MI) have underlying coronary atherosclerosis, not all patients with coronary artery disease (CAD) develop MI. We sought to address the hypothesis that some of the genetic factors which establish atherosclerosis may be distinct from those that predispose to vulnerable plaques and thrombus formation. METHODS AND RESULTS: We carried out a genome-wide association study for MI in the UK Biobank (n∼472 000), followed by a meta-analysis with summary statistics from the CARDIoGRAMplusC4D Consortium (n∼167 000). Multiple independent replication analyses and functional approaches were used to prioritize loci and evaluate positional candidate genes. Eight novel regions were identified for MI at the genome wide significance level, of which effect sizes at six loci were more robust for MI than for CAD without the presence of MI. Confirmatory evidence for association of a locus on chromosome 1p21.3 harbouring choline-like transporter 3 (SLC44A3) with MI in the context of CAD, but not with coronary atherosclerosis itself, was obtained in Biobank Japan (n∼165 000) and 16 independent angiography-based cohorts (n∼27 000). Follow-up analyses did not reveal association of the SLC44A3 locus with CAD risk factors, biomarkers of coagulation, other thrombotic diseases, or plasma levels of a broad array of metabolites, including choline, trimethylamine N-oxide, and betaine. However, aortic expression of SLC44A3 was increased in carriers of the MI risk allele at chromosome 1p21.3, increased in ischaemic (vs. non-diseased) coronary arteries, up-regulated in human aortic endothelial cells treated with interleukin-1ß (vs. vehicle), and associated with smooth muscle cell migration in vitro. CONCLUSIONS: A large-scale analysis comprising ∼831 000 subjects revealed novel genetic determinants of MI and implicated SLC44A3 in the pathophysiology of vulnerable plaques.

Baseline Colonoscopy Findings Associated With 10-Year Outcomes in a Screening Cohort Undergoing Colonoscopy Surveillance.

BACKGROUND & AIMS: Few studies have evaluated long-term outcomes of ongoing colonoscopic screening and surveillance in a screening population. We aimed to determine the 10-year risk for advanced neoplasia (defined as adenomas ≥10mm, adenomas with villous histology or high-grade dysplasia, or colorectal cancer [CRC]) and assessed whether baseline colonoscopy findings were associated with long-term outcomes. METHODS: We collected data from the Department of Veterans Affairs Cooperative Studies Program Study on 3121 asymptomatic veterans (50-75 years old) who underwent a screening colonoscopy from 1994 through 1997 at 13 medical centers and were then followed for 10 years or until death. We included 1915 subjects with at least 1 surveillance colonoscopy and estimated cumulative incidence of advanced neoplasia by Kaplan-Meier curves. We then fit a longitudinal joint model to estimate risk of advanced neoplasia at each subsequent examination after baseline, adjusting for multiple colonoscopies within individuals. RESULTS: Through 10 years of follow-up, there were 146 individuals among all baseline colonoscopy groups found to have at least 1 incident advanced neoplasia. The cumulative 10-year incidence of advanced neoplasia was highest among those with baseline CRC (43.7%; 95% CI 13.0%-74.4%), followed by those with baseline advanced adenoma (AA) (21.9%; 95% CI 15.7-28.1). The cumulative 10-year incidence of advanced neoplasia was 6.3% (95% CI 4.1%-8.5%) and 4.1% (95% CI 2.7%-5.4%) for baseline 1 to 2 small adenomas (<1cm, and without villous histology or high-grade dysplasia) and no neoplasia, respectively (log-rank P = .10). After adjusting for prior surveillance, the risk of advanced neoplasia at each subsequent examination was not significantly increased in veterans with 1 or 2 small adenomas at baseline (odds ratio 0.96; 95% CI 0.67-1.41) compared with veterans with no baseline neoplasia. CONCLUSIONS: Baseline screening colonoscopy findings associate with advanced neoplasia within 10 years. Individuals with only 1 or 2 small adenomas at baseline have a low risk of advanced neoplasia over 10 years. Alternative surveillance strategies, could be considered for these individuals.

High-Risk Adenomas at Screening Colonoscopy Remain Predictive of Future High-Risk Adenomas Despite an Intervening Negative Colonoscopy.

