Genomic Insights into Gestational Weight Gain: Uncovering Tissue-Specific Mechanisms and Pathways.

Increasing gestational weight gain (GWG) is linked to adverse outcomes in pregnant persons and their children. The Early Growth Genetics (EGG) Consortium identified previously genetic variants that could contribute to early, late, and total GWG from fetal and maternal genomes. However, the biologic mechanisms and tissue-Specificity of these variants in GWG is unknown. We evaluated the association between genetically predicted gene expression in five relevant maternal (subcutaneous and visceral adipose, breast, uterus, and whole blood) from GTEx (v7) and fetal (placenta) tissues and early, late, and total GWG using S-PrediXcan. We tested enrichment of pre-defined biological pathways for nominally (P < 0.05) significant associations using the GENE2FUNC module from Functional Mapping and Annotation of Genome-Wide Association Studies. After multiple testing correction, we did not find significant associations between maternal and fetal gene expression and early, late, or total GWG. There was significant enrichment of several biological pathways, including metabolic processes, secretion, and intracellular transport, among nominally significant genes from the maternal analyses (false discovery rate p-values: 0.016 to 9.37×10). Enriched biological pathways varied across pregnancy. Though additional research is necessary, these results indicate that diverse biological pathways are likely to impact GWG, with their influence varying by tissue and weeks of gestation.

Overcome the Limitation of Phenome-Wide Association Studies (PheWAS): Extension of PheWAS to Efficient and Robust Large-Scale ICD Codes Analysis.

The Phenome-wide association studies (PheWAS) have become widely used for efficient, high-throughput evaluation of relationship between a genetic factor and a large number of disease phenotypes, typically extracted from a DNA biobank linked with electronic medical records (EMR). Phecodes, billing code-derived disease case-control status, are usually used as outcome variables in PheWAS and logistic regression has been the standard choice of analysis method. Since the clinical diagnoses in EMR are often inaccurate with errors which can lead to biases in the odds ratio estimates, much effort has been put to accurately define the cases and controls to ensure an accurate analysis. Specifically in order to correctly classify controls in the population, an exclusion criteria list for each Phecode was manually compiled to obtain unbiased odds ratios. However, the accuracy of the list cannot be guaranteed without extensive data curation process. The costly curation process limits the efficiency of large-scale analyses that take full advantage of all structured phenotypic information available in EMR. Here, we proposed to estimate relative risks (RR) instead. We first demonstrated the desired nature of RR that overcomes the inaccuracy in the controls via theoretical formula. With simulation and real data application, we further confirmed that RR is unbiased without compiling exclusion criteria lists. With RR as estimates, we are able to efficiently extend PheWAS to a larger-scale, phenome construction agnostic analysis of phenotypes, using ICD 9/10 codes, which preserve much more disease-related clinical information than Phecodes.

Development and validation of the patient-reported outcome for older people living with HIV/AIDS in China (PROHIV-OLD).

BACKGROUND: The involvement of quality of life as the UNAIDS fourth 90 target to monitor the global HIV response highlighted the development of patient-reported outcome (PRO) measures to help address the holistic needs of people living with HIV/AIDS (PLWHA) beyond viral suppression. This study developed and tested preliminary measurement properties of a new patient-reported outcome (PROHIV-OLD) measure designed specifically to capture influences of HIV on patients aged 50 and older in China. METHODS: Ninety-three older people living with HIV/AIDS (PLWHA) were interviewed to solicit items and two rounds of patient cognitive interviews were conducted to modify the content and wording of the initial items. A validation study was then conducted to refine the initial instrument and evaluate measurement properties. Patients were recruited between February 2021 and November 2021, and followed six months later after the first investigation. Classical test theory (CTT) and item response theory (IRT) were used to select items using the baseline data. The follow-up data were used to evaluate the measurement properties of the final instrument. RESULTS: A total of 600 patients were recruited at the baseline. Of the 485 patients who completed the follow-up investigation, 483 were included in the validation sample. The final scale of PROHIV-OLD contained 25 items describing five dimensions (physical symptoms, mental status, illness perception, family relationship, and treatment). All the PROHIV-OLD dimensions had satisfactory reliability with Cronbach's alpha coefficient, McDonald's ω, and composite reliability of each dimension being all higher than 0.85. Most dimensions met the test-retest reliability standard except for the physical symptoms dimension (ICC = 0.64). Confirmatory factor analysis supported the structural validity of the final scale, and the model fit index satisfied the criterion. The correlations between dimensions of PROHIV-OLD and MOS-HIV met hypotheses in general. Significant differences on scores of the PROHIV-OLD were found between demographic and clinical subgroups, supporting known-groups validity. CONCLUSIONS: The PROHIV-OLD was found to have good feasibility, reliability and validity for evaluating health outcome of Chinese older PLWHA. Other measurement properties such as responsiveness and interpretability will be further examined.

