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Pancreatic cancer is among the most well-characterized cancer types, yet a large proportion of the heritability of pancreatic cancer risk remains unclear. Here, we performed a large transcriptome-wide association study to systematically investigate associations between genetically predicted gene expression in normal pancreas tissue and pancreatic cancer risk. Using data from 305 subjects of mostly European descent in the Genotype-Tissue Expression Project, we built comprehensive genetic models to predict normal pancreas tissue gene expression, modifying the UTMOST (unified test for molecular signatures). These prediction models were applied to the genetic data of 8,275 pancreatic cancer cases and 6,723 controls of European ancestry. Thirteen genes showed an association of genetically predicted expression with pancreatic cancer risk at an FDR ≤ 0.05, including seven previously reported genes (, and ) and six novel genes not yet reported for pancreatic cancer risk [6q27: OR (95% confidence interval (CI), 1.54 (1.25-1.89); 13q12.13: OR (95% CI), 0.78 (0.70-0.88); 14q24.3: OR (95% CI), 1.35 (1.17-1.56); 17q12: OR (95% CI), 6.49 (2.96-14.27); 17q21.1: OR (95% CI), 1.94 (1.45-2.58); and 20p13: OR (95% CI): 1.41 (1.20-1.66)]. The associations for 10 of these genes (, and ) remained statistically significant even after adjusting for risk SNPs identified in previous genome-wide association study. Collectively, this analysis identified novel candidate susceptibility genes for pancreatic cancer that warrant further investigation. SIGNIFICANCE: A transcriptome-wide association analysis identified seven previously reported and six novel candidate susceptibility genes for pancreatic cancer risk.
©2020 American Association for Cancer Research.
OBJECTIVE - To examine whether F2-isoprostanes, a marker of systematic oxidative stress, are associated with antimüllerian hormone (AMH), an indicator of ovarian reserve, in a population-based cohort of women of black and white ethnicities.
DESIGN - Cross-sectional analysis.
SETTING - Not applicable.
PATIENTS - The CARDIA Women's Study, a population-based cohort. Black (n = 398) and white (n = 432) late reproductive-aged women (mean age 40 ± 3.6 years) without histories of gynecologic surgery.
MAIN OUTCOME MEASURES - Log-transformed serum AMH concentrations.
RESULTS - Linear regression models evaluated whether plasma F2-isoprostanes were associated with log-transformed AMH after adjustment for age, race, smoking, body mass index, and oral contraceptive pill use. Higher levels of F2-isoprostanes were associated with lower AMH levels (β -0.048 per standard deviation, 95% confidence interval -0.087, -0.01). The observed associations were stronger at younger ages (P=.04 for interaction between levels of age and F2-isoprostanes). Indicators of other steps in the oxidative stress pathway (superoxide dismutase, paraoxonase activity, oxidized low-density lipoprotein cholesterol, and carotenoids) were not associated with AMH, although lower phospholipase A2 activity (β 0.036 per standard deviation, 95% confidence interval 0.001, 0.071) was associated with lower AMH across all ages.
CONCLUSION - In a population-based cohort, higher levels of F2-isoprostanes were associated with lower ovarian reserve, particularly at younger ages.
Copyright © 2020 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.
BACKGROUND/PURPOSE - Wilms tumor (WT) poses a cancer health disparity to black children globally, which has not been evaluated thoroughly for other pediatric renal cancers. We aimed to characterize health disparities among Tennessee children treated for any renal cancer.
METHODS - The Tennessee Cancer Registry (TCR) was queried for patients ≤18 years having any renal cancer (n = 160). To clarify treatment and outcomes, we performed a retrospective cohort study of pediatric renal cancer patients in our institutional cancer registry (ICR; n = 121). Diagnoses in both registries included WT, Sarcoma/Other, and Renal Cell Carcinoma. Wilcoxon/Pearson, Kaplan-Meier, and logistic regression were completed.
RESULTS - In both registries, WT comprised the most common renal cancer and youngest median age. Sarcoma was intermediate in frequency and age, and RCC was least common, having the oldest age (p < 0.001). In the TCR, black patients comprised 26% of all patients, presented more commonly with distant disease than white patients (37% v. 16%; p = 0.021), and showed worse overall survival (73% v. 89%; p = 0.018), while the ICR showed similar survival between race groups (92% v. 93%, p = 0.868). Sarcoma and metastases were independent predictors of death in both registries (p ≤ 0.002).
