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Common single-nucleotide polymorphisms (SNPs) are predicted to collectively explain 40-50% of phenotypic variation in human height, but identifying the specific variants and associated regions requires huge sample sizes 1 . Here, using data from a genome-wide association study of 5.4 million individuals of diverse ancestries, we show that 12,111 independent SNPs that are significantly associated with height account for nearly all of the common SNP-based heritability. These SNPs are clustered within 7,209 non-overlapping genomic segments with a mean size of around 90 kb, covering about 21% of the genome. The density of independent associations varies across the genome and the regions of increased density are enriched for biologically relevant genes. In out-of-sample estimation and prediction, the 12,111 SNPs (or all SNPs in the HapMap 3 panel 2 ) account for 40% (45%) of phenotypic variance in populations of European ancestry but only around 10-20% (14-24%) in populations of other ancestries. Effect sizes, associated regions and gene prioritization are similar across ancestries, indicating that reduced prediction accuracy is likely to be explained by linkage disequilibrium and differences in allele frequency within associated regions. Finally, we show that the relevant biological pathways are detectable with smaller sample sizes than are needed to implicate causal genes and variants. Overall, this study provides a comprehensive map of specific genomic regions that contain the vast majority of common height-associated variants. Although this map is saturated for populations of European ancestry, further research is needed to achieve equivalent saturation in other ancestries., (© 2022. The Author(s).)

Objective: To investigate percutaneous coronary intervention (PCI) practice in an international cohort of patients with spontaneous coronary artery dissection (SCAD). To explore factors associated with complications and study angiographic and longer term outcomes., Methods: SCAD patients (n=215, 94% female) who underwent PCI from three national cohort studies were investigated and compared with a matched cohort of conservatively managed SCAD patients (n=221)., Results: SCAD-PCI patients were high risk at presentation with only 8.8% undergoing PCI outside the context of ST-elevation myocardial infarction/cardiac arrest, thrombolysis in myocardial infarction (TIMI) 0/1 flow or proximal dissections. PCI complications occurred in 38.6% (83/215), with 13.0% (28/215) serious complications. PCI-related complications were associated with more extensive dissections (multiple vs single American Heart Association coronary segments, OR 1.9 (95% CI: 1.06-3.39),p=0.030), more proximal dissections (proximal diameter per mm, OR 2.25 (1.38-3.67), p=0.001) and dissections with no contrast penetration of the false lumen (Yip-Saw 2 versus 1, OR 2.89 (1.12-7.43), p=0.028). SCAD-PCI involved long lengths of stent (median 46mm, IQR: 29-61mm). Despite these risks, SCAD-PCI led to angiographic improvements in those with reduced TIMI flow in 84.3% (118/140). Worsening TIMI flow was only seen in 7.0% (15/215) of SCAD-PCI patients. Post-PCI major adverse cardiovascular and cerebrovascular events (MACCE) and left ventricular function outcomes were favourable., Conclusion: While a conservative approach to revascularisation is favoured, SCAD cases with higher risk presentations may require PCI. SCAD-PCI is associated with longer stent lengths and a higher risk of complications but leads to overall improvements in coronary flow and good medium-term outcomes in patients., Competing Interests: Competing interests: DA has received research funding to support a clinical research fellow from Abbott Vascular Inc. He has also received funding from AstraZeneca Inc. for unrelated research and has undertaken consultancy to support research funds for General Electric Inc. TJ has received consultancy/speaker fees from Abbott Vascular, Boston Scientific, Medtronic and Terumo. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Aims: Fibromuscular dysplasia (FMD) and spontaneous coronary artery dissection (SCAD) are related, non-atherosclerotic arterial diseases mainly affecting middle-aged women. Little is known about their physiopathological mechanisms. We aimed to identify rare genetic causes to elucidate molecular mechanisms implicated in FMD and SCAD., Methods and Results: We analysed 29 exomes that included familial and sporadic FMD. We identified one rare loss-of-function variant (LoF) (frequencygnomAD = 0.000075) shared by two FMD sisters in the prostaglandin I2 receptor gene (PTGIR), a key player in vascular remodelling. Follow-up was conducted by targeted or Sanger sequencing (1071 FMD and 363 SCAD patients) or lookups in exome (264 FMD) or genome sequences (480 SCAD), all independent and unrelated. It revealed four additional LoF allele carriers, in addition to several rare missense variants, among FMD patients, and two LoF allele carriers among SCAD patients, including one carrying a rare splicing mutation (c.768 + 1C>G). We used burden test to test for enrichment in patients compared to gnomAD controls, which detected a putative enrichment in FMD (PTRAPD = 8 × 10-4), but not a significant enrichment (PTRAPD = 0.12) in SCAD. The biological effects of variants on human prostaclycin receptor (hIP) signalling and protein expression were characterized using transient overexpression in human cells. We confirmed the LoFs (Q163X and P17RfsX6) and one missense (L67P), identified in one FMD and one SCAD patient, to severely impair hIP function in vitro., Conclusions: Our study shows that rare genetic mutations in PTGIR are enriched among FMD patients and found in SCAD patients, suggesting a role for prostacyclin signalling in non-atherosclerotic stenosis and dissection., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Smoking is a major heritable and modifiable risk factor for many diseases, including cancer, common respiratory disorders and cardiovascular diseases. Fourteen genetic loci have previously been associated with smoking behaviour-related traits. We tested up to 235,116 single nucleotide variants (SNVs) on the exome-array for association with smoking initiation, cigarettes per day, pack-years, and smoking cessation in a fixed effects meta-analysis of up to 61 studies (up to 346,813 participants). In a subset of 112,811 participants, a further one million SNVs were also genotyped and tested for association with the four smoking behaviour traits. SNV-trait associations with P < 5 × 10 -8 in either analysis were taken forward for replication in up to 275,596 independent participants from UK Biobank. Lastly, a meta-analysis of the discovery and replication studies was performed. Sixteen SNVs were associated with at least one of the smoking behaviour traits (P < 5 × 10 -8 ) in the discovery samples. Ten novel SNVs, including rs12616219 near TMEM182, were followed-up and five of them (rs462779 in REV3L, rs12780116 in CNNM2, rs1190736 in GPR101, rs11539157 in PJA1, and rs12616219 near TMEM182) replicated at a Bonferroni significance threshold (P < 4.5 × 10 -3 ) with consistent direction of effect. A further 35 SNVs were associated with smoking behaviour traits in the discovery plus replication meta-analysis (up to 622,409 participants) including a rare SNV, rs150493199, in CCDC141 and two low-frequency SNVs in CEP350 and HDGFRP2. Functional follow-up implied that decreased expression of REV3L may lower the probability of smoking initiation. The novel loci will facilitate understanding the genetic aetiology of smoking behaviour and may lead to the identification of potential drug targets for smoking prevention and/or cessation.