INTRODUCTION: Limited data inform the current postpolypectomy surveillance guidelines, which suggest a shortened interval to third colonoscopy after a negative second examination if high-risk adenomas (HRA) were present on the initial screening colonoscopy. Therefore, we examined the risk of HRA at third colonoscopy stratified by findings on 2 previous examinations in a prospective screening colonoscopy cohort of US veterans. METHODS: We identified participants who had 3 or more colonoscopies from CSP#380. We examined the risk of HRA on the third examination based on findings from the previous 2 examinations. Multivariate logistic regression was used to adjust for multiple covariates. RESULTS: HRA were found at the third examination in 114 (12.8%) of 891 participants. Those with HRA on both previous examinations had the greatest incidence of HRA at third examination (14/56, 25.0%). Compared with those with no adenomas on both previous examinations, participants with HRA on the first examination remained at significantly increased risk for HRA at the third examination at 3 years after a negative second examination (odds ratio [OR] 3.41, 95% confidence interval [CI] 1.28-9.08), 5 years (OR 3.14, 95% CI 1.49-6.61), and 7 years (OR 2.89, 95% CI 1.08-7.74). DISCUSSION: In a screening population, HRA on the first examination identified individuals who remained at increased risk for HRA at the third examination, even after a negative second examination. This finding supports current colorectal cancer surveillance guidelines, which suggest a shortened, 5-year time interval to third colonoscopy after a negative second examination if high-risk findings were present on the baseline examination.

Advanced neoplasia in Veterans at screening colonoscopy using the National Cancer Institute Risk Assessment Tool.

BACKGROUND: Adapting screening strategy to colorectal cancer (CRC) risk may improve efficiency for all stakeholders however limited tools for such risk stratification exist. Colorectal cancers usually evolve from advanced neoplasms that are present for years. We applied the National Cancer Institute (NCI) CRC Risk Assessment Tool, which calculates future risk of CRC, to determine whether it could be used to predict current advanced neoplasia (AN) in a veteran cohort undergoing a baseline screening colonoscopy. METHODS: This was a prospective assessment of the relationship between future CRC risk predicted by the NCI tool, and the presence of AN at screening colonoscopy. Family, medical, dietary and physical activity histories were collected at the time of screening colonoscopy and used to calculate absolute CRC risk at 5, 10 and 20 years. Discriminatory accuracy was assessed. RESULTS: Of 3121 veterans undergoing screening colonoscopy, 94% had complete data available to calculate risk (N = 2934, median age 63 years, 100% men, and 15% minorities). Prevalence of AN at baseline screening colonoscopy was 11 % (N = 313). For tertiles of estimated absolute CRC risk at 5 years, AN prevalences were 6.54% (95% CI, 4.99, 8.09), 11.26% (95% CI, 9.28-13.24), and 14.21% (95% CI, 12.02-16.40). For tertiles of estimated risk at 10 years, the prevalences were 6.34% (95% CI, 4.81-7.87), 11.25% (95% CI, 9.27-13.23), and 14.42% (95% CI, 12.22-16.62). For tertiles of estimated absolute CRC risk at 20 years, current AN prevalences were 7.54% (95% CI, 5.75-9.33), 10.53% (95% CI, 8.45-12.61), and 12.44% (95% CI, 10.2-14.68). The area under the curve for predicting current AN was 0.60 (95% CI; 0.57-0.63, p < 0.0001) at 5 years, 0.60 (95% CI, 0.57-0.63, p < 0.0001) at 10 years and 0.58 (95% CI, 0.54-0.61, p < 0.0001) at 20 years. CONCLUSION: The NCI tool had modest discriminatory function for estimating the presence of current advanced neoplasia in veterans undergoing a first screening colonoscopy. These findings are comparable to other clinically utilized cancer risk prediction models and may be used to inform the benefit-risk assessment of screening, particularly for patients with competing comorbidities and lower risk, for whom a non-invasive screening approach is preferred.

Associations Between Residential Proximity to Traffic and Vascular Disease in a Cardiac Catheterization Cohort.

OBJECTIVE: Exposure to mobile source emissions is nearly ubiquitous in developed nations and is associated with multiple adverse health outcomes. There is an ongoing need to understand the specificity of traffic exposure associations with vascular outcomes, particularly in individuals with cardiovascular disease. APPROACH AND RESULTS: We performed a cross-sectional study using 2124 individuals residing in North Carolina, United States, who received a cardiac catheterization at the Duke University Medical Center. Traffic-related exposure was assessed via 2 metrics: (1) the distance between the primary residence and the nearest major roadway; and (2) location of the primary residence in regions defined based on local traffic patterns. We examined 4 cardiovascular disease outcomes: hypertension, peripheral arterial disease, the number of diseased coronary vessels, and recent myocardial infarction. Statistical models were adjusted for race, sex, smoking, type 2 diabetes mellitus, body mass index, hyperlipidemia, and home value. Results are expressed in terms of the odds ratio (OR). A 23% decrease in residential distance to major roadways was associated with higher prevalence of peripheral arterial disease (OR=1.29; 95% confidence interval, 1.08-1.55) and hypertension (OR=1.15; 95% confidence interval, 1.01-1.31). Associations with peripheral arterial disease were strongest in men (OR=1.42; 95% confidence interval, 1.17-1.74) while associations with hypertension were strongest in women (OR=1.21; 95% confidence interval, 0.99-1.49). Neither myocardial infarction nor the number of diseased coronary vessels were associated with traffic exposure. CONCLUSIONS: Traffic-related exposure is associated with peripheral arterial disease and hypertension while no associations are observed for 2 coronary-specific vascular outcomes.

