👤 Corina Stewart

BackgroundThe Montreal Cognitive Assessment (MoCA) is widely used for cognitive screening. Despite numerous studies showing that MoCA scores are affected by demographic variables including age, education, and race, the instrument is typically evaluated using a raw score or simple one-point education correction in clinical practice.ObjectiveIn this study, we comprehensively evaluate the diagnostic accuracy of the MoCA in a large cohort of individuals being evaluated for mild cognitive impairment or dementia.MethodsWe used data from the National Alzheimer's Coordinating Center (NACC) database to examine diagnostic accuracy of the MoCA, using both raw scores and Z-scores subject to non-linear demographic correction. We present comprehensive accuracy statistics, concordance with Show less

Health and financial literacy decline in aging, but it is unclear why. In this study, we hypothesized that older people who are carriers of the APOE ε4 allele exhibit a steeper decline in literacy over time. Participants were 851 community-dwelling older adults without dementia at analytic baseline (188 ε4 carriers and 663 noncarriers). Literacy was assessed at baseline and each year thereafter for up to 14 years. In a linear mixed-effects model adjusted for age, gender, and education, ε4 was associated with a lower starting level of literacy (b = -3.60, SE b = 1.00, p < 0.001) and, critically, a roughly 40% steeper decline in literacy over time (b = -0.41, SE b = 0.14, p = 0.004). The association between ε4 and literacy decline persisted after adjusting for global cognition at baseline (b = -0.35, SE b = 0.14, p = 0.012) and among a subgroup of participants with no cognitive impairment at baseline (b = -0.34, SE b = 0.14, p = 0.016). ε4 contributes to literacy decline among older adults, presumably due in part to the accumulation of neuropathologies associated with ε4. We discuss the potential clinical implications of ε4-related literacy decline. Show less

G protein-coupled receptors (GPCRs) play key roles in physiology and are central targets for drug discovery and development, yet the design of protein agonists and antagonists has been challenging as GPCRs are integral membrane proteins and conformationally dynamic. Here we describe computational Show less

GATA family transcription factors are somatically variable (SV) in esophageal adenocarcinomas (EAC) and inducible by simulated reflux. Our study examines the mechanisms whereby GATA family members (GATA4, GATA6, and the atypical TRPS-1) influence oncogenesis during the Barrett's esophagus (BE) metaplasia-dysplasia transition preceding EAC. RNAseq analyses of esophageal cell lines and lesion-derived adult stem cells (ASCs) in conjunction shRNA- or CRISPR-facilitated gene silencing, together with reanalysis of The Cancer Genome Atlas data, spatial transcriptomics, and organ-on-a-chip studies were used. Although a gastroesophageal reflux disease history positively correlated with GATA4/6 somatically variable and a columnar-associated gene signature (ANPEP/GATA4) in The Cancer Genome Atlas EAC cases, it negatively associated with a squamous lineage-linked signature (TP63/SOX15) containing TRPS1. In experimental data, opposing effects on regulators of squamous and columnar lineage identity were uncovered between TRPS1 and classical GATA factors (GATA4/6). Interrogation of this GATA "fulcrum" defined further genes (CGN, IL6R, and GPRC5B) targeted for TRPS1-mediated suppression or GATA4/6 activation. A novel spatial transcriptomic signature of BE-associated high-grade dysplasia (HGD) captured GATA fulcrum action, through GPRC5B expression. Functionally, GPRC5B was found to be low-pH-responsive, to increase proliferative and colony formation rates, and when overexpressed facilitate a hyperproliferative HGD-like transformation of BE-ASCs. Using an organ-on-a-chip platform, cellular overgrowth, reduced luminal villus structures, lower goblet cell numbers, and loss of intestine-associated marker gene expression (TFF3/MUC2) were observed following GPRC5B overexpression in BE-ASCs, mirroring HGD. This study identifies critical GATA factor-mediated processes underlying cellular phenotype in the BE-HGD-EAC transition and identifies GATA-inducible GPRC5B as a functional marker and possible driver of progression through HGD to EAC. Show less