Background: Geographical differences may impact the treatment of heart failure (HF) and the results of clinical trials. We have investigated the differences between geographical areas across Europe in the BIOSTAT-CHF program., Methods: Patients with worsening HF enrolled in BIOSTAT-CHF were subdivided, according to the European geographical areas, into those from Northern countries (The Netherlands, Norway, Sweden, UK), Central countries (Germany, Poland, Serbia, Slovenia), and Mediterranean countries (France, Greece, Italy). Patients were compared for baseline characteristics, treatment, and outcomes. The primary endpoint was a composite of all-cause mortality or HF hospitalization., Results: Among 2516 patients enrolled in BIOSTAT-CHF, 814 (32.3%) were from Northern European centers, 816 (32.4%) from Central European centers, and 886 (35.2%) from Mediterranean centers. Patients from Northern European centers were older, had more severe signs and symptoms of HF, and with lower incidence of non-cardiac comorbidities such as chronic kidney dysfunction, diabetes and, hypertension, compared to those from the Central and Mediterranean centers. Patients receiving ≥ 50% of the target dose of both ACE-I/ARB after the up-titration phase were higher in the Northern European centers compared with the other regions (60% versus 58.7% in the Central European centers and 46.5% in the Mediterranean ones; p < 0.001). The primary endpoint occurred at a higher rate in the Northern centers (44.3% versus 37.4% in central centers and 39.6% in Mediterranean centers; p = 0.014), this difference became non-significant after the adjustment for important confounders. Importantly, treatment up-titration reduced the event rates regardless of the geographical region (p for interaction > 0.05)., Conclusion: The BIOSTAT-CHF study showed significant differences in the clinical features, treatment and prognosis in European patients with HF. Patients from the Mediterranean centers less often had the HF treatments up-titrated; however, the treatment up-titration benefited patients irrespective of their geographical region and should be part of the "default" clinical practice.