A new test for trait mean and variance detects unreported loci for blood-pressure variation.

Variability in quantitative traits has clinical, ecological, and evolutionary significance. Most genetic variants identified for complex quantitative traits have only a detectable effect on the mean of trait. We have developed the mean-variance test (MVtest) to simultaneously model the mean and log-variance of a quantitative trait as functions of genotypes and covariates by using estimating equations. The advantages of MVtest include the facts that it can detect effect modification, that multiple testing can follow conventional thresholds, that it is robust to non-normal outcomes, and that association statistics can be meta-analyzed. In simulations, we show control of type I error of MVtest over several alternatives. We identified 51 and 37 previously unreported associations for effects on blood-pressure variance and mean, respectively, in the UK Biobank. Transcriptome-wide association studies revealed 633 significant unique gene associations with blood-pressure mean variance. MVtest is broadly applicable to studies of complex quantitative traits and provides an important opportunity to detect novel loci.

Access to Healthcare Among Young Adult Probationers Participating in a Pilot Health-Focused Reentry Program.

Justice-involved adults experience disparities in healthcare access. This pilot study examines healthcare access among young adult probationers (n = 66) receiving 6-months of Service Navigation and Health Coaching support implemented between 2017 and 2021. Data are from baseline, 6-month follow-up and satisfaction surveys. Between baseline and follow-up, the proportion of insured young adult participants (66%-88%; p < .001) and those using healthcare services (36%-71%; p < .001) increased significantly; report of unmet physical healthcare needs decreased significantly (44%-26%; p = .003). Satisfaction data revealed increased self-efficacy, motivation, focus, and improved organizational, goal setting, and communication skills. The program improved healthcare access by increasing health insurance and recent use of healthcare services. Longitudinal studies are needed to assess maintenance of these outcomes and potential impacts on disparities in health status and access to care indicators. Integrating navigation and coaching supports to advance the well-being of justice-involved young adults is a promising mechanism to facilitate healthcare access.

Evaluation and Measurement Properties of a Patient-Reported Experience Measure for Home Dialysis.

BACKGROUND: No previously validated patient-reported experience measures exist for use among patients undergoing home dialysis. We tested the Home Dialysis Care Experience survey, a newly developed 26-item experience measure, among patients from 30 dialysis facilities in the United States. METHODS: Using mail and telephone survey modalities, we approached 1372 patients treated with peritoneal dialysis or home hemodialysis for participation. Using the results from completed surveys, we evaluated item calibration by assessing item floor and ceiling effects. We tested three sets of composite scores and used factor analysis to assess model fit for each. We evaluated associations of composite scores with global ratings and separately with patient and dialysis facility characteristics. Finally, we measured test-retest reliability in patients who completed the survey at two separate time points. RESULTS: Overall, 495 eligible patients completed at least one survey (response rate 36%). Of these, 49 completed the survey in Spanish and 61 completed a second survey within 30 days. We did not detect significant floor or ceiling effects, except for one item that demonstrated >90% responses at the top response option. Analyses supported one 12-item composite scale with high internal consistency reliability: Quality of Home Dialysis Care and Operations (Cronbach alpha=0.85). This scale strongly correlated with overall staff rating ( r =0.73) and overall center rating ( r =0.70). Patient demographic and dialysis facility characteristics were not consistently associated with composite scale scores or overall staff or center ratings. Intraclass correlation coefficients in the test-retest population were 0.74 for the Quality scale, 0.88 for overall staff rating, and 0.90 for overall center rating. CONCLUSIONS: The Home Dialysis Care Experience survey is a 26-item measure that includes one composite scale and two global rating scores and is an informative tool to evaluate patient experience of care for home dialysis.

