The Polygenic and Monogenic Basis of Blood Traits and Diseases

Blood cells play essential roles in human health, underpinning physiological processes such as immunity, oxygen transport, and clotting, which when perturbed cause a significant global health burden. Here we integrate data from UK Biobank and a large-scale international collaborative effort, including data for 563,085 European ancestry participants, and discover 5,106 new genetic variants independently associated with 29 blood cell phenotypes covering a range of variation impacting hematopoiesis. We holistically characterize the genetic architecture of hematopoiesis, assess the relevance of the omnigenic model to blood cell phenotypes, delineate relevant hematopoietic cell states influenced by regulatory genetic variants and gene networks, identify novel splice-altering variants mediating the associations, and assess the polygenic prediction potential for blood traits and clinical disorders at the interface of complex and Mendelian genetics. These results show the power of large-scale blood cell trait GWAS to interrogate clinically meaningful variants across a wide allelic spectrum of human variation. Analysis of blood cell traits in the UK Biobank and other cohorts illuminates the full genetic architecture of hematopoietic phenotypes, with evidence supporting the omnigenic model for complex traits and linking polygenic burden with monogenic blood diseases

Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus

A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk

Novel Loci for Adiponectin Levels and Their Influence on Type 2 Diabetes and Metabolic Traits : A Multi-Ethnic Meta-Analysis of 45,891 Individuals

J. Kaprio, S. Ripatti ja M.-L. Lokki työryhmien jäseniä.Peer reviewe

Factors Associated with Revision Surgery after Internal Fixation of Hip Fractures

Background: Femoral neck fractures are associated with high rates of revision surgery after management with internal fixation. Using data from the Fixation using Alternative Implants for the Treatment of Hip fractures (FAITH) trial evaluating methods of internal fixation in patients with femoral neck fractures, we investigated associations between baseline and surgical factors and the need for revision surgery to promote healing, relieve pain, treat infection or improve function over 24 months postsurgery. Additionally, we investigated factors associated with (1) hardware removal and (2) implant exchange from cancellous screws (CS) or sliding hip screw (SHS) to total hip arthroplasty, hemiarthroplasty, or another internal fixation device. Methods: We identified 15 potential factors a priori that may be associated with revision surgery, 7 with hardware removal, and 14 with implant exchange. We used multivariable Cox proportional hazards analyses in our investigation. Results: Factors associated with increased risk of revision surgery included: female sex, [hazard ratio (HR) 1.79, 95% confidence interval (CI) 1.25-2.50; P = 0.001], higher body mass index (fo

Supraventricular arrhythmia, N-terminal pro-brain natriuretic peptide and troponin T concentration in relation to incidence of atrial fibrillation : a prospective cohort study

Background: Frequent supraventricular arrhythmia is associated with increased incidence of atrial fibrillation. However, it is unknown whether the prognostic significance of supraventricular arrhythmia is modified by plasma levels of N-terminal pro-brain natriuretic peptide (NT-proBNP) or troponin T (TnT). This study examined the interrelationships between NT-proBNP, TnT levels and frequent supraventricular arrhythmia, and whether these biomarkers and a measure of frequent supraventricular arrhythmia could improve risk assessment for incidence of AF. Methods: Supraventricular extrasystoles (SVEs) and supraventricular tachycardias were assessed from 24-h electrocardiograph recordings in 373 individuals initially without AF. Elevated NT-pro-BNP, TnT and SVEs was defined as a measurement in the top quartile of the study population distribution. Incident cases of AF were retrieved by linkage with the Swedish National Patient Register. Results: During a mean follow-up of 15.4 years, 88 subjects had a diagnosis of AF. After multivariable adjustment, individuals with both elevated NT-proBNP and frequent SVEs had a significantly increased incidence of AF, compared to subjects without elevated NT-proBNP or frequent SVEs (hazard ratio (HR) 4.61, 95% confidence interval (CI) 2.45–8.69), and compared to individuals with either elevated NT-proBNP or frequent SVEs (both P < 0.05). HRs for frequent SVEs alone or elevated NT-proBNP alone were 2.32 (95% CI 1.33–4.06) and 1.52 (95% CI 0.76–3.05), respectively. The addition of NT-pro-BNP and SVEs to a validated risk prediction score for AF, CHARGE-AF, resulted in improved prediction (Harrell’s C 0.751 (95% CI 0.702–0.799) vs 0.720 (95% CI 0.669–0.771), P = 0.015). Conclusion: Subjects with both elevated NT-proBNP and frequent SVEs have substantially increased risk of AF, and the use of these variables could improve long-term prediction of incident AF

Modifiable risk factors predict incident atrial fibrillation and heart failure

Objective Heart failure (HF) frequently complicates atrial fibrillation (AF) and significantly increases mortality risk. Limited data exist on the modifiable risk factors associated with development of HF in AF patients. Methods We examined two large, prospective, population-based cohorts without prior AF or HF at baseline: Malmö Preventive Project (MPP, n=32 625) and Malmö Diet and Cancer Study (MDCS, n=27 695). Using Lunn-McNeil competing risks, multivariable Cox models were constructed to determine hazard ratios (HR) and 95% confidence intervals (CI) of risk factors for incident HF with AF, and AF alone. Results Mean follow-up in MPP and MDCS was 27.6±8.4 and 17.7±5.3 years. In MPP, body mass index (HR 1.11, 95% CI 1.09 to 1.13 vs HR 1.05, 95% CI 1.04 to 1.06 per kg/m 2), systolic blood pressure (HR 1.20, 95% CI 1.24 to 1.26 vs HR 1.08, 95% CI 1.06 to 1.10 per 10 mm Hg) and current cigarette smoking (HR 1.73, 95% CI 1.54 to 1.95 vs HR 1.23, 95% CI 1.15 to 1.32) had stronger associations with incident AF with HF compared with AF alone (all p for difference 50% of the PAR. Randomised trials are needed to assess whether risk factor modification can reduce the incidence of AF with HF and reduce mortality

