Liquid Biopsy of Lung Cancer Before Pathological Diagnosis Is Associated With Shorter Time to Treatment.

PURPOSE: Studies have investigated the early use of liquid biopsy (LBx) during the diagnostic workup of patients presenting with clinical evidence of advanced lung cancer, but real-world adoption and impact has not been characterized. The aim of this study was to determine whether the use of LBx before diagnosis (Dx; LBx-Dx) enables timely comprehensive genomic profiling (CGP) and shortens time until treatment initiation for advanced non-small-cell lung cancer (aNSCLC). MATERIALS AND METHODS: This study used the Flatiron Health-Foundation Medicine electronic health record-derived deidentified clinicogenomic database of patients with aNSCLC from approximately 280 US cancer clinics. RESULTS: Of 1,076 patients with LBx CGP ordered within 30 days prediagnosis/postdiagnosis, we focused on 56 (5.2%) patients who ordered LBx before diagnosis date (median 8 days between order and diagnosis, range, 1-28). Compared with 1,020 patients who ordered LBx after diagnosis (Dx-LBx), LBx-Dx patients had similar stage and ctDNA tumor fraction (TF). LBx-Dx patients received CGP results a median of 1 day after Dx versus 25 days for Dx-LBx patients. Forty-three percent of LBx-Dx were positive for an National Comprehensive Cancer Network driver, and 32% had ctDNA TF >1% but were driver negative (presumed true negatives). In 748 patients with previously untreated aNSCLC, median time from Dx to therapy was shorter in the LBx-Dx versus Dx-LBx group (21 v 35 days; P < .001). CONCLUSION: Early LBx in anticipation of pathologic diagnosis of aNSCLC was uncommon in this real-world cohort, yet this emerging paradigm was associated with an abbreviated time to CGP results and faster therapy initiation. Forthcoming prospective studies will clarify the utility of LBx in parallel with biopsy for diagnostic confirmation for patients presenting with suspected advanced lung cancer.

Evidence for extensive pleiotropy among pharmacogenes.

AIM: We sought to identify potential pleiotropy involving pharmacogenes. METHODS: We tested 184 functional variants in 34 pharmacogenes for associations using a custom grouping of International Classification and Disease, Ninth Revision billing codes extracted from deidentified electronic health records of 6892 patients. RESULTS: We replicated several associations including ABCG2 (rs2231142) and gout (p = 1.73 × 10(-7); odds ratio [OR]: 1.73; 95% CI: 1.40-2.12); and SLCO1B1 (rs4149056) and jaundice (p = 2.50 × 10(-4); OR: 1.67; 95% CI: 1.27-2.20). CONCLUSION: In this systematic screen for phenotypic associations with functional variants, several novel genotype-phenotype combinations also achieved phenome-wide significance, including SLC15A2 rs1143672 and renal osteodystrophy (p = 2.67 × 10(-) (6); OR: 0.61; 95% CI: 0.49-0.75).

Population Stratification in the Context of Diverse Epidemiologic Surveys Sans Genome-Wide Data.

Population stratification or confounding by genetic ancestry is a potential cause of false associations in genetic association studies. Estimation of and adjustment for genetic ancestry has become common practice thanks in part to the availability of ancestry informative markers on genome-wide association study (GWAS) arrays. While array data is now widespread, these data are not ubiquitous as several large epidemiologic and clinic-based studies lack genome-wide data. One such large epidemiologic-based study lacking genome-wide data accessible to investigators is the National Health and Nutrition Examination Surveys (NHANES), population-based cross-sectional surveys of Americans linked to demographic, health, and lifestyle data conducted by the Centers for Disease Control and Prevention. DNA samples (n = 14,998) were extracted from biospecimens from consented NHANES participants between 1991-1994 (NHANES III, phase 2) and 1999-2002 and represent three major self-identified racial/ethnic groups: non-Hispanic whites (n = 6,634), non-Hispanic blacks (n = 3,458), and Mexican Americans (n = 3,950). We as the Epidemiologic Architecture for Genes Linked to Environment study genotyped candidate gene and GWAS-identified index variants in NHANES as part of the larger Population Architecture using Genomics and Epidemiology I study for collaborative genetic association studies. To enable basic quality control such as estimation of genetic ancestry to control for population stratification in NHANES san genome-wide data, we outline here strategies that use limited genetic data to identify the markers optimal for characterizing genetic ancestry. From among 411 and 295 autosomal SNPs available in NHANES III and NHANES 1999-2002, we demonstrate that markers with ancestry information can be identified to estimate global ancestry. Despite limited resolution, global genetic ancestry is highly correlated with self-identified race for the majority of participants, although less so for ethnicity. Overall, the strategies outlined here for a large epidemiologic study can be applied to other datasets accessible for genotype-phenotype studies but are sans genome-wide data.

