Showing papers by "Nilesh J. Samani published in 2018"
TL;DR: In insights into the role of alcohol consumption in the genetic architecture of hypertension, a large two-stage investigation incorporating joint testing of main genetic effects and single nucleotide variant (SNV)-alcohol consumption interactions is conducted.
Abstract: Heavy alcohol consumption is an established risk factor for hypertension; the mechanism by which alcohol consumption impact blood pressure (BP) regulation remains unknown. We hypothesized that a genome-wide association study accounting for gene-alcohol consumption interaction for BP might identify additional BP loci and contribute to the understanding of alcohol-related BP regulation. We conducted a large two-stage investigation incorporating joint testing of main genetic effects and single nucleotide variant (SNV)-alcohol consumption interactions. In Stage 1, genome-wide discovery meta-analyses in ≈131K individuals across several ancestry groups yielded 3,514 SNVs (245 loci) with suggestive evidence of association (P < 1.0 x 10-5). In Stage 2, these SNVs were tested for independent external replication in ≈440K individuals across multiple ancestries. We identified and replicated (at Bonferroni correction threshold) five novel BP loci (380 SNVs in 21 genes) and 49 previously reported BP loci (2,159 SNVs in 109 genes) in European ancestry, and in multi-ancestry meta-analyses (P < 5.0 x 10-8). For African ancestry samples, we detected 18 potentially novel BP loci (P < 5.0 x 10-8) in Stage 1 that warrant further replication. Additionally, correlated meta-analysis identified eight novel BP loci (11 genes). Several genes in these loci (e.g., PINX1, GATA4, BLK, FTO and GABBR2) have been previously reported to be associated with alcohol consumption. These findings provide insights into the role of alcohol consumption in the genetic architecture of hypertension.
1,218 citations
Evangelos Evangelou1, Evangelos Evangelou2, Helen R. Warren3, Helen R. Warren4 +338 more•Institutions (93)
TL;DR: In this article, the largest genetic association study of blood pressure traits (systolic, diastolic and pulse pressure) to date in over 1 million people of European ancestry was conducted.
Abstract: High blood pressure is a highly heritable and modifiable risk factor for cardiovascular disease We report the largest genetic association study of blood pressure traits (systolic, diastolic and pulse pressure) to date in over 1 million people of European ancestry We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also highlight shared genetic architecture between blood pressure and lifestyle exposures Our findings identify new biological pathways for blood pressure regulation with potential for improved cardiovascular disease prevention in the future
728 citations
University of Leicester1, University of Cambridge2, National Institute for Health Research3, Baker IDI Heart and Diabetes Institute4, Manchester Academic Health Science Centre5, Imperial College London6, St Bartholomew's Hospital7, Icahn School of Medicine at Mount Sinai8, Wellcome Trust Centre for Human Genetics9, Queen Mary University of London10
TL;DR: The genomic score developed and evaluated here substantially advances the concept of using genomic information to stratify individuals with different trajectories of CAD risk and highlights the potential for genomic screening in early life to complement conventional risk prediction.
522 citations
TL;DR: Exome-wide analysis identifies rare and low-frequency coding variants associated with body mass index that confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity.
Abstract: Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are ~10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed ~7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity.
252 citations
National University of Singapore1, University of Groningen2, University of Leicester3, Wrocław Medical University4, University of Brescia5, Charité6, Robertson Centre for Biostatistics7, Stavanger University Hospital8, National and Kapodistrian University of Athens9, University of Dundee10, French Institute of Health and Medical Research11
TL;DR: Network analysis showed that biomarker profiles specific for HFrEF are related to cellular proliferation and metabolism, whereas biomarkers specific for HFpEF arerelated to inflammation and extracellular matrix reorganization.
163 citations
University Medical Center Groningen1, University of Göttingen2, National Institutes of Health3, University of Bergen4, Stavanger University Hospital5, National and Kapodistrian University of Athens6, University of Dundee7, University of Brescia8, University of Leicester9, Wrocław Medical University10, French Institute of Health and Medical Research11
TL;DR: Overall, comorbidities were associated with a lower QoL, but this was more pronounced in patients with HFrEF.
120 citations
Yun J. Sung1, Thomas W. Winkler2, Lisa de las Fuentes1, Amy R. Bentley3 +326 more•Institutions (104)
TL;DR: The identified loci show strong evidence for regulatory features and support shared pathophysiology with cardiometabolic and addiction traits and highlight a role in BP regulation for biological candidates such as modulators of vascular structure and function.