Aims: The current pandemic coronavirus SARS-CoV-2 infects a wide age group but predominantly elderly individuals, especially men and those with cardiovascular disease. Recent reports suggest an association with use of renin-angiotensin-aldosterone system (RAAS) inhibitors. Angiotensin-converting enzyme 2 (ACE2) is a functional receptor for coronaviruses. Higher ACE2 concentrations might lead to increased vulnerability to SARS-CoV-2 in patients on RAAS inhibitors., Methods and Results: We measured ACE2 concentrations in 1485 men and 537 women with heart failure (index cohort). Results were validated in 1123 men and 575 women (validation cohort).The median age was 69 years for men and 75 years for women. The strongest predictor of elevated concentrations of ACE2 in both cohorts was male sex (estimate = 0.26, P < 0.001; and 0.19, P < 0.001, respectively). In the index cohort, use of ACE inhibitors, angiotensin receptor blockers (ARBs), or mineralocorticoid receptor antagonists (MRAs) was not an independent predictor of plasma ACE2. In the validation cohort, ACE inhibitor (estimate = -0.17, P = 0.002) and ARB use (estimate = -0.15, P = 0.03) were independent predictors of lower plasma ACE2, while use of an MRA (estimate = 0.11, P = 0.04) was an independent predictor of higher plasma ACE2 concentrations., Conclusion: In two independent cohorts of patients with heart failure, plasma concentrations of ACE2 were higher in men than in women, but use of neither an ACE inhibitor nor an ARB was associated with higher plasma ACE2 concentrations. These data might explain the higher incidence and fatality rate of COVID-19 in men, but do not support previous reports suggesting that ACE inhibitors or ARBs increase the vulnerability for COVID-19 through increased plasma ACE2 concentrations., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

Objectives: This study used optical coherence tomography to investigate the mechanism of false lumen (FL) formation in spontaneous coronary artery dissection (SCAD) by studying: 1) differences between fenestrated and nonfenestrated SCAD; 2) vasa vasorum density; and 3) light attenuation characteristics of the FL., Background: SCAD is an increasingly recognized cause of acute coronary syndromes, characterized by FL formation and compression of the true lumen (TL). The mechanisms underlying FL formation remain poorly understood., Methods: A total of 65 SCAD patients (68 vessels) who underwent acute OCT imaging as part of routine clinical care were included. Images were classified by the absence or presence of a connection (fenestration) between the TL and FL. Indexed measurements of TL stenosis, external elastic lamina (EEL) area, FL area, and light attenuation of the FL were assessed. Vasa vasorum densities of SCAD cases were compared with those in control non-SCAD myocardial infarction cases., Results: In nonfenestrated cases, there was significantly larger expansion of the EEL area (9.1% vs. -1.9%; p <0.05) and a larger FL area (73.6% vs. 53.2%, respectively; p <0.05) in dissected segments. No significant differences were found between vasa vasorum density in SCAD and those in control subjects. The FL contents were heterogeneous but attenuated less light than whole blood or thrombus (4.28 ± 0.55 mm -1 vs. 5.08 ± 0.56 mm -1 ; p < 0.05; vs. 4.96 ± 0.56 mm -1 ; p < 0.05)., Conclusions: These observational data suggest that the absence of a fenestration leads to increased FL pressure and compression of the TL. Although vasa vasorum may still be implicated in pathogenesis, increased vasa vasorum density could be an epiphenomenon of vascular healing., (Copyright © 2019 American College of Cardiology Foundation. All rights reserved.)

Aims: Association of elevated circulating levels of trimethylamine N-oxide (TMAO) with adverse outcomes in patients with heart failure (HF) has been described. However, response of TMAO levels to treatment and medications has not been investigated. Therefore, we investigated whether TMAO levels are responsive to guideline-recommended treatment and medications, and further reflect changes in outcomes., Methods and Results: TMAO levels were investigated in the systems BIOlogy Study to TAilored Treatment in Chronic Heart Failure (BIOSTAT-CHF), which addressed response to guideline-recommended pharmacological treatment. TMAO levels in 2234 patients with new-onset or progressively worsening HF showed strong associations with adverse events (mortality and/or rehospitalisation) at 1, 2 and 3 years [hazard ratio (HR) 1.37-1.51, P ≤ 0.019). Analysis of 972 patients with plasma available at both enrolment and follow-up visit showed reductions of B-type natriuretic peptide (BNP) levels with guideline-based treatment (P < 0.001), but not for TMAO levels. Moreover, patients with higher TMAO levels than median before and after treatment showed increased association with adverse outcomes [HR 2.21, 95% confidence interval (CI) 1.43-3.43, P < 0.001] compared to patients with lower than median levels either before or after treatment (HR 1.13, 95% CI 0.63-2.04, P = 0.684 and HR 1.14, 95% CI 0.64-2.03, P = 0.662, respectively)., Conclusion: TMAO levels were associated with adverse outcomes (mortality and/or rehospitalisation) in BIOSTAT-CHF, and did not respond to guideline-based pharmacological treatment in contrast to BNP levels which did as expected. Lower TMAO levels were associated with favourable outcome regardless of treatment., (© 2018 The Authors. European Journal of Heart Failure © 2018 European Society of Cardiology.)