Elevated premature ventricular complex counts on 24-hour electrocardiogram predict incident atrial fibrillation and heart failure—A prospective population-based cohort study

BackgroundPremature ventricular complexes (PVCs) are known to predict heart failure (HF) and premature atrial contractions (PACs) are known to predict atrial fibrillation (AF) and stroke. PVCs and PACs share pathophysiological mechanisms; however, the combined effects of PVCs and PACs on HF, AF, and stroke risk have not been studied.ObjectivesTo study elevated PVC counts on 24-hour electrocardiogram monitoring (24hECG) in relation to incidence of AF, HF, and stroke, and whether this effect is altered by PAC frequency.MethodsThe prospective population-based Malmö Diet and Cancer study includes 24hECG registrations in 375 AF- and HF-free subjects (mean age 65 years, 55% women). During 17 years of follow-up there were 28 HF, 89 AF, and 28 stroke events. The hazard ratios (HR) of elevated PVC counts (defined as the top quartile, ≥77/24 hours) vs lower quartiles were assessed using multivariable adjusted Cox regression models.ResultsElevated PVC counts predicted incident AF (HR 1.9, 95% confidence interval [CI] 1.2–3.0) and HF (HR 3.1, 95% CI 1.4–7.0). Results were similar after adjustment for NT-proBNP and PACs. Multiform PVCs were associated with even higher risks (HR 2.8, 95% CI: 1.7–4.6 for AF; HR 5.0, 95% CI 2.2–11.7 for HF), as was the presence of both elevated PACs and PVCs (9% of the population, HR 4.1, 95% CI 2.4–6.8 for AF and HR 4.3, 95% CI 1.7–11.4 for HF). No significant association was found between elevated PVC counts and incident stroke.ConclusionElevated PVC counts predict incident AF and HF, particularly if PVCs are multiform or occur in combination with elevated PAC counts

Irregularity and lack of p waves in short tachycardia episodes predict atrial fibrillation and ischemic stroke

Background: Atrial fibrillation (AF) is defined as an irregular supraventricular tachycardia (SVT) without p waves, with duration >30 seconds. Whether AF characteristics during short SVT episodes predict AF and stroke is not known. Objective: The purpose of this study was to determine whether irregularity and lack of p waves, alone or in combination, during short SVT episodes increase the risk of incident AF and ischemic stroke. Methods: The population-based Malmö Diet and Cancer study includes 24-hour ECG screening of 377 AF-free individuals (mean age 64.5 years; 43% men) who were prospectively followed for >13 years. There were 65 AF events and 25 ischemic stroke events during follow-up. Subjects with an SVT episode ≥5 beats were identified, and the longest SVT episode was assessed for irregularity and lack of p waves. The association between SVT classification and AF and stroke was assessed using multivariable adjusted Cox regression. Results: The incidence of AF increased with increasing abnormality of the SVTs. The risk-factor adjusted hazard ratio for AF was 4.95 (95% confidence interval 2.06–11.9; P <.0001) for those with short irregular SVTs (<70 beats) without p waves. The incidence of ischemic stroke was highest in the group with regular SVT episodes without p waves (hazard ratio 14.2; 95% confidence interval 3.76–57.6; P <.0001, adjusted for age and sex). Conclusion: Characteristics of short SVT episodes detected at 24-hour ECG screening are associated with incident AF and ischemic stroke. Short irregular SVTs without p waves likely represent early stages of AF or atrial myopathy. Twenty-four–hour ECG could identify subjects suitable for primary prevention efforts

Diagnostic yield is dependent on monitoring duration. Insights from a full-disclosure mobile cardiac telemetry system

Background: Despite the advancement of electrocardiogram (ECG) monitoring methods, the most important factor influencing diagnostic yield (DY) may still be monitoring duration. Ambulatory ECG monitoring, typically with 24–48 hours duration, is widely used but may result in underdiagnosis of rare arrhythmias. Aims: This study aimed to examine the relationship between the DY and monitoring duration in a large patient cohort and investigate sex and age differences in the presentation of arrhythmias. Methods: The study population consisted of 25 151 patients (57.8% women; median [interquartile range, IQR], 71 [64–78] years), who were examined with mobile cardiac telemetry during 2017 in the United States, using the PocketECGTM that continuously transmits a signal on a beat-to-beat basis. We investigated the occurrence of atrial fibrillation at a burden of both ≤1% (atrial fibrillation [AF], ≤1%) and ≤10% (AF ≤10%), premature ventricular contractions (PVC; >10 000 per 24 hours), non-sustained ventricular tachycardias (nsVT), sustained ventricular tachycardias (VT ≥30 seconds), atrioventricular blocks (AVB), pauses of >3 seconds duration, and bradycardia (heart rate <40 beats per minute for ≥60 seconds). Results: The median (IQR) recording duration was 15.4, 8.2–28.2) days. The DY increased gradually with monitoring duration for all types of investigated arrhythmias. Compared to DY after up to 30 days of monitoring, a standard 24 hours monitoring resulted in DY for males/females of 20%/18% for AF ≤1%, 29%/28% for AF ≤10%, 45%/40% for PVCs, 17%/11% for nsVT, 17%/11% for VT ≥30 seconds, 49%/42 for AVB, 27%/20% for pauses, 36%/29% for bradycardia. Conclusion: A substantial number of patients suffering from arrhythmias may remain undiagnosed due to insufficient ECG monitoring time