CONCLUSIONS - Black children in Tennessee presented with more advanced disease and experienced worse survival when combining all renal cancer types, particularly RCC and Sarcoma. When treated at a comprehensive pediatric cancer center, these survival disparities appear diminished.
TYPE OF STUDY - Prognostic study.
LEVEL OF EVIDENCE - Level II (retrospective cohort).
Copyright © 2020 Elsevier Inc. All rights reserved.
The availability of large datasets from multiple sources [e.g. registries, biobanks, electronic health records (EHRs), claims or billing databases, implantable devices, wearable sensors, and mobile apps], coupled with advances in computing and analytic technologies, have provided new opportunities for conducting innovative health research. Equally, improved digital access to health information has facilitated the conduct of efficient randomized controlled trials (RCTs) upon which clinical management decisions can be based, for instance, by permitting the identification of eligible patients for recruitment and/or linkage for follow-up via their EHRs. Given these advances in cardiovascular data science and the complexities they behold, it is important that health professionals have clarity on the appropriate use and interpretation of observational, so-called 'real-world', and randomized data in cardiovascular medicine. The Cardiovascular Roundtable of the European Society of Cardiology (ESC) held a workshop to explore the future of RCTs and the current and emerging opportunities for gathering and exploiting complex observational datasets in cardiovascular research. The aim of this article is to provide a perspective on the appropriate use of randomized and observational data and to outline the ESC plans for supporting the collection and availability of clinical data to monitor and improve the quality of care of patients with cardiovascular disease in Europe and provide an infrastructure for undertaking pragmatic RCTs. Moreover, the ESC continues to campaign for greater engagement amongst regulators, industry, patients, and health professionals in the development and application of a more efficient regulatory framework that is able to take maximal advantage of new opportunities for improving the design and efficiency of observational studies and RCT in patients with cardiovascular disease.
Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: firstname.lastname@example.org.
BACKGROUND - Only a handful of genetic discovery efforts in apparent treatment-resistant hypertension (aTRH) have been described.
METHODS - We conducted a case-control genome-wide association study of aTRH among persons treated for hypertension, using data from 10 cohorts of European ancestry (EA) and 5 cohorts of African ancestry (AA). Cases were treated with 3 different antihypertensive medication classes and had blood pressure (BP) above goal (systolic BP ≥ 140 mm Hg and/or diastolic BP ≥ 90 mm Hg) or 4 or more medication classes regardless of BP control (nEA = 931, nAA = 228). Both a normotensive control group and a treatment-responsive control group were considered in separate analyses. Normotensive controls were untreated (nEA = 14,210, nAA = 2,480) and had systolic BP/diastolic BP < 140/90 mm Hg. Treatment-responsive controls (nEA = 5,266, nAA = 1,817) had BP at goal (<140/90 mm Hg), while treated with one antihypertensive medication class. Individual cohorts used logistic regression with adjustment for age, sex, study site, and principal components for ancestry to examine the association of single-nucleotide polymorphisms with case-control status. Inverse variance-weighted fixed-effects meta-analyses were carried out using METAL.
RESULTS - The known hypertension locus, CASZ1, was a top finding among EAs (P = 1.1 × 10-8) and in the race-combined analysis (P = 1.5 × 10-9) using the normotensive control group (rs12046278, odds ratio = 0.71 (95% confidence interval: 0.6-0.8)). Single-nucleotide polymorphisms in this locus were robustly replicated in the Million Veterans Program (MVP) study in consideration of a treatment-responsive control group. There were no statistically significant findings for the discovery analyses including treatment-responsive controls.
CONCLUSION - This genomic discovery effort for aTRH identified CASZ1 as an aTRH risk locus.
© American Journal of Hypertension, Ltd 2019. All rights reserved. For Permissions, please email: email@example.com.
AIMS - Clopidogrel is prescribed for the prevention of atherothrombotic events. While investigations have identified genetic determinants of inter-individual variability in on-treatment platelet inhibition (e.g. CYP2C19*2), evidence that these variants have clinical utility to predict major adverse cardiovascular events (CVEs) remains controversial.