X-chromosome and kidney function: evidence from a multi-trait genetic analysis of 908,697 individuals reveals sex-specific and sex-differential findings in genes regulated by androgen response elements.

X-chromosomal genetic variants are understudied but can yield valuable insights into sexually dimorphic human traits and diseases. We performed a sex-stratified cross-ancestry X-chromosome-wide association meta-analysis of seven kidney-related traits (n = 908,697), identifying 23 loci genome-wide significantly associated with two of the traits: 7 for uric acid and 16 for estimated glomerular filtration rate (eGFR), including four novel eGFR loci containing the functionally plausible prioritized genes ACSL4, CLDN2, TSPAN6 and the female-specific DRP2. Further, we identified five novel sex-interactions, comprising male-specific effects at FAM9B and AR/EDA2R, and three sex-differential findings with larger genetic effect sizes in males at DCAF12L1 and MST4 and larger effect sizes in females at HPRT1. All prioritized genes in loci showing significant sex-interactions were located next to androgen response elements (ARE). Five ARE genes showed sex-differential expressions. This study contributes new insights into sex-dimorphisms of kidney traits along with new prioritized gene targets for further molecular research.

Developmental Risk for Infants with Cleft Lip with or Without Cleft Palate Based on Caregiver-Proxy Reports.

OBJECTIVES: (1) Assess caregiver-reported development in infants born with cleft lip ± alveolus (CL ± A) and cleft lip and palate (CLP); (2) determine factors associated with increased developmental risk; and (3) determine consistency of developmental risk before and after surgery for cleft lip. DESIGN: Prospective, longitudinal assessment of development. Time (T) 1, prior to lip closure; T2, 2 months post lip closure. SETTING: Three US craniofacial teams and online parent support groups. PARTICIPANTS: 123 total caregivers (96% mothers); 100 at T1, 92 at T2, and 69 at both T1 and T2. MEASURE: Ages and Stages Questionnaire-3 (ASQ-3): Communication, Gross Motor, Fine Motor, Problem Solving, Personal Social Domains. RESULTS: At T1 47%; at T2 42% passed all 5 Domains; 36% of infants pass all 5 Domains at both T1 and T2. Infants with CLP were at greatest risk on Communication [B = 1.449 (CI = .149-20.079), p = .038; Odds Ratio (OR) = 4.3 (CI = .923-19.650)] and Gross Motor Domains [B = 1.753 (CI = .316-20.605), p = .034; OR = 5.8 (CI = 1.162-28.671)]. Male infants were at greatest risk on Fine Motor [B = 1.542 (CI = .495-20.005), p = .009; OR = 4.7 (CI = 1.278-17.101)] and Problem Solving Domains [B = 1.200 (CI = .118-19.708), p = .044; OR = 3.3 (CI = .896-12.285)]. CONCLUSIONS: Based on caregiver report, infants with CL ± A and CLP meet referral criteria at a high rate. Infants with CLP and male infants were at greatest risk. Regular developmental screening is recommended.

Psychometric properties of the Fluoride Hesitancy Identification Tool (FHIT).

INTRODUCTION: Some caregivers are hesitant about topical fluoride for their children despite evidence that fluoride prevents caries and is safe. Recent work described a five domain model of caregivers' topical fluoride hesitancy. We developed the Fluoride Hesitancy Identification Tool (FHIT) item pool based on the model. This study sought to evaluate the FHIT's psychometric properties in an effort to generate a short, simple to score, reliable, and valid tool that measures caregivers' topical fluoride hesitancy. METHODS: In 2021 and 2022, we conducted an observational, cross-sectional study of caregivers, collecting data from two independent caregiver samples (n1 = 523; n2 = 612). The FHIT item pool included 33 items. We used confirmatory factor analyses (CFA) to examine whether the FHIT items measured five separate domains as hypothesized and to reduce the number of items. We then fit item response theory (IRT) models and computed Cronbach's alpha for each domain. Last, we examined the construct validity of the FHIT and evaluated scoring approaches. RESULTS: After dropping 8 items, CFA supported a five factor model of topical fluoride hesitancy, with no cross-loadings (RMSEA = 0.079; SRMR = 0.057; CFI = 0.98; TLI = 0.98). We further reduced the items to four per domain (20 items total). Marginal alphas showed that the item sets provided reliability of ≥0.90 at hesitancy levels at and above average. The domains correlated more strongly with each other and topical fluoride refusal than with other questions on the survey. DISCUSSION: Our results support the FHIT's ability to reliably and validly measure five domains of topical fluoride hesitancy using the average score of the four items in each domain.