Abstract: Genome-wide association analysis advanced understanding of blood pressure (BP), a major risk factor for vascular conditions such as coronary heart disease and stroke Accounting for smoking behavior may help identify BP loci and extend our knowledge of its genetic architecture We performed genome-wide association meta-analyses of systolic and diastolic BP incorporating gene-smoking interactions in 610,091 individuals Stage 1 analysis examined ∼188 million SNPs and small insertion/deletion variants in 129,913 individuals from four ancestries (European, African, Asian, and Hispanic) with follow-up analysis of promising variants in 480,178 additional individuals from five ancestries We identified 15 loci that were genome-wide significant (p < 5 × 10−8) in stage 1 and formally replicated in stage 2 A combined stage 1 and 2 meta-analysis identified 66 additional genome-wide significant loci (13, 35, and 18 loci in European, African, and trans-ancestry, respectively) A total of 56 known BP loci were also identified by our results (p < 5 × 10−8) Of the newly identified loci, ten showed significant interaction with smoking status, but none of them were replicated in stage 2 Several loci were identified in African ancestry, highlighting the importance of genetic studies in diverse populations The identified loci show strong evidence for regulatory features and support shared pathophysiology with cardiometabolic and addiction traits They also highlight a role in BP regulation for biological candidates such as modulators of vascular structure and function (CDKN1B, BCAR1-CFDP1, PXDN, EEA1), ciliopathies (SDCCAG8, RPGRIP1L), telomere maintenance (TNKS, PINX1, AKTIP), and central dopaminergic signaling (MSRA, EBF2)
110 citations
Harvard University1, University of Mississippi Medical Center2, Technische Universität München3, University of Ottawa4, University of Oxford5, Wellcome Trust Centre for Human Genetics6, University of Vic7, National Institute for Health Research8, Icahn School of Medicine at Mount Sinai9, University of Lübeck10, Washington University in St. Louis11, Wellcome Trust Sanger Institute12, University of Cambridge13, University of Pennsylvania14
TL;DR: A genetic predisposition to enhanced nitric oxide signaling is associated with reduced risks of coronary heart disease, peripheral arterial disease, and stroke and may prove useful in the prevention or treatment of cardiovascular disease.
Abstract: Background:Nitric oxide signaling plays a key role in the regulation of vascular tone and platelet activation. Here, we seek to understand the impact of a genetic predisposition to enhanced nitric ...
85 citations
University Medical Center Groningen1, Charité2, National Institutes of Health3, University of Bergen4, Stavanger University Hospital5, National and Kapodistrian University of Athens6, University of Brescia7, University of Leicester8, Wrocław Medical University9, University of Lorraine10, University of Dundee11
TL;DR: The association between abdominal fat, measured via waist‐to‐hip ratio (WHR), BMI and all‐cause mortality in patients with HF is analysed.
Abstract: Aims:
A higher body mass index (BMI) is associated with better survival in heart failure (HF) patients, also known as the obesity paradox. However, BMI does not account for body composition. We therefore analysed the association between abdominal fat, measured via waist‐to‐hip ratio (WHR), BMI and all‐cause mortality in patients with HF.
Methods and results:
For this analysis, 1738 patients from the Scottish BIOlogy Study to TAilored Treatment in Chronic Heart Failure (BIOSTAT‐CHF) validation study were included. Patients without waist and hip measurements were excluded. WHR was defined as waist circumference/hip circumference, divided into tertiles and split for sex. A linear regression of principal components from an extensive panel of biomarkers was performed to provide insight in the pathophysiology behind a higher WHR. In total, 1479 patients were included, of which 33% were female and mean age was 75 ±11 years. A higher WHR was independently associated with a higher BMI, a higher prevalence of diabetes and higher New York Heart Association functional class. There was a significant interaction between sex and WHR on its association with mortality (P <0.001). In women, a higher WHR was associated with a higher mortality risk [hazard ratio (HR) 2.23, 95% confidence interval (CI) 1.37–3.63; P =0.001], whereas no significant association was found in men (HR 0.87, 95% CI 0.63–1.20; P = 0.409). We found a strong association between a higher WHR and elevated markers of inflammation and MAPK cascade in women, while these associations were less profound in men.
Conclusions:
A higher WHR was associated with a higher risk of death in female but not in male HF patients. These findings challenge the obesity paradox, and suggest that fat deposition is pathophysiologically harmful and may be a target for therapy in female patients with HF.
84 citations
Harvard University1, Broad Institute2, Yale University3, University of Mississippi Medical Center4, Technische Universität München5, University of Ottawa6, University of Oxford7, Wellcome Trust Centre for Human Genetics8, University of Vic9, University of Leicester10, Icahn School of Medicine at Mount Sinai11, University of Lübeck12, Wellcome Trust Sanger Institute13, University of Cambridge14, Brigham and Women's Hospital15, Vanderbilt University16, University of Missouri–Kansas City17, UCLA Medical Center18, University of Washington19, Kaiser Permanente20, University of Virginia21, Johns Hopkins University School of Medicine22, University of Pennsylvania23
TL;DR: In this paper, the authors found that less than 3% of protein-coding genetic variants are predicted to result in loss of protein function through the introduction of a stop codon, frameshift, or the disruption of an essential splice site; however, such predicted loss-of-function (pLOF) variants provide insight into effector transcript and direction of biological effect.
Abstract: Less than 3% of protein-coding genetic variants are predicted to result in loss of protein function through the introduction of a stop codon, frameshift, or the disruption of an essential splice site; however, such predicted loss-of-function (pLOF) variants provide insight into effector transcript and direction of biological effect. In >400,000 UK Biobank participants, we conduct association analyses of 3759 pLOF variants with six metabolic traits, six cardiometabolic diseases, and twelve additional diseases. We identified 18 new low-frequency or rare (allele frequency < 5%) pLOF variant-phenotype associations. pLOF variants in the gene GPR151 protect against obesity and type 2 diabetes, in the gene IL33 against asthma and allergic disease, and in the gene IFIH1 against hypothyroidism. In the gene PDE3B, pLOF variants associate with elevated height, improved body fat distribution and protection from coronary artery disease. Our findings prioritize genes for which pharmacologic mimics of pLOF variants may lower risk for disease.