Background: The 6-minute walk test (6MWT) is a simple and inexpensive way of measuring exercise capacity in patients with heart failure (HF) that predicts morbidity and mortality. However, there are few reports from large multicentre cohorts assessing the predictive value of baseline and changing walk distance., Methods and Results: In BIOSTAT-CHF, a 6MWT was performed at baseline (n = 1714) and 9 months (n = 1520). Cox proportional hazards models were used to assess the associations between 6MWT distance and the composite of HF hospitalization and/or death. Median follow-up was 21 months. The median (pct 25-75 ) of the 6MWT distance at baseline was 300 m (200-388 m). Independent predictors of a shorter 6MWT distance included older age, female sex, higher heart rate, New York Heart Association class III/IV, orthopnoea, ischaemic heart disease, a previous stroke, current malignancy, and higher N-terminal pro-B-type natriuretic peptide (all P < 0.05). Patients in the lowest baseline 6MWT tertile (≤ 240 m) were less likely to receive guideline-recommended doses of disease-modifying therapies (P < 0.05). Compared to patients in the highest baseline 6MWT tertile (> 360 m), those in the lowest and middle tertiles had a worse prognosis [adjusted hazard ratio (HR) 1.73, 95% confidence interval (CI) 1.38-2.18]. Patients with a decrease in the distance walked had a worse prognosis (adjusted HR for each 50 m decrease 1.09, 95% CI 1.06-1.12). 6MWT distance was not modified by treatment up-titration nor the 6MWT improved the BIOSTAT-CHF prognostic models., Conclusions: The 6-minute walk test distance at baseline and a decline in walking distance were both associated with worse prognosis but did not improve the prognostic models. 6MWT distance was not modified by treatment up-titration and its use for assessing the benefits of pharmacologic treatment up-titration may be limited., (© 2019 The Authors. European Journal of Heart Failure © 2019 European Society of Cardiology.)

Objectives: Coronary angiography is regularly performed in patients with worsening signs and/or symptoms of heart failure (HF). However, little is known on the determinants, findings and associated clinical outcomes of coronary angiography performed in patients with worsening HF., Methods: The BIOSTAT-CHF (a systems BIOlogy Study to TAilored Treatment in Chronic Heart Failure) programme enrolled 2516 patients with worsening symptoms and/or signs of HF, either hospitalised or in the outpatient setting. All patients were included in the present analysis., Results: Of the 2516 patients included, 315 (12.5%) underwent coronary angiography within the 30 days after the onset of worsening symptoms and/or signs of HF. Subjects who underwent angiography were more often observed as inpatients, had more often an overt acute coronary syndrome, had higher troponin I levels, were younger and had better renal function (all p≤0.01). Patients who underwent coronary angiography had a lower risk of the primary outcome of death and/or HF hospitalisation (adjusted HR=0.71, 95% CI 0.57 to 0.89, p=0.003) and death (adjusted HR=0.59, 95% CI 0.43 to 0.80, p=0.001). Among the patients who underwent coronary angiography, those with a coronary stenosis (39%) had a worse prognosis than those without stenosis (adjusted HR for the primary outcome=1.71, 95% CI 1.10 to 2.64, p=0.016)., Conclusions: Coronary angiography was performed in <13% of patients with symptoms and/or signs of worsening HF. These patients were remarkably different from those who did not undergo coronary angiography and had a lower risk of subsequent events. The presence of coronary stenosis on coronary angiography was associated with a worse prognosis., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Introduction: From a prospective multicentre multicountry clinical trial, we developed and validated risk models to predict prospective all-cause mortality and hospitalizations because of heart failure (HF) in patients with HF., Methods and Results: BIOSTAT-CHF is a research programme designed to develop and externally validate risk models to predict all-cause mortality and HF hospitalizations. The index cohort consisted of 2516 patients with HF from 69 centres in 11 European countries. The external validation cohort consisted of 1738 comparable patients from six centres in Scotland, UK. Patients from the index cohort had a mean age of 69 years, 27% were female, 83% were in New York Heart Association (NYHA) class II-III and the mean left ventricular ejection fraction (LVEF) was 31%. The full prediction models for mortality, hospitalization owing to HF, and the combined outcome, yielded c-statistic values of 0.73, 0.69, and 0.71, respectively. Predictors of mortality and hospitalization owing to HF were remarkably different. The five strongest predictors of mortality were more advanced age, higher blood urea nitrogen and N-terminal pro-B-type natriuretic peptide, lower haemoglobin, and failure to prescribe a beta-blocker. The five strongest predictors of hospitalization owing to HF were more advanced age, previous hospitalization owing to HF, presence of oedema, lower systolic blood pressure and lower estimated glomerular filtration rate. Patients from the validation cohort were aged 74 years, 34% were female, 85% were in NYHA class II-III, and mean LVEF was 41%; c-statistic values for the full and compact model were comparable to the index cohort., Conclusion: A small number of variables, which are usually readily available in the routine clinical setting, provide useful prognostic information for patients with HF. Predictors of mortality were remarkably different from predictors of hospitalization owing to HF., (© 2017 The Authors. European Journal of Heart Failure © 2017 European Society of Cardiology.)