Development of Portable Electronic Health Record Based Algorithms to Identify Individuals with Diabetic Retinopathy.

Objectives: To develop, validate and implement algorithms to identify diabetic retinopathy (DR) cases and controls from electronic health care records (EHR)s. Methods : We developed and validated EHR-based algorithms to identify DR cases and individuals with type I or II diabetes without DR (controls) in three independent EHR systems: Vanderbilt University Medical Center Synthetic Derivative (VUMC), the VA Northeast Ohio Healthcare System (VANEOHS), and Massachusetts General Brigham (MGB). Cases were required to meet one of three criteria: 1) two or more dates with any DR ICD-9/10 code documented in the EHR, or 2) at least one affirmative health-factor or EPIC code for DR along with an ICD9/10 code for DR on a different day, or 3) at least one ICD-9/10 code for any DR occurring within 24 hours of an ophthalmology exam. Criteria for controls included affirmative evidence for diabetes as well as an ophthalmology exam. Results: The algorithms, developed and evaluated in VUMC through manual chart review, resulted in a positive predictive value (PPV) of 0.93 for cases and negative predictive value (NPV) of 0.97 for controls. Implementation of algorithms yielded similar metrics in VANEOHS (PPV=0.94; NPV=0.86) and lower in MGB (PPV=0.84; NPV=0.76). In comparison, use of DR definition as implemented in Phenome-wide association study (PheWAS) in VUMC, yielded similar PPV (0.92) but substantially reduced NPV (0.48). Implementation of the algorithms to the Million Veteran Program identified over 62,000 DR cases with genetic data including 14,549 African Americans and 6,209 Hispanics with DR. Conclusions/Discussion: We demonstrate the robustness of the algorithms at three separate health-care centers, with a minimum PPV of 0.84 and substantially improved NPV than existing high-throughput methods. We strongly encourage independent validation and incorporation of features unique to each EHR to enhance algorithm performance for DR cases and controls.

Session Introduction: Drug-repurposing and discovery in the era of "big" real-world data: how the incorporation of observational data, genetics, and other -omic technologies can move us forward.

This PSB 2024 session discusses the many broad biological, computational, and statistical approaches currently being used for therapeutic drug target identification and repurposing of existing treatments. Drug repurposing efforts have the potential to dramatically improve the treatment landscape by more rapidly identifying drug targets and alternative strategies for untreated or poorly managed diseases. The overarching theme for this session is the use and integration of real-world data to identify drug-disease pairs with potential therapeutic use. These drug-disease pairs may be identified through genomic, proteomic, biomarkers, protein interaction analyses, electronic health records, and chemical profiling. Taken together, this session combines novel applications of methods and innovative modeling strategies with diverse real-world data to suggest new pharmaceutical treatments for human diseases.

EVALUATING THE RELATIONSHIPS BETWEEN GENETIC ANCESTRY AND THE CLINICAL PHENOME.