Pleiotropic and sex-specific effects of cancer GWAS SNPs on melanoma risk in the population architecture using genomics and epidemiology (PAGE) study.

BACKGROUND: Several regions of the genome show pleiotropic associations with multiple cancers. We sought to evaluate whether 181 single-nucleotide polymorphisms previously associated with various cancers in genome-wide association studies were also associated with melanoma risk. METHODS: We evaluated 2,131 melanoma cases and 20,353 controls from three studies in the Population Architecture using Genomics and Epidemiology (PAGE) study (EAGLE-BioVU, MEC, WHI) and two collaborating studies (HPFS, NHS). Overall and sex-stratified analyses were performed across studies. RESULTS: We observed statistically significant associations with melanoma for two lung cancer SNPs in the TERT-CLPTM1L locus (Bonferroni-corrected p<2.8x10-4), replicating known pleiotropic effects at this locus. In sex-stratified analyses, we also observed a potential male-specific association between prostate cancer risk variant rs12418451 and melanoma risk (OR=1.22, p=8.0x10-4). No other variants in our study were associated with melanoma after multiple comparisons adjustment (p>2.8e-4). CONCLUSIONS: We provide confirmatory evidence of pleiotropic associations with melanoma for two SNPs previously associated with lung cancer, and provide suggestive evidence for a male-specific association with melanoma for prostate cancer variant rs12418451. This SNP is located near TPCN2, an ion transport gene containing SNPs which have been previously associated with hair pigmentation but not melanoma risk. Previous evidence provides biological plausibility for this association, and suggests a complex interplay between ion transport, pigmentation, and melanoma risk that may vary by sex. If confirmed, these pleiotropic relationships may help elucidate shared molecular pathways between cancers and related phenotypes.

Mining diverse small RNA species in the deep transcriptome.

Transcriptomes of many species are proving to be exquisitely diverse, and many investigators are now using high-throughput sequencing to quantify non-protein-coding RNAs, namely small RNAs (sRNA). Unfortunately, most studies are focused solely on microRNA changes, and many investigators are not analyzing the full compendium of sRNA species present in their large datasets. We provide here a rationale to include all types of sRNAs in sRNA sequencing analyses, which will aid in the discovery of their biological functions and physiological relevance.

Rare variant APOC3 R19X is associated with cardio-protective profiles in a diverse population-based survey as part of the Epidemiologic Architecture for Genes Linked to Environment Study.