METHODS AND RESULTS - We assessed the impact of 31 candidate gene polymorphisms on adenosine diphosphate (ADP)-stimulated platelet reactivity in 3391 clopidogrel-treated coronary artery disease patients of the International Clopidogrel Pharmacogenomics Consortium (ICPC). The influence of these polymorphisms on CVEs was tested in 2134 ICPC patients (N = 129 events) in whom clinical event data were available. Several variants were associated with on-treatment ADP-stimulated platelet reactivity (CYP2C19*2, P = 8.8 × 10-54; CES1 G143E, P = 1.3 × 10-16; CYP2C19*17, P = 9.5 × 10-10; CYP2B6 1294 + 53 C > T, P = 3.0 × 10-4; CYP2B6 516 G > T, P = 1.0 × 10-3; CYP2C9*2, P = 1.2 × 10-3; and CYP2C9*3, P = 1.5 × 10-3). While no individual variant was associated with CVEs, generation of a pharmacogenomic polygenic response score (PgxRS) revealed that patients who carried a greater number of alleles that associated with increased on-treatment platelet reactivity were more likely to experience CVEs (β = 0.17, SE 0.06, P = 0.01) and cardiovascular-related death (β = 0.43, SE 0.16, P = 0.007). Patients who carried eight or more risk alleles were significantly more likely to experience CVEs [odds ratio (OR) = 1.78, 95% confidence interval (CI) 1.14-2.76, P = 0.01] and cardiovascular death (OR = 4.39, 95% CI 1.35-14.27, P = 0.01) compared to patients who carried six or fewer of these alleles.
CONCLUSION - Several polymorphisms impact clopidogrel response and PgxRS is a predictor of cardiovascular outcomes. Additional investigations that identify novel determinants of clopidogrel response and validating polygenic models may facilitate future precision medicine strategies.
Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: firstname.lastname@example.org.
OBJECTIVES - Studies suggest that mitochondrial dysfunction underlies some forms of sepsis-induced organ failure. We sought to test the hypothesis that variations in mitochondrial DNA haplogroup affect susceptibility to sepsis-associated delirium, a common manifestation of acute brain dysfunction during sepsis.
DESIGN - Retrospective cohort study.
SETTING - Medical and surgical ICUs at a large tertiary care center.
PATIENTS - Caucasian and African American adults with sepsis.
MEASUREMENTS AND MAIN RESULTS - We determined each patient's mitochondrial DNA haplogroup using single-nucleotide polymorphisms genotyping data in a DNA databank and extracted outcomes from linked electronic medical records. We then used zero-inflated negative binomial regression to analyze age-adjusted associations between mitochondrial DNA haplogroups and duration of delirium, identified using the Confusion Assessment Method for the ICU. Eight-hundred ten patients accounted for 958 sepsis admissions, with 802 (84%) by Caucasians and 156 (16%) by African Americans. In total, 795 patient admissions (83%) involved one or more days of delirium. The 7% of Caucasians belonging to mitochondrial DNA haplogroup clade IWX experienced more delirium than the 49% in haplogroup H, the most common Caucasian haplogroup (age-adjusted rate ratio for delirium 1.36; 95% CI, 1.13-1.64; p = 0.001). Alternatively, among African Americans the 24% in haplogroup L2 experienced less delirium than those in haplogroup L3, the most common African haplogroup (adjusted rate ratio for delirium 0.60; 95% CI, 0.38-0.94; p = 0.03).
CONCLUSIONS - Variations in mitochondrial DNA are associated with development of and protection from delirium in Caucasians and African Americans during sepsis. Future studies are now required to determine whether mitochondrial DNA and mitochondrial dysfunction contribute to the pathogenesis of delirium during sepsis so that targeted treatments can be developed.
Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through trans-ancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these, 147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.
The mitochondrial antiviral signaling protein (MAVS) orchestrates host antiviral innate immune response to RNA virus infection. However, how MAVS signaling is controlled to eradicate virus while preventing self-destructive inflammation remains obscure. Here, we show that protein geranylgeranylation, a posttranslational lipid modification of proteins, limits MAVS-mediated immune signaling by targeting Rho family small guanosine triphosphatase Rac1 into the mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) at the mitochondria-ER junction. Protein geranylgeranylation and subsequent palmitoylation promote Rac1 translocation into MAMs upon viral infection. MAM-localized Rac1 limits MAVS' interaction with E3 ligase Trim31 and hence inhibits MAVS ubiquitination, aggregation, and activation. Rac1 also facilitates the recruitment of caspase-8 and cFLIP to the MAVS signalosome and the subsequent cleavage of Ripk1 that terminates MAVS signaling. Consistently, mice with myeloid deficiency of protein geranylgeranylation showed improved survival upon influenza A virus infection. Our work revealed a critical role of protein geranylgeranylation in regulating antiviral innate immune response.