There is a desire in research to move away from the concept of race as a clinical factor because it is a societal construct used as an imprecise proxy for geographic ancestry. In this study, we leverage the biobank from Vanderbilt University Medical Center, BioVU, to investigate relationships between genetic ancestry proportion and the clinical phenome. For all samples in BioVU, we calculated six ancestry proportions based on 1000 Genomes references: eastern African (EAFR), western African (WAFR), northern European (NEUR), southern European (SEUR), eastern Asian (EAS), and southern Asian (SAS). From PheWAS, we found phecode categories significantly enriched neoplasms for EAFR, WAFR, and SEUR, and pregnancy complication in SEUR, NEUR, SAS, and EAS (p < 0.003). We then selected phenotypes hypertension (HTN) and atrial fibrillation (AFib) to further investigate the relationships between these phenotypes and EAFR, WAFR, SEUR, and NEUR using logistic regression modeling and non-linear restricted cubic spline modeling (RCS). For EAS and SAS, we chose renal failure (RF) for further modeling. The relationships between HTN and AFib and the ancestries EAFR, WAFR, and SEUR were best fit by the linear model (beta p < 1x10-4 for all) while the relationships with NEUR were best fit with RCS (HTN ANOVA p = 0.001, AFib ANOVA p < 1x10-4). For RF, the relationship with SAS was best fit with a linear model (beta p < 1x10-4) while RCS model was a better fit for EAS (ANOVA p < 1x10-4). In this study, we identify relationships between genetic ancestry and phenotypes that are best fit with non-linear modeling techniques. The assumption of linearity for regression modeling is integral for proper fitting of a model and there is no knowing a priori to modeling if the relationship is truly linear.

Evidence of recent and ongoing admixture in the U.S. and influences on health and disparities.

Many researchers in genetics and social science incorporate information about race in their work. However, migrations (historical and forced) and social mobility have brought formerly separated populations of humans together, creating younger generations of individuals who have more complex and diverse ancestry and race profiles than older age groups. Here, we sought to better understand how temporal changes in genetic admixture influence levels of heterozygosity and impact health outcomes. We evaluated variation in genetic ancestry over 100 birth years in a cohort of 35,842 individuals with electronic health record (EHR) information in the Southeastern United States. Using the software STRUCTURE, we analyzed 2,678 ancestrally informative markers relative to three ancestral clusters (African, East Asian, and European) and observed rising levels of admixture for all clinically-defined race groups since 1990. Most race groups also exhibited increases in heterozygosity and long-range linkage disequilibrium over time, further supporting the finding of increasing admixture in young individuals in our cohort. These data are consistent with United States Census information from broader geographic areas and highlight the changing demography of the population. This increased diversity challenges classic approaches to studies of genotype-phenotype relationships which motivated us to explore the relationship between heterozygosity and disease diagnosis. Using a phenome-wide association study approach, we explored the relationship between admixture and disease risk and found that increased admixture resulted in protective associations with female reproductive disorders and increased risk for diseases with links to autoimmune dysfunction. These data suggest that tendencies in the United States population are increasing ancestral complexity over time. Further, these observations imply that, because both prevalence and severity of many diseases vary by race groups, complexity of ancestral origins influences health and disparities.

Genome-wide association meta-analysis identifies risk loci for abdominal aortic aneurysm and highlights PCSK9 as a therapeutic target.

Abdominal aortic aneurysm (AAA) is a common disease with substantial heritability. In this study, we performed a genome-wide association meta-analysis from 14 discovery cohorts and uncovered 141 independent associations, including 97 previously unreported loci. A polygenic risk score derived from meta-analysis explained AAA risk beyond clinical risk factors. Genes at AAA risk loci indicate involvement of lipid metabolism, vascular development and remodeling, extracellular matrix dysregulation and inflammation as key mechanisms in AAA pathogenesis. These genes also indicate overlap between the development of AAA and other monogenic aortopathies, particularly via transforming growth factor ß signaling. Motivated by the strong evidence for the role of lipid metabolism in AAA, we used Mendelian randomization to establish the central role of nonhigh-density lipoprotein cholesterol in AAA and identified the opportunity for repurposing of proprotein convertase, subtilisin/kexin-type 9 (PCSK9) inhibitors. This was supported by a study demonstrating that PCSK9 loss of function prevented the development of AAA in a preclinical mouse model.

A Pilot Randomized Clinical Trial of Pediatric Cystic Fibrosis Pulmonary Exacerbations Treatment Strategies.