BACKGROUND: A founder mutation was recently discovered and described as conferring favorable lipid profiles and reduced subclinical atherosclerotic disease in a Pennsylvania Amish population. Preliminary data have suggested that this null mutation APOC3 R19X (rs76353203) is rare in the general population. METHODS AND RESULTS: To better describe the frequency and lipid profile in the general population, we as part of the Population Architecture using Genomics and Epidemiology I Study and the Epidemiological Architecture for Genes Linked to Environment Study genotyped rs76353203 in 1113 Amish participants from Ohio and Indiana and 19 613 participants from the National Health and Nutrition Examination Surveys (NHANES III, 1999 to 2002, and 2007 to 2008). We found no carriers among the Ohio and Indiana Amish. Of the 19 613 NHANES participants, we identified 31 participants carrying the 19X allele, for an overall allele frequency of 0.08%. Among fasting adults, the 19X allele was associated with lower triglycerides (n=7603; ß=-71.20; P=0.007) and higher high-density lipoprotein cholesterol (n=8891; ß=15.65; P=0.0002) and, although not significant, lower low-density lipoprotein cholesterol (n=6502; ß= -4.85; P=0.68) after adjustment for age, sex, and race/ethnicity. On average, 19X allele participants had approximately half the triglyceride levels (geometric means, 51.3 to 69.7 versus 134.6 to 141.3 mg/dL), >20% higher high-density lipoprotein cholesterol levels (geometric means, 56.8 to 74.4 versus 50.38 to 53.36 mg/dL), and lower low-density lipoprotein cholesterol levels (geometric means, 104.5 to 128.6 versus 116.1 to 125.7 mg/dL) compared with noncarrier participants. CONCLUSIONS: These data demonstrate that APOC3 19X exists in the general US population in multiple racial/ethnic groups and is associated with cardio-protective lipid profiles.

GWATCH: a web platform for automated gene association discovery analysis.

BACKGROUND: As genome-wide sequence analyses for complex human disease determinants are expanding, it is increasingly necessary to develop strategies to promote discovery and validation of potential disease-gene associations. FINDINGS: Here we present a dynamic web-based platform - GWATCH - that automates and facilitates four steps in genetic epidemiological discovery: 1) Rapid gene association search and discovery analysis of large genome-wide datasets; 2) Expanded visual display of gene associations for genome-wide variants (SNPs, indels, CNVs), including Manhattan plots, 2D and 3D snapshots of any gene region, and a dynamic genome browser illustrating gene association chromosomal regions; 3) Real-time validation/replication of candidate or putative genes suggested from other sources, limiting Bonferroni genome-wide association study (GWAS) penalties; 4) Open data release and sharing by eliminating privacy constraints (The National Human Genome Research Institute (NHGRI) Institutional Review Board (IRB), informed consent, The Health Insurance Portability and Accountability Act (HIPAA) of 1996 etc.) on unabridged results, which allows for open access comparative and meta-analysis. CONCLUSIONS: GWATCH is suitable for both GWAS and whole genome sequence association datasets. We illustrate the utility of GWATCH with three large genome-wide association studies for HIV-AIDS resistance genes screened in large multicenter cohorts; however, association datasets from any study can be uploaded and analyzed by GWATCH.

Accuracy of administratively-assigned ancestry for diverse populations in an electronic medical record-linked biobank.

Recently, the development of biobanks linked to electronic medical records has presented new opportunities for genetic and epidemiological research. Studies based on these resources, however, present unique challenges, including the accurate assignment of individual-level population ancestry. In this work we examine the accuracy of administratively-assigned race in diverse populations by comparing assigned races to genetically-defined ancestry estimates. Using 220 ancestry informative markers, we generated principal components for patients in our dataset, which were used to cluster patients into groups based on genetic ancestry. Consistent with other studies, we find a strong overall agreement (Kappa  = 0.872) between genetic ancestry and assigned race, with higher rates of agreement for African-descent and European-descent assignments, and reduced agreement for Hispanic, East Asian-descent, and South Asian-descent assignments. These results suggest caution when selecting study samples of non-African and non-European backgrounds when administratively-assigned race from biobanks is used.

Pleiotropic associations of risk variants identified for other cancers with lung cancer risk: the PAGE and TRICL consortia.