74 citations
Utrecht University1, University of Washington2, St George's, University of London3, Washington University in St. Louis4, University of Edinburgh5, California Pacific Medical Center6, University of Alabama at Birmingham7, deCODE genetics8, University of Iceland9, Erasmus University Rotterdam10, University of Tampere11, University of Hamburg12, University of Groningen13, University of Glasgow14, University of Pennsylvania15, University of Michigan16, Greifswald University Hospital17, Leiden University18, Boston University19, University College London20, Johns Hopkins University21, Cleveland Clinic22, University of Texas Health Science Center at Houston23, University College Cork24, Case Western Reserve University25, Uppsala University26, Vanderbilt University27, Broad Institute28, Harvard University29, National Institutes of Health30, University of Trieste31, University of Split32, University of California, Los Angeles33, Icahn School of Medicine at Mount Sinai34, University of Pittsburgh35, Technische Universität München36, University of Maryland, Baltimore37, University of Mainz38, University of Turku39, University of Leicester40, Del Rosario University41, Ludwig Maximilian University of Munich42, Wake Forest University43, Guy's and St Thomas' NHS Foundation Trust44, Emory University45, University of North Carolina at Chapel Hill46, Queen Mary University of London47, University of Zagreb48, Kaiser Permanente49, Maastricht University50
TL;DR: Findings implicate developmental pathways, and identify transcription factors, ion-channel genes, and cell-junction/cell-signaling proteins in atrio-ventricular conduction, identifying potential targets for drug development.
Abstract: Electrocardiographic PR interval measures atrio-ventricular depolarization and conduction, and abnormal PR interval is a risk factor for atrial fibrillation and heart block. Our genome-wide association study of over 92,000 European-descent individuals identifies 44 PR interval loci (34 novel). Examination of these loci reveals known and previously not-yet-reported biological processes involved in cardiac atrial electrical activity. Genes in these loci are over-represented in cardiac disease processes including heart block and atrial fibrillation. Variants in over half of the 44 loci were associated with atrial or blood transcript expression levels, or were in high linkage disequilibrium with missense variants. Six additional loci were identified either by meta-analysis of ~105,000 African and European-descent individuals and/or by pleiotropic analyses combining PR interval with heart rate, QRS interval, and atrial fibrillation. These findings implicate developmental pathways, and identify transcription factors, ion-channel genes, and cell-junction/cell-signaling proteins in atrio-ventricular conduction, identifying potential targets for drug development.
01 Jan 2018
TL;DR: In this article, the authors performed genome-wide association meta-analyses of systolic and diastolic BP incorporating gene-smoking interactions in 610,091 individuals.
Abstract: Genome-wide association analysis advanced understanding of blood pressure (BP), a major risk factor for vascular conditions such as coronary heart disease and stroke. Accounting for smoking behavior may help identify BP loci and extend our knowledge of its genetic architecture. We performed genome-wide association meta-analyses of systolic and diastolic BP incorporating gene-smoking interactions in 610,091 individuals. Stage 1 analysis examined ∼18.8 million SNPs and small insertion/deletion variants in 129,913 individuals from four ancestries (European, African, Asian, and Hispanic) with follow-up analysis of promising variants in 480,178 additional individuals from five ancestries. We identified 15 loci that were genome-wide significant (p < 5 × 10-8) in stage 1 and formally replicated in stage 2. A combined stage 1 and 2 meta-analysis identified 66 additional genome-wide significant loci (13, 35, and 18 loci in European, African, and trans-ancestry, respectively). A total of 56 known BP loci were also identified by our results (p < 5 × 10-8). Of the newly identified loci, ten showed significant interaction with smoking status, but none of them were replicated in stage 2. Several loci were identified in African ancestry, highlighting the importance of genetic studies in diverse populations. The identified loci show strong evidence for regulatory features and support shared pathophysiology with cardiometabolic and addiction traits. They also highlight a role in BP regulation for biological candidates such as modulators of vascular structure and function (CDKN1B, BCAR1-CFDP1, PXDN, EEA1), ciliopathies (SDCCAG8, RPGRIP1L), telomere maintenance (TNKS, PINX1, AKTIP), and central dopaminergic signaling (MSRA, EBF2).
University of Groningen1, University of Göttingen2, National Institutes of Health3, University of Stavanger4, University of Bergen5, National and Kapodistrian University of Athens6, University of Dundee7, University of Brescia8, University of Leicester9, Glenfield Hospital10, Wrocław Medical University11, French Institute of Health and Medical Research12
TL;DR: In patients with new-onset and worsening HF, higher plasma FGF23 levels were independently associated with volume overload, less successful uptitration of ACEi/ARBs and an increased risk of all-cause mortality and HF hospitalization.
University of Groningen1, University of Göttingen2, Charité3, National Institutes of Health4, University of Bergen5, Stavanger University Hospital6, National and Kapodistrian University of Athens7, University of Dundee8, University of Brescia9, University of Leicester10, Wrocław Medical University11, University of Lorraine12
TL;DR: The association between potassium and uptitration of angiotensin‐converting enzyme inhibitors (ACEi)/angiotens in receptor blockers (ARB) and its association with outcome was investigated.