The Gulf War Era Cohort and Biorepository: A Longitudinal Research Resource of Veterans of the 1990-1991 Gulf War Era.

The US Department of Veterans Affairs (VA) Gulf War Era Cohort and Biorepository (GWECB) is a nationally representative longitudinal cohort of US veterans who served during the 1990-1991 Gulf War era. The GWECB combines survey data, such as demographic, health behavior, and environmental exposure data; medical records; and a linked biorepository of blood specimens that can support a broad range of future research regarding health concerns unique to veterans of this era. To build this resource, the VA Cooperative Studies Program initiated a pilot study (2014-2016) to establish the GWECB and evaluate the processes required to build and maintain the resource. Participants (n = 1,275) consented to future sharing of their data and biospecimens for research purposes. Here we describe the pilot study, including recruitment and enrollment procedures, data collection and management, quality control, and challenges experienced. The GWECB data available to investigators under approved sharing mechanisms and the procedures for accessing them are extensively detailed. The study's consenting documents and a website link for the research survey are provided. Our hope is that new research drawing on the GWECB data and biospecimens will result in effective treatments and improved approaches to address the health concerns of Gulf War-era veterans.

Short-term effects of fine particulate matter and ozone on the cardiac conduction system in patients undergoing cardiac catheterization.

BACKGROUND: Air pollution-induced changes in cardiac electrophysiological properties could be a pathway linking air pollution and cardiovascular events. The evidence of air pollution effects on the cardiac conduction system is incomplete yet. We investigated short-term effects of particulate matter ≤ 2.5 µm in aerodynamic diameter (PM2.5) and ozone (O3) on cardiac electrical impulse propagation and repolarization as recorded in surface electrocardiograms (ECG). METHODS: We analyzed repeated 12-lead ECG measurements performed on 5,332 patients between 2001 and 2012. The participants came from the Duke CATHGEN Study who underwent cardiac catheterization and resided in North Carolina, United States (NC, U.S.). Daily concentrations of PM2.5 and O3 at each participant's home address were predicted with a hybrid air quality exposure model. We used generalized additive mixed models to investigate the associations of PM2.5 and O3 with the PR interval, QRS interval, heart rate-corrected QT interval (QTc), and heart rate (HR). The temporal lag structures of the associations were examined using distributed-lag models. RESULTS: Elevated PM2.5 and O3 were associated with four-day lagged lengthening of the PR and QRS intervals, and with one-day lagged increases in HR. We observed immediate effects on the lengthening of the QTc interval for both PM2.5 and O3, as well as delayed effects for PM2.5 (lagged by 3 - 4 days). The associations of PM2.5 and O3 with the PR interval and the association of O3 with the QRS interval persisted until up to seven days after exposure. CONCLUSIONS: In patients undergoing cardiac catheterization, short-term exposure to air pollution was associated with increased HR and delays in atrioventricular conduction, ventricular depolarization and repolarization.

Metabolomic Quantitative Trait Loci (mQTL) Mapping Implicates the Ubiquitin Proteasome System in Cardiovascular Disease Pathogenesis.

Levels of certain circulating short-chain dicarboxylacylcarnitine (SCDA), long-chain dicarboxylacylcarnitine (LCDA) and medium chain acylcarnitine (MCA) metabolites are heritable and predict cardiovascular disease (CVD) events. Little is known about the biological pathways that influence levels of most of these metabolites. Here, we analyzed genetics, epigenetics, and transcriptomics with metabolomics in samples from a large CVD cohort to identify novel genetic markers for CVD and to better understand the role of metabolites in CVD pathogenesis. Using genomewide association in the CATHGEN cohort (N = 1490), we observed associations of several metabolites with genetic loci. Our strongest findings were for SCDA metabolite levels with variants in genes that regulate components of endoplasmic reticulum (ER) stress (USP3, HERC1, STIM1, SEL1L, FBXO25, SUGT1) These findings were validated in a second cohort of CATHGEN subjects (N = 2022, combined p = 8.4x10-6-2.3x10-10). Importantly, variants in these genes independently predicted CVD events. Association of genomewide methylation profiles with SCDA metabolites identified two ER stress genes as differentially methylated (BRSK2 and HOOK2). Expression quantitative trait loci (eQTL) pathway analyses driven by gene variants and SCDA metabolites corroborated perturbations in ER stress and highlighted the ubiquitin proteasome system (UPS) arm. Moreover, culture of human kidney cells in the presence of levels of fatty acids found in individuals with cardiometabolic disease, induced accumulation of SCDA metabolites in parallel with increases in the ER stress marker BiP. Thus, our integrative strategy implicates the UPS arm of the ER stress pathway in CVD pathogenesis, and identifies novel genetic loci associated with CVD event risk.