Obesity, a widespread global health issue affecting millions, is characterized by excess fat deposition and metabolic dysfunction, significantly elevating the risk of comorbidities like type 2 diabetes, cardiovascular disease, and certain cancers, all of which contribute to rising rates of preventable morbidity and mortality. Current approaches to obesity, including lifestyle modifications, and pharmacotherapy, often face limitations such as poor long-term adherence, side effects, and insufficient targeting of the complex, multifactorial pathways underlying the disease. Herein we report a dual, RNA-mediated combinatorial approach using targeting lipid nanoparticles (LNP) for the treatment of obesity. LNPs were co-encapsulated with mRNA encoding Interleukin-27 (mIL-27) to coactivate PGC-1α, PPARα, and UCP-1, thereby promoting adipocyte differentiation and enhancing adaptive thermogenesis within adipocytes, and siRNA targeting Dipeptidyl peptidase-4 (siDPP-4) to silence the primary inhibitory enzyme of GLP-1, and GIP within the incretin system, effectively restoring glucose homeostasis. Following post translational silencing of DPP-4 and upregulation of IL-27 in a diet-induced obesity (DIO) mice model, increased expression of thermogenic biomarkers PGC-1α, PPARα, and UCP-1 was observed at the molecular, protein, and tissue level, and insulin sensitivity was restored. Importantly, this gene modulation led to a 21.1 % reduction of bodyweight after treatment in the DIO model. These findings demonstrate for the first time a dual RNA-mediated combinatorial approach, leveraging liver targeting LNP delivery with synergistic effects from incretin system regulation and induction of adipocyte differentiation and thermogenesis after codelivery of siDPP-4 and mIL-27. This innovative strategy provides a promising alternate framework for addressing obesity and its associated metabolic dysfunction. Show less

Lipoprotein(a) (Lp[a]) is an established predictor of cardiovascular risk but associations with secondary events are less certain, and data on understudied ethnic groups are scarce. This study aimed to assess the association between Lp(a) and secondary events and explore variation in Lp(a) levels by ethnicity in first-time acute coronary syndrome (ACS) patients, to inform future risk prediction models. The Multi-Ethnic New Zealand Study of Acute Coronary Syndromes (MENZACS) is a longitudinal multi-centre cohort study of 1900 patients enrolled during their ACS admission. Baseline plasma Lp(a) concentrations were measured using an isoform-insensitive assay measured in nmol/L. The primary outcome was a composite of all-cause mortality or cardiovascular readmission, ascertained through national health datasets. Cox regression models were used to assess the association between Lp(a) levels and outcomes, adjusted for clinical risk factors. The mean age was 61 years, 20 % were female, and 73 % were European, 14 % Māori, 5 % Pacific peoples, 4 % Indian and 3 % other ethnicities. Of 1890 alive at discharge, 493 (26 %) experienced the primary outcome over a median follow-up of 4.9 years. Higher Lp(a) levels were associated with increased risk of secondary events. Compared to the lowest quartile (≤7 nmol/L), the adjusted hazard ratio for the highest quartile (>92 nmol/L) was 1.46 (95 %CI 1.12-1.89, p = 0.004). In this ACS cohort, Lp(a) concentrations varied by ethnicity, being highest amongst Indian participants (median 27 nmol/L) and lowest amongst Māori participants (median 12 nmol/L). Elevated Lp(a) concentrations are associated with secondary events following ACS. Further research is needed to define optimal thresholds for increased risk and explore ethnic-specific implications for secondary prevention. Show less

The highly conserved long non-coding RNA (lncRNA) MIR505HG has been primarily recognized as a precursor for microRNAs (miR)-424 and miR-503. However, studies have since demonstrated that MIR503HG has distinct functions from its associated miRNAs, playing important roles in cell proliferation, invasion, apoptosis, and differentiation. While these miRNAs are known to influence cardiomyocyte differentiation, the specific role of MIR503HG in heart development remains unexplored. We seek to determine how MIR503HG deletion impacts ventricular chamber development and to identify underlying molecular mechanisms. To study the role of the lncRNA in vivo, we generated a functional MIR503HG knockout mouse model (MIR503HG-/-) using a synthetic polyadenylation signal to terminate MIR503HG transcription without affecting miR-424/503 expression. We performed morphological analyses on embryonic and adult hearts using microCT along with cardiac functional analysis via transthoracic echocardiography. We further apply single-nuclei RNA sequencing (snRNA-seq) on adult hearts to identify potential molecular mechanisms underlying the observed phenotypes. Functional deletion of MIR503HG alone was associated with reduced compact myocardium thickness and increased trabecular myocardium in the left ventricle (LV) at embryonic day 17.5 compared to wild-type mice, indicating a LV non-compaction (LVNC) phenotype. Moreover, adult MIR503HG-/- mutant hearts showed increased trabecular complexity, impaired LV relaxation, and mitral valve regurgitation. SnRNA-seq further revealed altered expression of several genes associated with cardiomyocyte function and LVNC, including Actc1, Mib1, Mybpc3, and Myh7. Lastly, Notch1 activity was also significantly increased in mutant hearts which has been previously associated with LVNC. MIR503HG plays a role in ventricular chamber development, and its deletion leads to an LVNC phenotype independent of the miRNA cluster within its locus, highlighting its importance in cardiac development and disease. We further suggest that abnormal Notch1 activity may underpin the LVNC phenotype presented. Show less