BACKGROUND: Genome-wide association studies have identified hundreds of genetic variants associated with specific cancers. A few of these risk regions have been associated with more than one cancer site; however, a systematic evaluation of the associations between risk variants for other cancers and lung cancer risk has yet to be performed. METHODS: We included 18023 patients with lung cancer and 60543 control subjects from two consortia, Population Architecture using Genomics and Epidemiology (PAGE) and Transdisciplinary Research in Cancer of the Lung (TRICL). We examined 165 single-nucleotide polymorphisms (SNPs) that were previously associated with at least one of 16 non-lung cancer sites. Study-specific logistic regression results underwent meta-analysis, and associations were also examined by race/ethnicity, histological cell type, sex, and smoking status. A Bonferroni-corrected P value of 2.5×10(-5) was used to assign statistical significance. RESULTS: The breast cancer SNP LSP1 rs3817198 was associated with an increased risk of lung cancer (odds ratio [OR] = 1.10; 95% confidence interval [CI] = 1.05 to 1.14; P = 2.8×10(-6)). This association was strongest for women with adenocarcinoma (P = 1.2×10(-4)) and not statistically significant in men (P = .14) with this cell type (P het by sex = .10). Two glioma risk variants, TERT rs2853676 and CDKN2BAS1 rs4977756, which are located in regions previously associated with lung cancer, were associated with increased risk of adenocarcinoma (OR = 1.16; 95% CI = 1.10 to 1.22; P = 1.1×10(-8)) and squamous cell carcinoma (OR = 1.13; CI = 1.07 to 1.19; P = 2.5×10(-5)), respectively. CONCLUSIONS: Our findings demonstrate a novel pleiotropic association between the breast cancer LSP1 risk region marked by variant rs3817198 and lung cancer risk.

Pleiotropic effects of genetic risk variants for other cancers on colorectal cancer risk: PAGE, GECCO and CCFR consortia.

OBJECTIVE: Genome-wide association studies have identified a large number of single nucleotide polymorphisms (SNPs) associated with a wide array of cancer sites. Several of these variants demonstrate associations with multiple cancers, suggesting pleiotropic effects and shared biological mechanisms across some cancers. We hypothesised that SNPs previously associated with other cancers may additionally be associated with colorectal cancer. In a large-scale study, we examined 171 SNPs previously associated with 18 different cancers for their associations with colorectal cancer. DESIGN: We examined 13 338 colorectal cancer cases and 40 967 controls from three consortia: Population Architecture using Genomics and Epidemiology (PAGE), Genetic Epidemiology of Colorectal Cancer (GECCO), and the Colon Cancer Family Registry (CCFR). Study-specific logistic regression results, adjusted for age, sex, principal components of genetic ancestry, and/or study specific factors (as relevant) were combined using fixed-effect meta-analyses to evaluate the association between each SNP and colorectal cancer risk. A Bonferroni-corrected p value of 2.92×10(-4) was used to determine statistical significance of the associations. RESULTS: Two correlated SNPs--rs10090154 and rs4242382--in Region 1 of chromosome 8q24, a prostate cancer susceptibility region, demonstrated statistically significant associations with colorectal cancer risk. The most significant association was observed with rs4242382 (meta-analysis OR=1.12; 95% CI 1.07 to 1.18; p=1.74×10(-5)), which also demonstrated similar associations across racial/ethnic populations and anatomical sub-sites. CONCLUSIONS: This is the first study to clearly demonstrate Region 1 of chromosome 8q24 as a susceptibility locus for colorectal cancer; thus, adding colorectal cancer to the list of cancer sites linked to this particular multicancer risk region at 8q24.

Replication of SCN5A Associations with Electrocardio-graphic Traits in African Americans from Clinical and Epidemiologic Studies.

The NAv1.5 sodium channel α subunit is the predominant α-subunit expressed in the heart and is associated with cardiac arrhythmias. We tested five previously identified SCN5A variants (rs7374138, rs7637849, rs7637849, rs7629265, and rs11129796) for an association with PR interval and QRS duration in two unique study populations: the Third National Health and Nutrition Examination Survey (NHANES III, n= 552) accessed by the Epidemiologic Architecture for Genes Linked to Environment (EAGLE) and a combined dataset (n= 455) from two biobanks linked to electronic medical records from Vanderbilt University (BioVU) and Northwestern University (NUgene) as part of the electronic Medical Records & Genomics (eMERGE) network. A meta-analysis including all three study populations (n~4,000) suggests that eight SCN5A associations were significant for both QRS duration and PR interval (p<5.0E-3) with little evidence for heterogeneity across the study populations. These results suggest that published SCN5A associations replicate across different study designs in a meta-analysis and represent an important first step in utility of multiple study designs for genetic studies and the identification/characterization of genetic variants associated with ECG traits in African-descent populations.