Rationale: Despite the high prevalence and clear morbidity of cystic fibrosis (CF) pulmonary exacerbations (PEx), there have been no published clinical trials of outpatient exacerbation management. Objectives: To assess the feasibility of a pediatric clinical trial in which treatment of mild PEx is assigned randomly to immediate oral antibiotics or tailored therapy (increased airway clearance alone with oral antibiotics added only for prespecified criteria). The outcome on which sample size was based was the proportion of tailored therapy participants who avoided oral antibiotics during the 28 days after randomization. Methods: In this randomized, open-label, pilot feasibility study at 10 U.S. sites, children 6-18 years of age with CF were enrolled at their well baseline visits and followed through their first randomized PEx. Results: One hundred twenty-one participants were enrolled, of whom 94 (78%) reported symptoms of PEx at least once; of these, 81 (86%) had at least one exacerbation that met randomization criteria, of whom 63 (78%) were randomized. Feasibility goals were met, including enrollment, early detection of symptoms of PEx, and ability to randomize. Among the 33 participants assigned to tailored therapy, 10 (30%) received oral antibiotics, while 29 of 30 (97%) assigned to immediate antibiotics received oral antibiotics. The avoidance of oral antibiotics in 70% (95% confidence interval, 54-85%) was statistically significantly different from our null hypothesis that <10% of participants assigned to the tailored therapy arm would avoid antibiotics. Conclusions: Our pilot study demonstrates that conducting a randomized trial of oral antibiotic treatment strategies for mild PEx in children with CF is feasible and that assignment to a tailored therapy arm may reduce antibiotic exposure. Clinical trial registered with www.clinicaltrials.gov (NCT04608019).

Individualized Implementation of Youth Quality of Life Instrument-Research Version (YQOL-R) Among Chinese Adolescents with Different Weight Status.

Purpose: This study implemented the individualized Youth Quality of Life Instrument-Research Version (YQOL-R) to estimate the quality of life (QoL) among Chinese adolescents with three different Body Mass Index (BMI) levels. The study aims to explore and provide a reference for developing individualized QoL (IQoL) measurements in China. Methods: The sample consisted of 822 aged 11-18 from nine schools. The data collection included all participants' primary characters (age, sex, annual household income, parental education, and recruitment community) and their self-report QoL. Precisely, based on the generic measurement of YQOL-R, we developed IQoL measurements by asking adolescents' perceived five most important things to them (IQOLimportance) and the aspects they most want to change (IQOLchange) from 19 facets, respectively. The one-way analysis of variance (ANOVA) was applied to compare total and subscale scores of IQOLimportance, IQOLchange, and YQOL-R among adolescents with three different weight status. Also, the data analysis used multivariable linear regression modeling to test the effects on scores of IQOLimportance and IQOLchange. Results: Overall, the obese adolescents identified "Having good physical health" as the most important (54.03%) and most like-to-change (42.65%); in contrast, the normal-weight group ranked "Being myself" as the top facet of IQOLimportance (52.42%) and "Having good friends" as the top facet of IQOLchange (43.12%). The obese adolescents' reported IQOLimportance scores are significantly lower than those of the normal-weight group (P=0.039). However, there is no significant difference in IQOLchange score among the three weight-status groups. The multivariable linear regression models indicated that adolescents who are girls (P=0.035), have higher educated fathers (P=0.049), and are overweight/obese (P=0.041) self-reported worse IQOLimportance score; yet, the girls (P=0.023) and older adolescents (P=0.004) answered lower IQOLchange scores. In addition, adolescents who had higher educated mothers (P=0.047; 0.023) and responded with higher total YQOL-R scores (P<0.001; <0.001) reported higher IQOLimportance and IQOLchange scores. Conclusion: In the current study, although the self-reported YQOL-R scores from different weight status did not present a significant difference, the obese group reported a statistical trend towards lower IQOLimportance scores than the normal-weight and overweight adolescents. These findings emphasize that IQOLimportance and IQOLchange could capture adolescents' perspectives with different weight statuses about their lives, which are unique as complementary health outcomes accompanying YQOL-R in health surveys and interventions among Chinese adolescents.

Uterine leiomyomata and keloids fibrosis origins: a mini-review of fibroproliferative diseases.