To execute a large-scale, decentralized, clinical-grade whole exome sequencing study, coined Tapestry, for clinical practice, research discovery, and genomic education. Between July 1, 2020, and May 31, 2024, we invited 1,287,608 adult Mayo Clinic patients to participate in Tapestry. Of those contacted, 114,673 patients were consented and 98,222 (65.2% women) are currently enrolled: 62,495 (63.6%) were recruited from Minnesota-, 18,353 (18.7%) from Florida- and 17,374 (17.7%) from Arizona-based practices. Saliva from participants was used to extract DNA, and whole exome sequencing plus ∼300,000 single nucleotide polymorphisms (ie, Exome+ assay) were sequenced by a clinical lab. Results for the Centers for Disease Control and Prevention Tier 1 genes (eg, hereditary breast, ovarian cancer syndrome: BRCA1/2; Lynch syndrome: MLH1, MSH2, MSH6, PMS2, and EPCAM; and familial hypercholesterolemia: APOB, LDLR, PCSK9, and LDLRAP1) were interpreted and entered into the electronic health record. The median age of participants was 59.1 years and ∼11% were from racial/ethnic groups under-represented in research. One thousand eight hundred nineteen (1.9%) participants had actionable pathogenic or likely pathogenic variants (50.0% BRCA1/2, 28.4% familial hypercholesterolemia, and 22.2% Lynch syndrome). Positive results were communicated by genetic counselors who educated patients and providers. Thus far, 62,758 patients' Exome+ assays are stored for research, and the Tapestry Data Access Committee has received 118 requests from investigators, of which 82 have been approved, resulting in the delivery of 1,117,410 Exome+ assays to researchers. A large, decentralized, clinical Exome+ assay study in a tertiary medical center detects actionable germline variants, educates patients as well as providers, and offers access to big data for discovery that advances human health. clinicaltrials.gov Identifier: NCT05212428. Show less

The need for the development of specific and robust methodologies to elucidate the intricate pathological mechanisms of neurodegenerative diseases and discover effective treatments for prevention and remediation is evident. Alzheimer's disease, in particular, has become more prevalent as the global population has aged. β-Secretase, the β-site amyloid precursor protein cleaving enzyme (BACE1), is the protease that produces the β-amyloid peptide, which is considered one of the driving factors of Alzheimer's disease and an important target for treatment development. However, an understanding of its activity, modulation, and regulation is far from complete. This is in large part due to the complex nature of following its activity. Beyond the common requirements for all biosensors (ease of preparation and use), BACE1 probes also demand both stability at acidic pH and membrane localization. To overcome these hurdles, we exploit the modular self-assembly provided by fluorescent quantum dot (QD) sensors. As compared to other fluorophores, QDs provide enhanced fluorescence brightness and photostability, and their large surface area enables functionalization with peptide substrates together with targeting elements that localize the sensor to the areas of maximal BACE1 activity, all achieved through His-tag self-assembly. Show less

All forms of diabetes result from insufficient functional β-cell mass. Thus, achieving the therapeutic goal of expanding β-cell mass requires a better mechanistic understanding of how β-cells proliferate. Glucose is a natural β-cell mitogen that mediates its effects in part through the glucose-responsive transcription factor, carbohydrate response element binding protein (ChREBP) and the anabolic transcription factor, MYC. However, mechanistic details by which glucose activates Myc at the transcriptional level are poorly understood. Here, siRNA was used to test the role of ChREBP in the glucose response of MYC, ChIP and ChIPseq to identify potential regulatory binding sites, chromatin conformation capture to identify DNA/DNA interactions, and an adenovirus was constructed to expresses x-dCas9 and an sgRNA that specifically disrupts the recruitment of ChREBP to a specific targeted ChoRE. We found that ChREBP is essential for glucose-mediated transcriptional induction of Myc, and for increases in Myc mRNA and protein abundance. Further, ChIPseq revealed that the carbohydrate response element (ChoRE) nearest to the Myc transcriptional start site (TSS) is immediately upstream of the gene encoding the lncRNA, Pvt1, 60,000 bp downstream of the Myc gene. Chromatin Conformation Capture (3C) confirmed a glucose-dependent interaction between these two sites. Transduction with an adenovirus expressing x-dCas9 and an sgRNA specifically targeting the highly conserved Pvt1 ChoRE, attenuates ChREBP recruitment, decreases Myc-Pvt1 DNA/DNA interaction, and decreases expression of the Pvt1 and Myc genes in response to glucose. Importantly, isolated and dispersed rat islet cells transduced with the ChoRE-disrupting adenovirus also display specific decreases in ChREBP-dependent, glucose-mediated expression of Pvt1 and Myc, as well as decreased glucose-stimulated β-cell proliferation. The mitogenic glucose response of Myc is mediated via glucose-dependent recruitment of ChREBP to the promoter of the Pvt1 gene and subsequent DNA looping with the Myc promoter. Show less