Abstract: Background:
Hyperkalaemia is a common co-morbidity in patients with heart failure with reduced ejection fraction (HFrEF). Whether it affects the use of renin–angiotensin–aldosterone system inhibitors and thereby negatively impacts outcome is unknown. Therefore, we investigated the association between potassium and uptitration of angiotensin-converting enzyme inhibitors (ACEi)/angiotensin receptor blockers (ARB) and its association with outcome.
Methods and results:
Out of 2516 patients from the BIOSTAT-CHF study, potassium levels were available in 1666 patients with HFrEF. These patients were sub-optimally treated with ACEi/ARB or beta-blockers and were anticipated and encouraged to be uptitrated. Potassium levels were available at inclusion and at 9 months. Outcome was a composite of all-cause mortality and heart failure hospitalization at 2 years. Patients' mean age was 67 ± 12 years and 77% were male. At baseline, median serum potassium was 4.3 (interquartile range 3.9–4.6) mEq/L. After 9 months, 401 (24.1%) patients were successfully uptitrated with ACEi/ARB. During this period, mean serum potassium increased by 0.16 ± 0.66 mEq/L (P 0.5 for all).
Conclusion:
Higher potassium levels are an independent predictor of enduring lower dosages of ACEi/ARB. Higher potassium levels do not attenuate the beneficial effects of ACEi/ARB uptitration.
TL;DR: An integrative analysis of genetic, transcriptomic and epigenomic data from human kidney is performed to pinpoint plausible molecular pathways of CKD genetic associations.
Abstract: Genome-wide association studies (GWAS) have identified >100 loci of chronic kidney disease-defining traits (CKD-dt). Molecular mechanisms underlying these associations remain elusive. Using 280 kidney transcriptomes and 9958 gene expression profiles from 44 non-renal tissues we uncover gene expression partners (eGenes) for 88.9% of CKD-dt GWAS loci. Through epigenomic chromatin segmentation analysis and variant effect prediction we annotate functional consequences to 74% of these loci. Our colocalisation analysis and Mendelian randomisation in >130,000 subjects demonstrate causal effects of three eGenes (NAT8B, CASP9 and MUC1) on estimated glomerular filtration rate. We identify a common alternative splice variant in MUC1 (a gene responsible for rare Mendelian form of kidney disease) and observe increased renal expression of a specific MUC1 mRNA isoform as a plausible molecular mechanism of the GWAS association signal. These data highlight the variants and genes underpinning the associations uncovered in GWAS of CKD-dt.
TL;DR: Height was associated with 32 diseases and genetically determined height associated with 12 diseases, and pathway analysis showed multiple height-associated pathways associating with individual diseases.
Abstract: Adult height is associated with risk of several diseases, but the breadth of such associations and whether these associations are primary or due to confounding are unclear. We examined the association of adult height with 50 diseases spanning multiple body systems using both epidemiological and genetic approaches, the latter to identify un-confounded associations and possible underlying mechanisms. We examined the associations for adult height (using logistic regression adjusted for potential confounders) and genetically determined height (using a two-sample Mendelian randomisation approach with height-associated genetic variants as instrumental variables) in 417,434 individuals of white ethnic background participating in the UK Biobank. We undertook pathway analysis of height-associated genes to identify biological processes that could link height and specific diseases. Height was associated with 32 diseases and genetically determined height associated with 12 diseases. Of these, 11 diseases showed a concordant association in both analyses, with taller height associated with reduced risks of coronary artery disease (odds ratio per standard deviation (SD) increase in height ORepi = 0.80, 95% CI 0.78–0.81; OR per SD increase in genetically determined height ORgen = 0.86, 95% CI 0.82–0.90), hypertension (ORepi = 0.83, 95% CI 0.82–0.84; ORgen = 0.88, 95% CI 0.85–0.91), gastro-oesophageal reflux disease (ORepi = 0.85, 95% CI 0.84–0.86; ORgen = 0.94, 95% CI 0.92–0.97), diaphragmatic hernia (ORepi = 0.81, 95% CI 0.79–0.82; ORgen = 0.91, 95% CI 0.88–0.94), but increased risks of atrial fibrillation (ORepi = 1.42, 95% CI 1.38–1.45; ORgen = 1.33, 95% CI 1.26–1.40), venous thromboembolism (ORepi = 1.18, 95% CI 1.16–1.21; ORgen = 1.15, 95% CI 1.11–1.19), intervertebral disc disorder (ORepi = 1.15, 95% CI 1.13–1.18; ORgen = 1.14, 95% CI 1.09–1.20), hip fracture (ORepi = 1.19, 95% CI 1.12–1.26; ORgen = 1.27, 95% CI 1.17–1.39), vasculitis (ORepi = 1.15, 95% CI 1.11–1.19; ORgen = 1.20, 95% CI 1.14–1.28), cancer overall (ORepi = 1.09, 95% CI 1.08–1.11; ORgen = 1.06, 95% CI 1.04–1.08) and breast cancer (ORepi = 1.08, 95% CI 1.06–1.10; ORgen = 1.07, 95% CI 1.03–1.11). Pathway analysis showed multiple height-associated pathways associating with individual diseases. Adult height is associated with risk of a range of diseases. We confirmed previously reported height associations for coronary artery disease, atrial fibrillation, venous thromboembolism, intervertebral disc disorder, hip fracture and cancer and identified potential novel associations for gastro-oesophageal reflux disease, diaphragmatic hernia and vasculitis. Multiple biological mechanisms affecting height may affect the risks of these diseases.