Utilization of an EMR-biorepository to identify the genetic predictors of calcineurin-inhibitor toxicity in heart transplant recipients.

Calcineurin-inhibitors CI are immunosuppressive agents prescribed to patients after solid organ transplant to prevent rejection. Although these drugs have been transformative for allograft survival, long-term use is complicated by side effects including nephrotoxicity. Given the narrow therapeutic index of CI, therapeutic drug monitoring is used to prevent acute rejection from underdosing and acute toxicity from overdosing, but drug monitoring does not alleviate long-term side effects. Patients on calcineurin-inhibitors for long periods almost universally experience declines in renal function, and a subpopulation of transplant recipients ultimately develop chronic kidney disease that may progress to end stage renal disease attributable to calcineurin inhibitor toxicity (CNIT). Pharmacogenomics has the potential to identify patients who are at high risk for developing advanced chronic kidney disease caused by CNIT and providing them with existing alternate immunosuppressive therapy. In this study we utilized BioVU, Vanderbilt University Medical Center's DNA biorepository linked to de-identified electronic medical records to identify a cohort of 115 heart transplant recipients prescribed calcineurin-inhibitors to identify genetic risk factors for CNIT We identified 37 cases of nephrotoxicity in our cohort, defining nephrotoxicity as a monthly median estimated glomerular filtration rate (eGFR)<30 mL/min/1.73 m2 at least six months post-transplant for at least three consecutive months. All heart transplant patients were genotyped on the Illumina ADME Core Panel, a pharmacogenomic genotyping platform that assays 184 variants across 34 genes. In Cox regression analysis adjusting for age at transplant, pre-transplant chronic kidney disease, pre-transplant diabetes, and the three most significant principal components (PCAs), we did not identify any markers that met our multiple-testing threshold. As a secondary analysis we also modeled post-transplant eGFR directly with linear mixed models adjusted for age at transplant, cyclosporine use, median BMI, and the three most significant principal components. While no SNPs met our threshold for significance, a SNP previously identified in genetic studies of the dosing of tacrolimus CYP34A rs776746, replicated in an adjusted analysis at an uncorrected p-value of 0.02 (coeff(S.E.)=14.60(6.41)). While larger independent studies will be required to further validate this finding, this study underscores the EMRs usefulness as a resource for longitudinal pharmacogenetic study designs.

Lipid trait-associated genetic variation is associated with gallstone disease in the diverse Third National Health and Nutrition Examination Survey (NHANES III).

BACKGROUND: Gallstone disease is one of the most common digestive disorders, affecting more than 30 million Americans. Previous twin studies suggest a heritability of 25% for gallstone formation. To date, one genome-wide association study (GWAS) has been performed in a population of European-descent. Several candidate gene studies have been performed in various populations, but most have been inconclusive. Given that gallstones consist of up to 80% cholesterol, we hypothesized that common genetic variants associated with high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG) would also be associated with gallstone risk. METHODS: To test this hypothesis, the Epidemiologic Architecture for Genes Linked to Environment (EAGLE) study as part of the Population Architecture using Genomics and Epidemiology (PAGE) study performed tests of association between 49 GWAS-identified lipid trait SNPs and gallstone disease in non-Hispanic whites (446 cases and 1,962 controls), non-Hispanic blacks (179 cases and 1,540 controls), and Mexican Americans (227 cases and 1,478 controls) ascertained for the population-based Third National Health and Nutrition Examination Survey (NHANES III). RESULTS: At a liberal significance threshold of 0.05, five, four, and four SNP(s) were associated with disease risk in non-Hispanic whites, non-Hispanic blacks, and Mexican Americans, respectively. No one SNP was associated with gallstone disease risk in all three racial/ethnic groups. The most significant association was observed for ABCG5 rs6756629 in non-Hispanic whites [odds ratio (OR) = 1.89; 95% confidence interval (CI) = 1.44-2.49; p = 0.0001). ABCG5 rs6756629 is in strong linkage disequilibrium with rs11887534 (D19H), a variant previously associated with gallstone disease risk in populations of European-descent. CONCLUSIONS: We replicated a previously associated variant for gallstone disease risk in non-Hispanic whites. Further discovery and fine-mapping efforts in diverse populations are needed to fully describe the genetic architecture of gallstone disease risk in humans.