Background: The chemokine receptors CCR2, CCR5, and CX3CR1 coordinate monocyte trafficking in homeostatic and inflammatory states. Multiple small human genetic studies have variably linked single nucleotide polymorphisms in these genes to cardiometabolic disease. We interrogated genome-wide association, exome sequencing, and exome array genotyping studies to ascertain the relationship between variation in these genes and coronary artery disease (CAD), myocardial infarction (MI), and glucometabolic traits., Methods and Results: We interrogated the CARDIoGRAMplusC4D (Coronary ARtery DIsease Genome wide Replication and Meta-analysis [CARDIoGRAM] plus The Coronary Artery Disease [C4D] Genetics) (60 801 cases and 123 504 controls), the MIGen and CARDIoGRAM Exome consortia (42 335 cases and 78 240 controls), and Exome Sequencing Project and Early-Onset Myocardial Infarction (ESP EOMI; 4703 cases and 5090 controls) data sets to ascertain the relationship between common, low frequency, and rare variation in CCR2, CCR5, or CX3CR1 with CAD and MI. We did not identify any variant associated with CAD or MI. We then explored common and low-frequency variation in South Asians through Pakistan Risk of Myocardial Infarction Study (PROMIS; 9058 cases and 8379 controls), identifying 6 variants associated with MI including CX3CR1 V249I. Finally, reanalysis of the European HapMap imputed Diabetes Genetics Replication and Meta-Analysis (DIAGRAM), Global Lipids Genetics Consortium (GLGC), Genetic Investigation of Anthropometric Traits (GIANT), and Meta-Analysis of Glucose and Insulin-related Traits Consortium (MAGIC) data sets revealed no association with glucometabolic traits although 3 single nucleotide polymorphisms in PROMIS were associated with type II diabetes mellitus., Conclusions: No chemokine receptor variant was associated with CAD, MI, or glucometabolic traits in large European ancestry cohorts. In a South Asian cohort, we identified single nucleotide polymorphism associations with MI and type II diabetes mellitus but these did not meet significance in cohorts of European ancestry. These findings suggest the need for larger studies in South Asians but exclude clinically meaningful associations with CAD and glucometabolic traits in Europeans., (© 2016 American Heart Association, Inc.)

Background: The mechanisms underlying the association between diabetes and coronary artery disease (CAD) risk are unclear. We aimed to assess this association by studying genetic variants that have been shown to associate with type 2 diabetes (T2DM). If the association between diabetes and CAD is causal, we expected to observe an association of these variants with CAD as well., Methods and Results: We studied all genetic variants currently known to be associated with T2DM at a genome-wide significant level (p < 5*10(-8)) in CARDIoGRAM, a genome-wide data-set of CAD including 22,233 CAD cases and 64,762 controls. Out of the 44 published T2DM SNPs 10 were significantly associated with CAD in CARDIoGRAM (OR>1, p < 0.05), more than expected by chance (p = 5.0*10(-5)). Considering all 44 SNPs, the average CAD risk observed per individual T2DM risk allele was 1.0076 (95% confidence interval (CI), 0.9973-1.0180). Such average risk increase was significantly lower than the increase expected based on i) the published effects of the SNPs on T2DM risk and ii) the effect of T2DM on CAD risk as observed in the Framingham Heart Study, which suggested a risk of 1.067 per allele (p = 7.2*10(-10) vs. the observed effect). Studying two risk scores based on risk alleles of the diabetes SNPs, one score using individual level data in 9856 subjects, and the second score on average effects of reported beta-coefficients from the entire CARDIoGRAM data-set, we again observed a significant - yet smaller than expected - association with CAD., Conclusions: Our data indicate that an association between type 2 diabetes related SNPs and CAD exists. However, the effects on CAD risk appear to be by far lower than what would be expected based on the effects of risk alleles on T2DM and the effect of T2DM on CAD in the epidemiological setting., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.