Diseases such as uterine leiomyomata (fibroids and benign tumors of the uterus) and keloids (raised scars) may share common etiology. Fibroids and keloids can co-occur in individuals, and both are highly heritable, suggesting they may share common genetic risk factors. Fibroproliferative diseases are common and characterized by scarring and overgrowth of connective tissue, impacting multiple organ systems. These conditions both have racial disparities in prevalence, with the highest prevalence observed among individuals of African ancestry. Several fibroproliferative diseases are more severe and common in populations of sub-Saharan Africa. This mini-review aims to provide a broad overview of the current knowledge of the evolutionary origins and causes of fibroproliferative diseases. We also discuss current hypotheses proposing that the increased prevalence of these diseases in African-derived populations is due to the selection for profibrotic alleles that are protective against helminth infections and provide examples from knowledge of uterine fibroid and keloid research.

Glycoprotein VI is Critical for the Detection and Progression of Abdominal Aortic Aneurysms.

A common feature in patients with abdominal aortic aneurysms (AAA) is the formation of a nonocclusive intraluminal thrombus (ILT) in regions of aortic dilation. Platelets are known to maintain hemostasis and propagate thrombosis through several redundant activation mechanisms, yet the role of platelet activation in the pathogenesis of AAA associated ILT is still poorly understood. Thus, we sought to investigate how platelet activation impacts the pathogenesis of AAA. Using RNA-sequencing, we identify that the platelet-associated transcripts are significantly enriched in the ILT compared to the adjacent aneurysm wall and healthy control aortas. We found that the platelet specific receptor glycoprotein VI (GPVI) is among the top enriched genes in AAA ILT and is increased on the platelet surface of AAA patients. Examination of a specific indicator of platelet activity, soluble GPVI (sGPVI), in two independent AAA patient cohorts is highly predictive of a AAA diagnosis and associates more strongly with aneurysm growth rate when compared to D-dimer in humans. Finally, intervention with the anti-GPVI antibody (J) in mice with established aneurysms blunted the progression of AAA in two independent mouse models. In conclusion, we show that levels of sGPVI in humans can predict a diagnosis of AAA and AAA growth rate, which may be critical in the identification of high-risk patients. We also identify GPVI as a novel platelet-specific AAA therapeutic target, with minimal risk of adverse bleeding complications, where none currently exist. KEY POINTS: Soluble glycoprotein VI, which is a platelet-derived blood biomarker, predicts a diagnosis of AAA, with high sensitivity and specificity in distinguishing patients with fast from slow-growing AAA.Blockade of glycoprotein VI in mice with established aneurysms reduces AAA progression and mortality, indicating therapeutic potential.

A genetically supported drug repurposing pipeline for diabetes treatment using electronic health records.

BACKGROUND: The identification of new uses for existing drug therapies has the potential to identify treatments for comorbid conditions that have the added benefit of glycemic control while also providing a rapid, low-cost approach to drug (re)discovery. METHODS: We developed and tested a genetically-informed drug-repurposing pipeline for diabetes management. This approach mapped genetically-predicted gene expression signals from the largest genome-wide association study for type 2 diabetes mellitus to drug targets using publicly available databases to identify drug-gene pairs. These drug-gene pairs were then validated using a two-step approach: 1) a self-controlled case-series (SCCS) using electronic health records from a discovery and replication population, and 2) Mendelian randomization (MR). FINDINGS: After filtering on sample size, 20 candidate drug-gene pairs were validated and various medications demonstrated evidence of glycemic regulation including two anti-hypertensive classes: angiotensin-converting enzyme inhibitors as well as calcium channel blockers (CCBs). The CCBs demonstrated the strongest evidence of glycemic reduction in both validation approaches (SCCS HbA1c and glucose reduction: -0.11%, p = 0.01 and -0.85 mg/dL, p = 0.02, respectively; MR: OR = 0.84, 95% CI = 0.81, 0.87, p = 5.0 x 10-25). INTERPRETATION: Our results support CCBs as a strong candidate medication for blood glucose reduction in addition to cardiovascular disease reduction. Further, these results support the adaptation of this approach for use in future drug-repurposing efforts for other conditions. FUNDING: National Institutes of Health, Medical Research Council Integrative Epidemiology Unit at the University of Bristol, UK Medical Research Council, American Heart Association, and Department of Veterans Affairs (VA) Informatics and Computing Infrastructure and VA Cooperative Studies Program.