University of Cambridge1, St George's, University of London2, Cleveland Clinic Lerner Research Institute3, University of Washington4, Amgen5, Queen Mary University of London6, Johns Hopkins University School of Medicine7, Erasmus University Rotterdam8, University of Copenhagen9, University of Trieste10, University College London11, University of Pittsburgh12, Fred Hutchinson Cancer Research Center13, Glenfield Hospital14, University of Leicester15, Maastricht University16, Erasmus University Medical Center17, Leiden University Medical Center18, Boston University19, University of Tampere20, University of Edinburgh21, University of Mississippi Medical Center22, Ludwig Maximilian University of Munich23, University of Glasgow24, Harvard University25, Broad Institute26, Utrecht University27, University of Iceland28, University Medical Center Groningen29, University of Greifswald30, Emory University31, UCLA Medical Center32, Los Angeles Biomedical Research Institute33, Greifswald University Hospital34, National Institutes of Health35, University of Utah36, Stanford University37, University of Split38, Kaiser Permanente39, University of Turku40, Wake Forest University41, King's College London42, Zhejiang Chinese Medical University43, Qatar Airways44, University of Dundee45
TL;DR: Putative functional coding variation associated with changes in the QRS interval duration is identified by combining Illumina HumanExome BeadChip genotype data from 77,898 participants of European ancestry and 7695 of African descent in the discovery cohort, followed by replication in 111,874 individuals from the UK Biobank and deCODE cohorts.
Abstract: Background: Genome-wide association studies conducted on QRS duration, an electrocardiographic measurement associated with heart failure and sudden cardiac death, have led to novel biological insights into cardiac function. However, the variants identified fall predominantly in non-coding regions and their underlying mechanisms remain unclear. Results: Here, we identify putative functional coding variation associated with changes in the QRS interval duration by combining Illumina HumanExome BeadChip genotype data from 77,898 participants of European ancestry and 7695 of African descent in our discovery cohort, followed by replication in 111,874 individuals of European ancestry from the UK Biobank and deCODE cohorts. We identify ten novel loci, seven within coding regions, including ADAMTS6, significantly associated with QRS duration in gene-based analyses. ADAMTS6 encodes a secreted metalloprotease of currently unknown function. In vitro validation analysis shows that the QRS-associated variants lead to impaired ADAMTS6 secretion and loss-of function analysis in mice demonstrates a previously unappreciated role for ADAMTS6 in connexin 43 gap junction expression, which is essential for myocardial conduction. Conclusions: Our approach identifies novel coding and non-coding variants underlying ventricular depolarization and provides a possible mechanism for the ADAMTS6-associated conduction changes.
University of Groningen1, University of Dundee2, Charité3, National Institutes of Health4, University of Glasgow5, University of Bergen6, Stavanger University Hospital7, National and Kapodistrian University of Athens8, University of Brescia9, Glenfield Hospital10, University of Leicester11, Wrocław Medical University12, University of Lorraine13
TL;DR: In patients with HFrEF, the presence of AF was associated with a homogeneously elevated cardiovascular risk marker profile, suggesting differences in underlying pathophysiological mechanisms of AF in these HF phenotypes, compared with patients with HFpEF.
Abstract: Aims:
The clinical correlates and consequences of atrial fibrillation (AF) might be different between heart failure with reduced vs. preserved ejection fraction (HFrEF vs. HFpEF). Biomarkers may provide insights into underlying pathophysiological mechanisms of AF in these different heart failure (HF) phenotypes.
Methods and results:
We performed a retrospective analysis of the BIOlogy Study to TAilored Treatment in Chronic Heart Failure (BIOSTAT-CHF), which was an observational cohort. We studied 2152 patients with HFrEF [ejection fraction (EF < 40%)], of which 1419 were in sinus rhythm (SR) and 733 had AF. Another 524 patients with HFpEF (EF ≥50%) were studied, of which 286 in SR and 238 with AF. For the comparison of biomarker profiles, 92 cardiovascular risk markers were measured (Proseek® Olink Cardiovascular III panel). The circulating risk marker pattern observed in HFrEF was different than the pattern in HFpEF: in HFrEF, AF was associated with higher levels of 77 of 92 (84%) risk markers compared to SR; whereas in HFpEF, many more markers were higher in SR than in AF. Over a median follow-up of 21 months, AF was associated with increased mortality risk [multivariable hazard ratio (HR) of 1.27; 95% confidence interval (CI) 1.09–1.48, P = 0.002]; there was no significant interaction between heart rhythm and EF group on outcome.
Conclusion:
In patients with HFrEF, the presence of AF was associated with a homogeneously elevated cardiovascular risk marker profile. In contrast, in patients with HFpEF, the presence of AF was associated with a more scattered risk marker profile, suggesting differences in underlying pathophysiological mechanisms of AF in these HF phenotypes.