Lsd1/Kdm1a functions both as a histone demethylase enzyme and as a scaffold for assembling chromatin modifier and transcription factor complexes to regulate gene expression. The relative contributions of Lsd1's demethylase and scaffolding functions during embryogenesis are not known. Here, we analyze two independent zebrafish Show less

Rare homozygous or biallelic variants in To characterize the historical weight trajectory in these patients. This analysis included data from 2 pivotal single-arm, open-label, Phase 3 trials (NCT02896192, NCT03287960). These were multicenter trials. Patients had obesity due to POMC/PCSK1 or LEPR deficiency. During the trial, patients were treated with setmelanotide. Historical data on measured weight and height were obtained during screening. A total of 17 patients (POMC, n = 8; PCSK1, n = 1; LEPR, n = 8) with historical weight and height data were included in this analysis. Before setmelanotide treatment, patients with obesity due to POMC/PCSK1 or LEPR deficiency were above the 95th percentile for weight throughout childhood, demonstrated continuous weight gain, and did not show long-term weight loss upon interventions (eg, diet, surgery, exercise). Setmelanotide treatment attenuated weight and body mass index trajectories over the observation period of 1 year. In patients with POMC, PCSK1, or LEPR deficiency, traditional interventions for weight loss had limited impact on the trajectory of severe early-onset obesity. However, setmelanotide treatment attenuated weight and body mass index trajectories and led to weight loss associated with health benefits in most individuals. Show less

An early symptom of Alzheimer's disease (AD) is an impaired sense of smell, for which the molecular basis remains elusive. Here, we generated human olfactory neurosphere-derived (ONS) cells from people with AD and mild cognitive impairment (MCI), and performed global RNA sequencing to determine gene expression changes. ONS cells expressed markers of neuroglial differentiation, providing a unique cellular model to explore changes of early AD-associated pathways. Our transcriptomics data from ONS cells revealed differentially expressed genes (DEGs) associated with cognitive processes in AD cells compared to MCI, or matched healthy controls (HC). A-Kinase Anchoring Protein 6 ( Show less

There is considerable interest in GIPR agonism to enhance the insulinotropic and extrapancreatic effects of GIP, thereby improving glycemic and weight control in type 2 diabetes (T2D) and obesity. Recent genetic epidemiological evidence has implicated higher GIPR-mediated GIP levels in raising coronary artery disease (CAD) risk, a potential safety concern for GIPR agonism. We therefore aimed to quantitatively assess whether the association between higher GIPR-mediated fasting GIP levels and CAD risk is mediated via GIPR or is instead the result of linkage disequilibrium (LD) confounding between variants at the Show less

A phase 2 trial has suggested that treatment with the melanocortin-4 receptor (MC4R) agonist setmelanotide is associated with a decrease in hunger and weight-related outcomes in participants with Bardet-Biedl syndrome (BBS) and Alström syndrome. Here, we present the study design of an ongoing, randomized, double-blind, placebo-controlled, phase 3 trial to assess the long-term efficacy and safety of setmelanotide for the treatment of obesity and hyperphagia in individuals with BBS or Alström syndrome (ClinicalTrials.gov identifier: NCT03746522). It was initially planned that ~30 participants aged ≥6 years with a clinical diagnosis of BBS or Alström syndrome would be enrolled. Participants with obesity as defined by a body mass index ≥30 kg/m This pivotal trial is designed to evaluate the efficacy and safety of setmelanotide for the treatment of obesity and hyperphagia in individuals with BBS and Alström syndrome. Study Design, Statistical Design, Study Protocols. Show less