Several clinical studies suggest the involvement of premature ageing processes in chronic obstructive pulmonary disease (COPD). Using an epidemiological approach, we studied whether accelerated ageing indicated by telomere length, a marker of biological age, is associated with COPD and asthma, and whether intrinsic age-related processes contribute to the interindividual variability of lung function. Our meta-analysis of 14 studies included 934 COPD cases with 15 846 controls defined according to the Global Lungs Initiative (GLI) criteria (or 1189 COPD cases according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria), 2834 asthma cases with 28 195 controls, and spirometric parameters (forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC) of 12 595 individuals. Associations with telomere length were tested by linear regression, adjusting for age, sex and smoking status. We observed negative associations between telomere length and asthma (β= -0.0452, p=0.024) as well as COPD (β= -0.0982, p=0.001), with associations being stronger and more significant when using GLI criteria than those of GOLD. In both diseases, effects were stronger in females than males. The investigation of spirometric indices showed positive associations between telomere length and FEV1 (p=1.07×10(-7)), FVC (p=2.07×10(-5)), and FEV1/FVC (p=5.27×10(-3)). The effect was somewhat weaker in apparently healthy subjects than in COPD or asthma patients. Our results provide indirect evidence for the hypothesis that cellular senescence may contribute to the pathogenesis of COPD and asthma, and that lung function may reflect biological ageing primarily due to intrinsic processes, which are likely to be aggravated in lung diseases.

Blood pressure (BP) is a heritable risk factor for cardiovascular disease. To investigate genetic associations with systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP), and pulse pressure (PP), we genotyped ~50,000 SNPs in up to 87,736 individuals of European ancestry and combined these in a meta-analysis. We replicated findings in an independent set of 68,368 individuals of European ancestry. Our analyses identified 11 previously undescribed associations in independent loci containing 31 genes including PDE1A, HLA-DQB1, CDK6, PRKAG2, VCL, H19, NUCB2, RELA, HOXC@ complex, FBN1, and NFAT5 at the Bonferroni-corrected array-wide significance threshold (p < 6 × 10(-7)) and confirmed 27 previously reported associations. Bioinformatic analysis of the 11 loci provided support for a putative role in hypertension of several genes, such as CDK6 and NUCB2. Analysis of potential pharmacological targets in databases of small molecules showed that ten of the genes are predicted to be a target for small molecules. In summary, we identified previously unknown loci associated with BP. Our findings extend our understanding of genes involved in BP regulation, which may provide new targets for therapeutic intervention or drug response stratification., (Copyright © 2014 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Objective: Haplogroup I of male-specific region of the human Y chromosome is associated with 50% increased risk of coronary artery disease. It is not clear to what extent conventional cardiovascular risk factors and genes of the male-specific region may explain this association., Approach and Results: A total of 1988 biologically unrelated men from 4 white European populations were genotyped using 11 Y chromosome single nucleotide polymorphisms and classified into 13 most common European haplogroups. Approximately 75% to 93% of the haplotypic variation of the Y chromosome in all cohorts was attributable to I, R1a, and R1b1b2 lineages. None of traditional cardiovascular risk factors, including body mass index, blood pressures, lipids, glucose, C-reactive protein, creatinine, and insulin resistance, was associated with haplogroup I of the Y chromosome in the joint inverse variance meta-analysis. Fourteen of 15 ubiquitous single-copy genes of the male-specific region were expressed in human macrophages. When compared with men with other haplogroups, carriers of haplogroup I had ≈ 0.61- and 0.64-fold lower expression of ubiquitously transcribed tetratricopeptide repeat, Y-linked gene (UTY) and protein kinase, Y-linked, pseudogene (PRKY) in macrophages (P=0.0001 and P=0.002, respectively)., Conclusions: Coronary artery disease predisposing haplogroup I of the Y chromosome is associated with downregulation of UTY and PRKY genes in macrophages but not with conventional cardiovascular risk factors.

Context: Recent studies have shown an association between cigarettes per day (CPD) and a nonsynonymous single-nucleotide polymorphism in CHRNA5, rs16969968., Objective: To determine whether the association between rs16969968 and smoking is modified by age at onset of regular smoking., Data Sources: Primary data., Study Selection: Available genetic studies containing measures of CPD and the genotype of rs16969968 or its proxy., Data Extraction: Uniform statistical analysis scripts were run locally. Starting with 94,050 ever-smokers from 43 studies, we extracted the heavy smokers (CPD >20) and light smokers (CPD ≤10) with age-at-onset information, reducing the sample size to 33,348. Each study was stratified into early-onset smokers (age at onset ≤16 years) and late-onset smokers (age at onset >16 years), and a logistic regression of heavy vs light smoking with the rs16969968 genotype was computed for each stratum. Meta-analysis was performed within each age-at-onset stratum., Data Synthesis: Individuals with 1 risk allele at rs16969968 who were early-onset smokers were significantly more likely to be heavy smokers in adulthood (odds ratio [OR] = 1.45; 95% CI, 1.36-1.55; n = 13,843) than were carriers of the risk allele who were late-onset smokers (OR = 1.27; 95% CI, 1.21-1.33, n = 19,505) (P = .01)., Conclusion: These results highlight an increased genetic vulnerability to smoking in early-onset smokers.