TL;DR: This study prioritized 68 genes as the most likely causal genes at genome-wide significant loci identified by GWAS of CAD and examined their regulatory roles in 286 metabolic and vascular tissue gene-protein sub-networks (“modules”).
Abstract: Genome-wide association studies (GWAS) have identified over two hundred chromosomal loci that modulate risk of coronary artery disease (CAD). The genes affected by variants at these loci are largely unknown and an untapped resource to improve our understanding of CAD pathophysiology and identify potential therapeutic targets. Here, we prioritized 68 genes as the most likely causal genes at genome-wide significant loci identified by GWAS of CAD and examined their regulatory roles in 286 metabolic and vascular tissue gene-protein sub-networks ("modules"). The modules and genes within were scored for CAD druggability potential. The scoring enriched for targets of cardiometabolic drugs currently in clinical use and in-depth analysis of the top-scoring modules validated established and revealed novel target tissues, biological processes, and druggable targets. This study provides an unprecedented resource of tissue-defined gene-protein interactions directly affected by genetic variance in CAD risk loci.
University of Amsterdam1, Academic Medical Center2, University of Leicester3, University of Groningen4, University of Lorraine5, Wrocław Medical University6, University of Brescia7, University of Dundee8, National and Kapodistrian University of Athens9, University of Stavanger10, National Institutes of Health11, University of Göttingen12
TL;DR: Up-titrating patients with heart failure based on biomarker values might have resulted in fewer deaths or hospitalizations compared with a hypothetical scenario in which all patients were successfully up-Titrated.
University of Groningen1, National University of Singapore2, Charité3, National Institutes of Health4, University of Glasgow5, Stavanger University Hospital6, National and Kapodistrian University of Athens7, University of Dundee8, University of Brescia9, University of Leicester10, Glenfield Hospital11, Wrocław Medical University12, French Institute of Health and Medical Research13
TL;DR: Using unsupervised cluster analysis, solely based on biomarker profiles, six distinct endotypes were identified with remarkable differences in characteristics, clinical outcome, and response to uptitration of guideline directed medical therapy.
Abstract: Aims:
We sought to determine subtypes of patients with heart failure (HF) with a distinct clinical profile and treatment response, using a wide range of biomarkers from various pathophysiological domains.
Methods and results:
We performed unsupervised cluster analysis using 92 established cardiovascular biomarkers to identify mutually exclusive subgroups (endotypes) of 1802 patients with HF and reduced ejection fraction (HFrEF) from the BIOSTAT-CHF project. We validated our findings in an independent cohort of 813 patients. Based on their biomarker profile, six endotypes were identified. Patients with endotype 1 were youngest, less symptomatic, had the lowest N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels and lowest risk for all-cause mortality or hospitalization for HF. Patients with endotype 4 had more severe symptoms and signs of HF, higher NT-proBNP levels and were at highest risk for all-cause mortality or hospitalization for HF [hazard ratio (HR) 1.4; 95% confidence interval (CI) 1.1–1.8]. Patients with endotypes 2, 3, and 5 were better uptitrated to target doses of beta-blockers (P < 0.02 for all). In contrast to other endotypes, patients with endotype 5 derived no potential survival benefit from uptitration of angiotensin-converting enzyme-inhibitor/angiotensin-II receptor blocker and beta-blockers (Pinteraction <0.001). Patients with endotype 2 (HR 1.29; 95% CI 1.10–1.42) experienced possible harm from uptitration of beta-blockers in contrast to patients with endotype 4 and 6 that experienced benefit (Pinteraction for all <0.001). Results were strikingly similar in the independent validation cohort.
Conclusion:
Using unsupervised cluster analysis, solely based on biomarker profiles, six distinct endotypes were identified with remarkable differences in characteristics, clinical outcome, and response to uptitration of guideline directed medical therapy.
TL;DR: First‐ and second‐degree relatives of patients affected by both familial and sporadic NS‐TADs may benefit from personalized screening programs.
Abstract: Background Nonsyndromic thoracic aortic diseases (NS‐TADs) are often silent entities until they present as life‐threatening emergencies. Despite familial inheritance being common, screening is not ...
TL;DR: The results show thatJCAD negatively regulates Hippo signaling in endothelial cells and it is suggested that JCAD contributes to atherosclerosis by mediating YAP activity and contributing to endothelial dysfunction.
Abstract: Objective— A large number of genetic loci have been associated with risk of coronary artery disease (CAD) through genome-wide association studies, however, for most loci the underlying biological m...
Johns Hopkins University1, University of Washington2, University of Iceland3, Queen Mary University of London4, Boston University5, Maastricht University6, Erasmus University Medical Center7, University of Edinburgh8, Broad Institute9, Harvard University10, University of Leicester11, Glenfield Hospital12, University of Copenhagen13, University of Mississippi Medical Center14, Ludwig Maximilian University of Munich15, University Medical Center Groningen16, Los Angeles Biomedical Research Institute17, University of Split18, Leiden University Medical Center19, Erasmus University Rotterdam20, St George's, University of London21, Utrecht University22, Fred Hutchinson Cancer Research Center23, University of Tampere24, University of Utah25, Emory University26, Wake Forest University27, National Institutes of Health28, University of Glasgow29, University of Aberdeen30, Technische Universität München31, Greifswald University Hospital32, King's College London33, Stanford University34, Turku University Hospital35, University College London36, University of Groningen37, Leiden University38, University of Mississippi39, University of London40
TL;DR: Analysis of ExomeChip-wide analyses shows a role for myocyte internal structure and interconnections in modulating QT interval duration, adding to previous known roles of potassium, sodium, and calcium ion regulation, as well as autonomic control.