Higher plasma vitamin C levels are associated with lower type 2 diabetes risk, but whether this association is causal is uncertain. To investigate this, we studied the association of genetically predicted plasma vitamin C with type 2 diabetes. We conducted genome-wide association studies of plasma vitamin C among 52,018 individuals of European ancestry to discover novel genetic variants. We performed Mendelian randomization analyses to estimate the association of genetically predicted differences in plasma vitamin C with type 2 diabetes in up to 80,983 case participants and 842,909 noncase participants. We compared this estimate with the observational association between plasma vitamin C and incident type 2 diabetes, including 8,133 case participants and 11,073 noncase participants. We identified 11 genomic regions associated with plasma vitamin C ( These findings indicate discordance between biochemically measured and genetically predicted plasma vitamin C levels in the association with type 2 diabetes among European populations. The null Mendelian randomization findings provide no strong evidence to suggest the use of vitamin C supplementation for type 2 diabetes prevention. Show less

The melanocortin 4 receptor (MC4R), a component of the leptin-melanocortin pathway, plays a part in bodyweight regulation. Severe early-onset obesity can be caused by biallelic variants in genes that affect the MC4R pathway. We report the results from trials of the MC4R agonist setmelanotide in individuals with severe obesity due to either pro-opiomelanocortin (POMC) deficiency obesity or leptin receptor (LEPR) deficiency obesity. These single-arm, open-label, multicentre, phase 3 trials were done in ten hospitals across Canada, the USA, Belgium, France, Germany, the Netherlands, and the UK. Participants aged 6 years or older with POMC or LEPR deficiency obesity received open-label setmelanotide for 12 weeks. Participants with at least 5 kg weight loss (or ≥5% if weighing <100 kg at baseline) entered an 8-week placebo-controlled withdrawal sequence (including 4 weeks each of blinded setmelanotide and placebo treatment) followed by 32 additional weeks of open-label treatment. The primary endpoint, which was assessed in participants who received at least one dose of study medication and had a baseline assessment (full analysis set), was the proportion of participants with at least 10% weight loss compared with baseline at approximately 1 year. A key secondary endpoint was mean percentage change in the most hunger score of the 11-point Likert-type scale at approximately 1 year on the therapeutic dose, which was assessed in a subset of participants aged 12 years or older in the full analysis set who demonstrated at least 5 kg weight loss (or ≥5% in paediatric participants if baseline bodyweight was <100 kg) over the 12-week open-label treatment phase and subsequently proceeded into the placebo-controlled withdrawal sequence, regardless of later disposition. These studies are registered with ClinicalTrials.gov, NCT02896192 and NCT03287960. Between Feb 14, 2017, and Sept 7, 2018, ten participants were enrolled in the POMC trial and 11 participants were enrolled in the LEPR trial, and included in the full analysis and safety sets. Eight (80%) participants in the POMC trial and five (45%) participants in the LEPR trial achieved at least 10% weight loss at approximately 1 year. The mean percentage change in the most hunger score was -27·1% (n=7; 90% CI -40·6 to -15·0; p=0·0005) in the POMC trial and -43·7% (n=7; -54·8 to -29·1; p<0·0001) in the LEPR trial. The most common adverse events were injection site reaction and hyperpigmentation, which were reported in all ten participants in the POMC trial; nausea was reported in five participants and vomiting in three participants. In the LEPR trial, the most commonly reported treatment-related adverse events were injection site reaction in all 11 participants, skin disorders in five participants, and nausea in four participants. No serious treatment-related adverse events occurred in both trials. Our results support setmelanotide for the treatment of obesity and hyperphagia caused by POMC or LEPR deficiency. Rhythm Pharmaceuticals. Show less

Central and peripheral mechanisms are both required for proper control of energy homeostasis. Among circulating plasma proteins, C1q/TNF-related proteins (CTRPs) have recently emerged as important regulators of sugar and fat metabolism. CTRP4, expressed in brain and adipose tissue, is unique among the family members in having two tandem globular C1q domains. We previously showed that central administration of recombinant CTRP4 suppresses food intake, suggesting a central nervous system role in regulating ingestive physiology. Whether this effect is pharmacological or physiological remains unclear. We used a loss-of-function knockout (KO) mouse model to clarify the physiological role of CTRP4. Under basal conditions, CTRP4 deficiency increased serum cholesterol levels and impaired glucose tolerance in male but not female mice fed a control low-fat diet. When challenged with a high-fat diet, male and female KO mice responded differently to weight gain and had different food intake patterns. On an obesogenic diet, male KO mice had similar weight gain as wild-type littermates. When fed ad libitum, KO male mice had greater meal number, shorter intermeal interval, and reduced satiety ratio. Female KO mice, in contrast, had lower body weight and adiposity. In the refeeding period following food deprivation, female KO mice had significantly higher food intake due to longer meal duration and reduced satiety ratio. Collectively, our data provide genetic evidence for a sex-dependent physiological role of CTRP4 in modulating food intake patterns and systemic energy metabolism. Show less