Fine Mapping and Identification of BMI Loci in African Americans.

Genome-wide association studies (GWASs) primarily performed in European-ancestry (EA) populations have identified numerous loci associated with body mass index (BMI). However, it is still unclear whether these GWAS loci can be generalized to other ethnic groups, such as African Americans (AAs). Furthermore, the putative functional variant or variants in these loci mostly remain under investigation. The overall lower linkage disequilibrium in AA compared to EA populations provides the opportunity to narrow in or fine-map these BMI-related loci. Therefore, we used the Metabochip to densely genotype and evaluate 21 BMI GWAS loci identified in EA studies in 29,151 AAs from the Population Architecture using Genomics and Epidemiology (PAGE) study. Eight of the 21 loci (SEC16B, TMEM18, ETV5, GNPDA2, TFAP2B, BDNF, FTO, and MC4R) were found to be associated with BMI in AAs at 5.8 × 10(-5). Within seven out of these eight loci, we found that, on average, a substantially smaller number of variants was correlated (r(2) > 0.5) with the most significant SNP in AA than in EA populations (16 versus 55). Conditional analyses revealed GNPDA2 harboring a potential additional independent signal. Moreover, Metabochip-wide discovery analyses revealed two BMI-related loci, BRE (rs116612809, p = 3.6 × 10(-8)) and DHX34 (rs4802349, p = 1.2 × 10(-7)), which were significant when adjustment was made for the total number of SNPs tested across the chip. These results demonstrate that fine mapping in AAs is a powerful approach for both narrowing in on the underlying causal variants in known loci and discovering BMI-related loci.

Genetic variants associated with fasting glucose and insulin concentrations in an ethnically diverse population: results from the Population Architecture using Genomics and Epidemiology (PAGE) study.

BACKGROUND: Multiple genome-wide association studies (GWAS) within European populations have implicated common genetic variants associated with insulin and glucose concentrations. In contrast, few studies have been conducted within minority groups, which carry the highest burden of impaired glucose homeostasis and type 2 diabetes in the U.S. METHODS: As part of the 'Population Architecture using Genomics and Epidemiology (PAGE) Consortium, we investigated the association of up to 10 GWAS-identified single nucleotide polymorphisms (SNPs) in 8 genetic regions with glucose or insulin concentrations in up to 36,579 non-diabetic subjects including 23,323 European Americans (EA) and 7,526 African Americans (AA), 3,140 Hispanics, 1,779 American Indians (AI), and 811 Asians. We estimated the association between each SNP and fasting glucose or log-transformed fasting insulin, followed by meta-analysis to combine results across PAGE sites. RESULTS: Overall, our results show that 9/9 GWAS SNPs are associated with glucose in EA (p = 0.04 to 9 × 10-15), versus 3/9 in AA (p= 0.03 to 6 × 10-5), 3/4 SNPs in Hispanics, 2/4 SNPs in AI, and 1/2 SNPs in Asians. For insulin we observed a significant association with rs780094/GCKR in EA, Hispanics and AI only. CONCLUSIONS: Generalization of results across multiple racial/ethnic groups helps confirm the relevance of some of these loci for glucose and insulin metabolism. Lack of association in non-EA groups may be due to insufficient power, or to unique patterns of linkage disequilibrium.

Assessment of a pharmacogenomic marker panel in a polypharmacy population identified from electronic medical records.