Abstract: BACKGROUND: QT interval, measured through a standard ECG, captures the time it takes for the cardiac ventricles to depolarize and repolarize. JT interval is the component of the QT interval that reflects ventricular repolarization alone. Prolonged QT interval has been linked to higher risk of sudden cardiac arrest. METHODS AND RESULTS: We performed an ExomeChip-wide analysis for both QT and JT intervals, including 209 449 variants, both common and rare, in 17 341 genes from the Illumina Infinium HumanExome BeadChip. We identified 10 loci that modulate QT and JT interval duration that have not been previously reported in the literature using single-variant statistical models in a meta-analysis of 95 626 individuals from 23 cohorts (comprised 83 884 European ancestry individuals, 9610 blacks, 1382 Hispanics, and 750 Asians). This brings the total number of ventricular repolarization associated loci to 45. In addition, our approach of using coding variants has highlighted the role of 17 specific genes for involvement in ventricular repolarization, 7 of which are in novel loci. CONCLUSIONS: Our analyses show a role for myocyte internal structure and interconnections in modulating QT interval duration, adding to previous known roles of potassium, sodium, and calcium ion regulation, as well as autonomic control. We anticipate that these discoveries will open new paths to the goal of making novel remedies for the prevention of lethal ventricular arrhythmias and sudden cardiac arrest.
TL;DR: A new genomic risk score for CAD, consisting of 1.7 million genetic variants, has been developed, enabling targeted primary intervention in combination with conventional risk factors and partially attenuated by lipid and blood pressure-lowering medication.
Abstract: Background Coronary artery disease (CAD) has substantial heritability and a polygenic architecture; however, genomic risk scores have not yet leveraged the totality of genetic information available nor been externally tested at population-scale to show potential utility in primary prevention. Methods Using a meta-analytic approach to combine large-scale genome-wide and targeted genetic association data, we developed a new genomic risk score for CAD (metaGRS), consisting of 1.7 million genetic variants. We externally tested metaGRS, individually and in combination with available conventional risk factors, in 22,242 CAD cases and 460,387 non-cases from UK Biobank. Findings In UK Biobank, a standard deviation increase in metaGRS had a hazard ratio (HR) of 1.71 (95% CI 1.68–1.73) for CAD, greater than any other externally tested genetic risk score. Individuals in the top 20% of the metaGRS distribution had a HR of 4.17 (95% CI 3.97–4.38) compared with those in the bottom 20%. The metaGRS had higher C-index (C=0.623, 95% CI 0.615–0.631) for incident CAD than any of four conventional factors (smoking, diabetes, hypertension, and body mass index), and addition of the metaGRS to a model of conventional risk factors increased C-index by 3.7%. In individuals on lipid-lowering or anti-hypertensive medications at recruitment, metaGRS hazard for incident CAD was significantly but only partially attenuated with HR of 2.83 (95% CI 2.61– 3.07) between the top and bottom 20% of the metaGRS distribution. Interpretation Recent genetic association studies have yielded enough information to meaningfully stratify individuals using the metaGRS for CAD risk in both early and later life, thus enabling targeted primary intervention in combination with conventional risk factors. The metaGRS effect was partially attenuated by lipid and blood pressure-lowering medication, however other prevention strategies will be required to fully benefit from earlier genomic risk stratification. Funding National Health and Medical Research Council of Australia, British Heart Foundation, Australian Heart Foundation.
University Medical Center Groningen1, Leicester Royal Infirmary2, University of Leicester3, University of Göttingen4, Charité5, National Institutes of Health6, Stavanger University Hospital7, University of Bergen8, National and Kapodistrian University of Athens9, University of Dundee10, Wrocław Medical University11, French Institute of Health and Medical Research12, University of Brescia13
TL;DR: An in‐depth investigation of the multifunctional HDL proteome is performed to reveal underlying pathophysiological mechanisms explaining the association between HDL and clinical outcome.
Abstract: Aims:
Previously, low high-density lipoprotein (HDL) cholesterol was found to be one of the strongest predictors of mortality and/or heart failure (HF) hospitalisation in patients with HF. We therefore performed in-depth investigation of the multifunctional HDL proteome to reveal underlying pathophysiological mechanisms explaining the association between HDL and clinical outcome.