This is a comprehensive review and analysis of 254 cases tested consecutively in the in-house College of American Pathologist-accredited molecular genetics laboratory within the New York City Office of Chief Medical Examiner between October 2015 and February 2018, using a multigene cardiac panel composed of 95 genes associated with cardiac channelopathy and cardiomyopathy. Demographics, autopsy findings, medical history, and postmortem genetic testing results were collected for each case. The majority of decedents were adults (>25 years old, 52.7%), followed by infants (<12 months, 25.6%), young adults (19-25 years old, 11.4%), and children (1-18 years old, 10.2%). There were more males (64.2%) than females (35.8%). The racial/ethnic composition of decedents was 40.2% Black, 29.9% Hispanic, 22.4% White, 5.1% Asian/Pacific Islander, and 2.8% mixed/unspecified. Overall, 45.7% of decedents had a negative autopsy, and the remaining had one to four cardiac findings (cardiac hypertrophy, dilation, atherosclerosis, and fatty change). Twenty-seven pathogenic/likely pathogenic variants (P/LP) and 99 variants of uncertain significance (VUS) were identified in 10.6% and 39% of decedents respectively. P/LP and VUS were found in 51 cardiac genes of the total 95 genes, where MYBPC3, TTN (predicted truncating variants), KCNH2, RYR2 and DSP genes had more than two P/LP variants identified. Among the 73 decedents who were suspected of having cardiac arrhythmia or cardiomyopathy, 20.3% had P/LP variants and 47.9% had VUS; among 23 decedents who had hypertensive cardiovascular diseases and 20 decedents with a history of substance use, 13% and 30% had P/LP variants, respectively. There were 26 referrals from medical examiners for genetic counseling and the outcomes are discussed. The study demonstrates characteristics of the diverse population typically seen by medical examiners in an urban center and our results support a broader implementation of molecular testing in sudden death. Show less

The melanocortin 4 receptor (MC4R) is a G protein-coupled receptor whose disruption causes obesity. We functionally characterized 61 MC4R variants identified in 0.5 million people from UK Biobank and examined their associations with body mass index (BMI) and obesity-related cardiometabolic diseases. We found that the maximal efficacy of β-arrestin recruitment to MC4R, rather than canonical Gα Show less

Pharmacological enhancers of lipoprotein lipase (LPL) are in preclinical or early clinical development for cardiovascular prevention. Studying whether these agents will reduce cardiovascular events or diabetes risk when added to existing lipid-lowering drugs would require large outcome trials. Human genetics studies can help prioritize or deprioritize these resource-demanding endeavors. To investigate the independent and combined associations of genetically determined differences in LPL-mediated lipolysis and low-density lipoprotein cholesterol (LDL-C) metabolism with risk of coronary disease and diabetes. In this genetic association study, individual-level genetic data from 392 220 participants from 2 population-based cohort studies and 1 case-cohort study conducted in Europe were included. Data were collected from January 1991 to July 2018, and data were analyzed from July 2014 to July 2018. Six conditionally independent triglyceride-lowering alleles in LPL, the p.Glu40Lys variant in ANGPTL4, rare loss-of-function variants in ANGPTL3, and LDL-C-lowering polymorphisms at 58 independent genomic regions, including HMGCR, NPC1L1, and PCSK9. Odds ratio for coronary artery disease and type 2 diabetes. Of the 392 220 participants included, 211 915 (54.0%) were female, and the mean (SD) age was 57 (8) years. Triglyceride-lowering alleles in LPL were associated with protection from coronary disease (approximately 40% lower odds per SD of genetically lower triglycerides) and type 2 diabetes (approximately 30% lower odds) in people above or below the median of the population distribution of LDL-C-lowering alleles at 58 independent genomic regions, HMGCR, NPC1L1, or PCSK9. Associations with lower risk were consistent in quintiles of the distribution of LDL-C-lowering alleles and 2 × 2 factorial genetic analyses. The 40Lys variant in ANGPTL4 was associated with protection from coronary disease and type 2 diabetes in groups with genetically higher or lower LDL-C. For a genetic difference of 0.23 SDs in LDL-C, ANGPTL3 loss-of-function variants, which also have beneficial associations with LPL lipolysis, were associated with greater protection against coronary disease than other LDL-C-lowering genetic mechanisms (ANGPTL3 loss-of-function variants: odds ratio, 0.66; 95% CI, 0.52-0.83; 58 LDL-C-lowering variants: odds ratio, 0.90; 95% CI, 0.89-0.91; P for heterogeneity = .009). Triglyceride-lowering alleles in the LPL pathway are associated with lower risk of coronary disease and type 2 diabetes independently of LDL-C-lowering genetic mechanisms. These findings provide human genetics evidence to support the development of agents that enhance LPL-mediated lipolysis for further clinical benefit in addition to LDL-C-lowering therapy. Show less