BACKGROUND: The ADME Core Panel assays 184 variants across 34 pharmacogenes, many of which are difficult to accurately genotype with standard multiplexing methods. METHODS: We genotyped 326 frequently medicated individuals of European descent in Vanderbilt's biorepository linked to de-identified electronic medical records, BioVU, on the ADME Core Panel to assess quality and performance of the assay. We compared quality control metrics and determined the extent of direct and indirect marker overlap between the ADME Core Panel and the Illumina Omni1-Quad. RESULTS: We found the quality of the ADME Core Panel data to be high, with exceptions in select copy number variants and markers in certain genes (notably CYP2D6). Most of the common variants on the ADME panel are genotyped by the Omni1, but absent rare variants and copy number variants could not be accurately tagged by single markers. CONCLUSION: Our frequently medicated study population did not convincingly differ in allele frequency from reference populations, suggesting that heterogeneous clinical samples (with respect to medications) have similar allele frequency distributions in pharmacogenetics genes compared with reference populations.

A systematic screen of FDA-approved drugs for inhibitors of biological threat agents.

BACKGROUND: The rapid development of effective medical countermeasures against potential biological threat agents is vital. Repurposing existing drugs that may have unanticipated activities as potential countermeasures is one way to meet this important goal, since currently approved drugs already have well-established safety and pharmacokinetic profiles in patients, as well as manufacturing and distribution networks. Therefore, approved drugs could rapidly be made available for a new indication in an emergency. METHODOLOGY/PRINCIPAL FINDINGS: A large systematic effort to determine whether existing drugs can be used against high containment bacterial and viral pathogens is described. We assembled and screened 1012 FDA-approved drugs for off-label broad-spectrum efficacy against Bacillus anthracis; Francisella tularensis; Coxiella burnetii; and Ebola, Marburg, and Lassa fever viruses using in vitro cell culture assays. We found a variety of hits against two or more of these biological threat pathogens, which were validated in secondary assays. As expected, antibiotic compounds were highly active against bacterial agents, but we did not identify any non-antibiotic compounds with broad-spectrum antibacterial activity. Lomefloxacin and erythromycin were found to be the most potent compounds in vivo protecting mice against Bacillus anthracis challenge. While multiple virus-specific inhibitors were identified, the most noteworthy antiviral compound identified was chloroquine, which disrupted entry and replication of two or more viruses in vitro and protected mice against Ebola virus challenge in vivo. CONCLUSIONS/SIGNIFICANCE: The feasibility of repurposing existing drugs to face novel threats is demonstrated and this represents the first effort to apply this approach to high containment bacteria and viruses.

Characterization of the Metabochip in diverse populations from the International HapMap Project in the Epidemiologic Architecture for Genes Linked to Environment (EAGLE) project.

Genome-wide association studies (GWAS) have identified hundreds of genomic regions associated with common human disease and quantitative traits. A major research avenue for mature genotype-phenotype associations is the identification of the true risk or functional variant for downstream molecular studies or personalized medicine applications. As part of the Population Architecture using Genomics and Epidemiology (PAGE) study, we as Epidemiologic Architecture for Genes Linked to Environment (EAGLE) are fine-mapping GWAS-identified genomic regions for common diseases and quantitative traits. We are currently genotyping the Metabochip, a custom content BeadChip designed for fine-mapping metabolic diseases and traits, in∼15,000 DNA samples from patients of African, Hispanic, and Asian ancestry linked to de-identified electronic medical records from the Vanderbilt University biorepository (BioVU). As an initial study of quality control, we report here the genotyping data for 360 samples of European, African, Asian, and Mexican descent from the International HapMap Project. In addition to quality control metrics, we report the overall allele frequency distribution, overall population differentiation (as measured by FST), and linkage disequilibrium patterns for a select GWAS-identified region associated with low-density lipoprotein cholesterol levels to illustrate the utility of the Metabochip for fine-mapping studies in the diverse populations expected in EAGLE, the PAGE study, and other efforts underway designed to characterize the complex genetic architecture underlying common human disease and quantitative traits.