Methods and results:
We selected a cohort of 90 HF patients with 1:1 cardiovascular death/survivor ratio from BIOSTAT-CHF. A novel optimised protocol for selective enrichment of lipoproteins was used to prepare plasma. Enriched lipoprotein content of samples was analysed using high resolution nanoscale liquid chromatography-mass spectrometry-based proteomics, utilising a label free approach. Within the HDL proteome, 49 proteins significantly differed between deaths and survivors. An optimised model of 12 proteins predicted death with 76% accuracy (Nagelkerke R2=0.37, P < 0.001). The strongest contributors to this model were filamin-A (related to crosslinking of actin filaments) [odds ratio (OR) 0.31, 95% confidence interval (CI) 0.15–0.61, P = 0.001] and pulmonary surfactant-associated protein B (related to alveolar capillary membrane function) (OR 2.50, 95% CI 1.57–3.98, P < 0.001). The model predicted mortality with an area under the curve of 0.82 (95% CI 0.77–0.87, P < 0.001). Internal cross validation resulted in 73.3 ± 7.2% accuracy.
Conclusion:
This study shows marked differences in composition of the HDL proteome between HF survivors and deaths. The strongest differences were seen in proteins reflecting crosslinking of actin filaments and alveolar capillary membrane function, posing potential pathophysiological mechanisms underlying the association between HDL and clinical outcome in HF.
TL;DR: This study shows that the CAD-associated genetic variant increases FURIN expression and that furin promotes monocyte/macrophage migration and proliferation while inhibiting apoptosis, providing a biological mechanism for the association between variation at the chromosome 15q26.1 locus and CAD risk.
Abstract: Objective- Genome-wide association studies have revealed a robust association between genetic variation on chromosome 15q26.1 and coronary artery disease (CAD) susceptibility; however, the underlying biological mechanism is still unknown. The lead CAD-associated genetic variant (rs17514846) at this locus resides in the FURIN gene. In advanced atherosclerotic plaques, furin is expressed primarily in macrophages. We investigated whether this CAD-associated variant alters FURIN expression and whether furin affects monocyte/macrophage behavior. Approach and Results- A quantitative reverse transcription polymerase chain reaction analysis showed that leukocytes from individuals carrying the CAD risk allele (A) of rs17514846 had increased FURIN expression. A chromatin immunoprecipitation assay revealed higher RNA polymerase II occupancy in the FURIN gene in mononuclear cells of individuals carrying this allele. A reporter gene assay in transiently transfected monocytes/macrophages indicated that the CAD risk allele had higher transcriptional activity than the nonrisk allele (C). An analysis of isogenic monocyte cell lines created by CRISPR (clustered regularly interspaced short palindromic repeats)-mediated genome editing showed that isogenic cells with the A/A genotype for rs17514846 had higher FURIN expression levels than the isogenic cells with the C/C genotype. An electrophoretic mobility shift assay exhibited preferential binding of a nuclear protein to the risk allele. Studies of monocytes/macrophages with lentivirus-mediated furin overexpression or shRNA (short hairpin RNA)-induced furin knockdown showed that furin overexpression promoted monocyte/macrophage migration, increased proliferation, and reduced apoptosis whereas furin knockdown had the opposite effects. Conclusions- Our study shows that the CAD-associated genetic variant increases FURIN expression and that furin promotes monocyte/macrophage migration and proliferation while inhibiting apoptosis, providing a biological mechanism for the association between variation at the chromosome 15q26.1 locus and CAD risk.
01 May 2018
TL;DR: The findings of this large-scale meta-analyses of the PR interval provide novel insights to the current understanding of atrioventricular conduction, which is critical for cardiac activity and an important determinant of health.
Abstract: Background: Electrical conduction from the cardiac sinoatrial node to the ventricles is critical for normal heart function. Genome-wide association studies have identified more than a dozen common genetic loci that are associated with PR interval. However, it is unclear whether rare and low-frequency variants also contribute to PR interval heritability.
Methods: We performed large-scale meta-analyses of the PR interval that included 83 367 participants of European ancestry and 9436 of African ancestry. We examined both common and rare variants associated with the PR interval.
Results: We identified 31 genetic loci that were significantly associated with PR interval after Bonferroni correction (P<1.2×10−6), including 11 novel loci that have not been reported previously. Many of these loci are involved in heart morphogenesis. In gene-based analysis, we found that multiple rare variants at MYH6 (P=5.9×10−11) and SCN5A (P=1.1×10−7) were associated with PR interval. SCN5A locus also was implicated in the common variant analysis, whereas MYH6 was a novel locus.
Conclusions: We identified common variants at 11 novel loci and rare variants within 2 gene regions that were significantly associated with PR interval. Our findings provide novel insights to the current understanding of atrioventricular conduction, which is critical for cardiac activity and an important determinant of health.
TL;DR: This study supports the view that cardiovascular susceptibility loci may exert their effect by influencing the atherosclerotic plaque characteristics, and provides data from public resources showing an association with decreased LDL (low-density lipoprotein) and increase HDL (high-density cholesterol) in the blood.
Abstract: Background: Atherosclerosis is a chronic inflammatory disease in part caused by lipid uptake in the vascular wall, but the exact underlying mechanisms leading to acute myocardial infarction and str...
Evangelos Evangelou1, Evangelos Evangelou2, Helen R. Warren3, Helen R. Warren4 +337 more•Institutions (93)
TL;DR: In the version of this article originally published, the name of author Martin H. de Borst was coded incorrectly in the XML and the error has now been corrected in the HTML version of the paper.
Abstract: In the version of this article originally published, the name of author Martin H. de Borst was coded incorrectly in the XML. The error has now been corrected in the HTML version of the paper.