It is unknown if adult human skeletal muscle has an epigenetic memory of earlier encounters with growth. We report, for the first time in humans, genome-wide DNA methylation (850,000 CpGs) and gene expression analysis after muscle hypertrophy (loading), return of muscle mass to baseline (unloading), followed by later hypertrophy (reloading). We discovered increased frequency of hypomethylation across the genome after reloading (18,816 CpGs) versus earlier loading (9,153 CpG sites). We also identified AXIN1, GRIK2, CAMK4, TRAF1 as hypomethylated genes with enhanced expression after loading that maintained their hypomethylated status even during unloading where muscle mass returned to control levels, indicating a memory of these genes methylation signatures following earlier hypertrophy. Further, UBR5, RPL35a, HEG1, PLA2G16, SETD3 displayed hypomethylation and enhanced gene expression following loading, and demonstrated the largest increases in hypomethylation, gene expression and muscle mass after later reloading, indicating an epigenetic memory in these genes. Finally, genes; GRIK2, TRAF1, BICC1, STAG1 were epigenetically sensitive to acute exercise demonstrating hypomethylation after a single bout of resistance exercise that was maintained 22 weeks later with the largest increase in gene expression and muscle mass after reloading. Overall, we identify an important epigenetic role for a number of largely unstudied genes in muscle hypertrophy/memory. Show less

Infection by most DNA viruses activates a cellular DNA damage response (DDR), which may be to the detriment or advantage of the virus. In the case of adenoviruses, they neutralize antiviral effects of DDR activation by targeting a number of proteins for rapid proteasome-mediated degradation. We have now identified a novel DDR protein, tankyrase 1 binding protein 1 (TNKS1BP1) (also known as Tab182), which is degraded during infection by adenovirus serotype 5 and adenovirus serotype 12. In both cases, degradation requires the action of the early region 1B55K (E1B55K) and early region 4 open reading frame 6 (E4orf6) viral proteins and is mediated through the proteasome by the action of cullin-based cellular E3 ligases. The degradation of Tab182 appears to be serotype specific, as the protein remains relatively stable following infection with adenovirus serotypes 4, 7, 9, and 11. We have gone on to confirm that Tab182 is an integral component of the CNOT complex, which has transcriptional regulatory, deadenylation, and E3 ligase activities. The levels of at least 2 other members of the complex (CNOT3 and CNOT7) are also reduced during adenovirus infection, whereas the levels of CNOT4 and CNOT1 remain stable. The depletion of Tab182 with small interfering RNA (siRNA) enhances the expression of early region 1A proteins (E1As) to a limited extent during adenovirus infection, but the depletion of CNOT1 is particularly advantageous to the virus and results in a marked increase in the expression of adenovirus early proteins. In addition, the depletion of Tab182 and CNOT1 results in a limited increase in the viral DNA level during infection. We conclude that the cellular CNOT complex is a previously unidentified major target for adenoviruses during infection. Show less

Metabolites derived from dietary choline and L-carnitine, such as trimethylamine N-oxide and betaine, have recently been identified as novel risk factors for atherosclerosis in mice and humans. We sought to identify genetic factors associated with plasma betaine levels and determine their effect on risk of coronary artery disease (CAD). A two-stage genome-wide association study (GWAS) identified two significantly associated loci on chromosomes 2q34 and 5q14.1. The lead variant on 2q24 (rs715) localizes to carbamoyl-phosphate synthase 1 (CPS1), which encodes a mitochondrial enzyme that catalyses the first committed reaction and rate-limiting step in the urea cycle. Rs715 is also significantly associated with decreased levels of urea cycle metabolites and increased plasma glycine levels. Notably, rs715 yield a strikingly significant and protective association with decreased risk of CAD in only women. These results suggest that glycine metabolism and/or the urea cycle represent potentially novel sex-specific mechanisms for the development of atherosclerosis. Show less