Essential hypertension is a multifactorial disorder and is the main risk factor for renal and cardiovascular complications. The research on the genetics of hypertension has been frustrated by the small predictive value of the discovered genetic variants. The HYPERGENES Project investigated associations between genetic variants and essential hypertension pursuing a 2-stage study by recruiting cases and controls from extensively characterized cohorts recruited over many years in different European regions. The discovery phase consisted of 1865 cases and 1750 controls genotyped with 1M Illumina array. Best hits were followed up in a validation panel of 1385 cases and 1246 controls that were genotyped with a custom array of 14 055 markers. We identified a new hypertension susceptibility locus (rs3918226) in the promoter region of the endothelial NO synthase gene (odds ratio: 1.54 [95% CI: 1.37-1.73]; combined P=2.58 · 10(-13)). A meta-analysis, using other in silico/de novo genotyping data for a total of 21 714 subjects, resulted in an overall odds ratio of 1.34 (95% CI: 1.25-1.44; P=1.032 · 10(-14)). The quantitative analysis on a population-based sample revealed an effect size of 1.91 (95% CI: 0.16-3.66) for systolic and 1.40 (95% CI: 0.25-2.55) for diastolic blood pressure. We identified in silico a potential binding site for ETS transcription factors directly next to rs3918226, suggesting a potential modulation of endothelial NO synthase expression. Biological evidence links endothelial NO synthase with hypertension, because it is a critical mediator of cardiovascular homeostasis and blood pressure control via vascular tone regulation. This finding supports the hypothesis that there may be a causal genetic variation at this locus.

Variants in the gene encoding the γ-subunit of the epithelial sodium channel (SCNN1G) are associated with both Mendelian and quantitative effects on blood pressure. Here, in 4 cohorts of 1611 white European families composed of a total of 8199 individuals, we undertook staged testing of candidate single-nucleotide polymorphisms for SCNN1G (supplemented with imputation based on data from the 1000 Genomes Project) followed by a meta-analysis in all of the families of the strongest candidate. We also examined relationships between the genotypes and relevant intermediate renal phenotypes, as well as expression of SCNN1G in human kidneys. We found that an intronic single-nucleotide polymorphism of SCNN1G (rs13331086) was significantly associated with age-, sex-, and body mass index-adjusted blood pressure in each of the 4 populations (P<0.05). In an inverse variance-weighted meta-analysis of this single-nucleotide polymorphism in all 4 of the populations, each additional minor allele copy was associated with a 1-mm Hg increase in systolic blood pressure and 0.52-mm Hg increase in diastolic blood pressure (SE=0.33, P=0.002 for systolic blood pressure; SE=0.21, P=0.011 for diastolic blood pressure). The same allele was also associated with higher 12-hour overnight urinary potassium excretion (P=0.04), consistent with increased epithelial sodium channel activity. Renal samples from hypertensive subjects showed a nonsignificant (P=0.07) 1.7-fold higher expression of SCNN1G compared with normotensive controls. These data provide genetic and phenotypic evidence in support of a role for a common genetic variant of SCNN1G in blood pressure determination.

Platelets are the second most abundant cell type in blood and are essential for maintaining haemostasis. Their count and volume are tightly controlled within narrow physiological ranges, but there is only limited understanding of the molecular processes controlling both traits. Here we carried out a high-powered meta-analysis of genome-wide association studies (GWAS) in up to 66,867 individuals of European ancestry, followed by extensive biological and functional assessment. We identified 68 genomic loci reliably associated with platelet count and volume mapping to established and putative novel regulators of megakaryopoiesis and platelet formation. These genes show megakaryocyte-specific gene expression patterns and extensive network connectivity. Using gene silencing in Danio rerio and Drosophila melanogaster, we identified 11 of the genes as novel regulators of blood cell formation. Taken together, our findings advance understanding of novel gene functions controlling fate-determining events during megakaryopoiesis and platelet formation, providing a new example of successful translation of GWAS to function.

Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140 mm Hg systolic blood pressure or  ≥90 mm Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention.

Plasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with plasma lipids in >100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P < 5 x 10(-8)), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (for example, CYP7A1, NPC1L1 and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma lipids that are also associated with CAD. Finally, we validated three of the novel genes-GALNT2, PPP1R3B and TTC39B-with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD.

Using genome-wide association, we identify common variants at 2p12-p13, 6q26, 17q23 and 19q13 associated with serum creatinine, a marker of kidney function (P = 10(-10) to 10(-15)). Of these, rs10206899 (near NAT8, 2p12-p13) and rs4805834 (near SLC7A9, 19q13) were also associated with chronic kidney disease (P = 5.0 x 10(-5) and P = 3.6 x 10(-4), respectively). Our findings provide insight into metabolic, solute and drug-transport pathways underlying susceptibility to chronic kidney disease.

Platelet response to activation varies widely between individuals but shows interindividual consistency and strong heritability. The genetic basis of this variation has not been properly explored. We therefore systematically measured the effect on function of sequence variation in 97 candidate genes in the collagen and adenosine-diphosphate (ADP) signaling pathways. Resequencing of the genes in 48 European DNA samples nearly doubled the number of known single nucleotide polymorphisms (SNPs) and informed the selection of 1327 SNPs for genotyping in 500 healthy Northern European subjects with known platelet responses to collagen-related peptide (CRP-XL) and ADP. This identified 17 novel associations with platelet function (P < .005) accounting for approximately 46% of the variation in response. Further investigations with platelets of known genotype explored the mechanisms behind some of the associations. SNPs in PEAR1 associated with increased platelet response to CRP-XL and increased PEAR1 protein expression after platelet degranulation. The minor allele of a 3' untranslated region (UTR) SNP (rs2769668) in VAV3 was associated with higher protein expression (P = .03) and increased P-selectin exposure after ADP activation (P = .004). Furthermore the minor allele of the intronic SNP rs17786144 in ITPR1 modified Ca(2+) levels after activation with ADP (P < .004). These data provide novel insights into key hubs within platelet signaling networks.

Elevated blood pressure is a common, heritable cause of cardiovascular disease worldwide. To date, identification of common genetic variants influencing blood pressure has proven challenging. We tested 2.5 million genotyped and imputed SNPs for association with systolic and diastolic blood pressure in 34,433 subjects of European ancestry from the Global BPgen consortium and followed up findings with direct genotyping (N ≤ 71,225 European ancestry, N ≤ 12,889 Indian Asian ancestry) and in silico comparison (CHARGE consortium, N = 29,136). We identified association between systolic or diastolic blood pressure and common variants in eight regions near the CYP17A1 (P = 7 × 10(-24)), CYP1A2 (P = 1 × 10(-23)), FGF5 (P = 1 × 10(-21)), SH2B3 (P = 3 × 10(-18)), MTHFR (P = 2 × 10(-13)), c10orf107 (P = 1 × 10(-9)), ZNF652 (P = 5 × 10(-9)) and PLCD3 (P = 1 × 10(-8)) genes. All variants associated with continuous blood pressure were associated with dichotomous hypertension. These associations between common variants and blood pressure and hypertension offer mechanistic insights into the regulation of blood pressure and may point to novel targets for interventions to prevent cardiovascular disease.

Background: Blood pressure (BP) is a heritable trait of major public health concern. The WNK1 and WNK4 genes, which encode proteins in the WNK family of serine-threonine kinases, are involved in renal electrolyte homeostasis. Mutations in the WNK1 and WNK4 genes cause a rare monogenic hypertensive syndrome, pseudohypoaldosteronism type II. We investigated whether polymorphisms in these WNK genes influence BP in the general population., Methods and Results: Associations between 9 single-nucleotide polymorphisms (SNPs) in WNK1 and 1 in WNK4 with ambulatory BP were studied in a population-based sample of 996 subjects from 250 white European families. The heritability estimates of mean 24-hour systolic BP (SBP) and diastolic BP (DBP) were 63.4% and 67.9%, respectively. We found statistically significant (P<0.05) associations of several common SNPs and haplotypes in WNK1 with mean 24-hour SBP and/or DBP. The minor allele (C) of rs880054, with a frequency of 44%, reduced mean 24-hour SBP and DBP by 1.37 (95% confidence interval, -2.45 to -0.23) and 1.14 (95% confidence interval, -1.93 to -0.38) mm Hg, respectively, per copy of the allele., Conclusions: Common variants in WNK1 contribute to BP variation in the general population. This study shows that a gene causing a rare monogenic form of hypertension also plays a significant role in BP regulation in the general population. The findings provide a basis to identify functional variants of WNK1, elucidate any interactions of these variants with dietary intake or with response to antihypertensive drugs, and determine their impact on cardiovascular morbidity and mortality.