Myocardial infarction (MI), a leading cause of death around the world, displays a complex pattern of inheritance. When MI occurs early in life, genetic inheritance is a major component to risk. Previously, rare mutations in low-density lipoprotein (LDL) genes have been shown to contribute to MI risk in individual families, whereas common variants at more than 45 loci have been associated with MI risk in the population. Here we evaluate how rare mutations contribute to early-onset MI risk in the population. We sequenced the protein-coding regions of 9,793 genomes from patients with MI at an early age (≤50 years in males and ≤60 years in females) along with MI-free controls. We identified two genes in which rare coding-sequence mutations were more frequent in MI cases versus controls at exome-wide significance. At low-density lipoprotein receptor (LDLR), carriers of rare non-synonymous mutations were at 4.2-fold increased risk for MI; carriers of null alleles at LDLR were at even higher risk (13-fold difference). Approximately 2% of early MI cases harbour a rare, damaging mutation in LDLR; this estimate is similar to one made more than 40 years ago using an analysis of total cholesterol. Among controls, about 1 in 217 carried an LDLR coding-sequence mutation and had plasma LDL cholesterol > 190 mg dl(-1). At apolipoprotein A-V (APOA5), carriers of rare non-synonymous mutations were at 2.2-fold increased risk for MI. When compared with non-carriers, LDLR mutation carriers had higher plasma LDL cholesterol, whereas APOA5 mutation carriers had higher plasma triglycerides. Recent evidence has connected MI risk with coding-sequence mutations at two genes functionally related to APOA5, namely lipoprotein lipase and apolipoprotein C-III (refs 18, 19). Combined, these observations suggest that, as well as LDL cholesterol, disordered metabolism of triglyceride-rich lipoproteins contributes to MI risk. Show less

Development of effective therapies for brain disorders has been hampered by a lack of translational cognitive testing methods. We present the first example of using the identical touchscreen-based cognitive test to assess mice and humans carrying disease-related genetic mutations. This new paradigm has significant implications for improving how we measure and model cognitive dysfunction in human disorders in animals, thus bridging the gap towards effective translation to the clinic. Show less

Recent genome-wide association studies have identified multiple loci robustly associated with plasma lipids, which also contribute to extreme lipid phenotypes. However, these common genetic variants explain <12% of variation in lipid traits. Adiposity is also an important determinant of plasma lipoproteins, particularly plasma TGs and HDL cholesterol (HDLc) concentrations. Thus, interactions between genes and clinical phenotypes may contribute to this unexplained heritability. We have applied a weighted genetic risk score (GRS) for both plasma TGs and HDLc in two large cohorts at the extremes of BMI. Both BMI and GRS were strongly associated with these lipid traits. A significant interaction between obese/lean status and GRS was noted for each of TG (P(Interaction) = 2.87 × 10(-4)) and HDLc (P(Interaction) = 1.05 × 10(-3)). These interactions were largely driven by SNPs tagging APOA5, glucokinase receptor (GCKR), and LPL for TG, and cholesteryl ester transfer protein (CETP), GalNAc-transferase (GALNT2), endothelial lipase (LIPG), and phospholipid transfer protein (PLTP) for HDLc. In contrast, the GRSLDL cholesterol × adiposity interaction was not significant. Sexual dimorphism was evident for the GRSHDL on HDLc in obese (P(Interaction) = 0.016) but not lean subjects. SNP by BMI interactions may provide biological insight into specific genetic associations and missing heritability. Show less

Enhancing β-cell proliferation is a major goal for type 1 and type 2 diabetes research. Unraveling the network of β-cell intracellular signaling pathways that promote β-cell replication can provide the tools to address this important task. In a previous Perspectives in Diabetes article, we discussed what was known regarding several important intracellular signaling pathways in rodent β-cells, including the insulin receptor substrate/phosphatidylinositol-3 kinase/Akt (IRS-PI3K-Akt) pathways, glycogen synthase kinase-3 (GSK3) and mammalian target of rapamycin (mTOR) S6 kinase pathways, protein kinase Cζ (PKCζ) pathways, and their downstream cell-cycle molecular targets, and contrasted that ample knowledge to the small amount of complementary data on human β-cell intracellular signaling pathways. In this Perspectives, we summarize additional important information on signaling pathways activated by nutrients, such as glucose; growth factors, such as epidermal growth factor, platelet-derived growth factor, and Wnt; and hormones, such as leptin, estrogen, and progesterone, that are linked to rodent and human β-cell proliferation. With these two Perspectives, we attempt to construct a brief summary of knowledge for β-cell researchers on mitogenic signaling pathways and to emphasize how little is known regarding intracellular events linked to human β-cell replication. This is a critical aspect in the long-term goal of expanding human β-cells for the prevention and/or cure of type 1 and type 2 diabetes. Show less