227 research outputs found
Identification of heart rate-associated loci and their effects on cardiac conduction and rhythm disorders
Get PDFElevated resting heart rate is associated with greater risk of cardiovascular disease and mortality. In a 2-stage meta-analysis of genome-wide association studies in up to 181,171 individuals, we identified 14 new loci associated with heart rate and confirmed associations with all 7 previously established loci. Experimental downregulation of gene expression in Drosophila melanogaster and Danio rerio identified 20 genes at 11 loci that are relevant for heart rate regulation and highlight a role for genes involved in signal transmission, embryonic cardiac development and the pathophysiology of dilated cardiomyopathy, congenital heart failure and/or sudden cardiac death. In addition, genetic susceptibility to increased heart rate is associated with altered cardiac conduction and reduced risk of sick sinus syndrome, and both heart rate-increasing and heart rate-decreasing variants associate with risk of atrial fibrillation. Our findings provide fresh insights into the mechanisms regulating heart rate and identify new therapeutic targets
Evaluation of common genetic variants identified by GWAS for early onset and morbid obesity in population-based samples
No full textBackgroundMeta-analysis of case–control genome-wide association studies (GWAS) for early onset and morbid obesity identified four variants in/near the PRL, PTER, MAF and NPC1 genes.ObjectiveWe aimed to validate association of these variants with obesity-related traits in population-based samples.DesignGenotypes and anthropometric traits were available in up to 31?083 adults from the Fenland, EPIC-Norfolk, Whitehall II, Ely and Hertfordshire studies and in 2042 children and adolescents from the European Youth Heart Study. In each study, we tested associations of rs4712652 (near-PRL), rs10508503 (near-PTER), rs1424233 (near-MAF) and rs1805081 (NPC1), or proxy variants (r 2>0.8), with the odds of being overweight and obese, as well as with body mass index (BMI), percentage body fat (%BF) and waist circumference (WC). Associations were adjusted for sex, age and age2 in adults and for sex, age, age group, country and maturity in children and adolescents. Summary statistics were combined using fixed effects meta-analysis methods.ResultsWe had 80% power to detect odds ratios of 1.046 to 1.092 for overweight and 1.067 to 1.136 for obesity. Variants near PRL, PTER and MAF were not associated with the odds of being overweight or obese, or with BMI, %BF or WC after meta-analysis (P>0.15). The NPC1 variant rs1805081 showed some evidence of association with %BF (?=0.013?s.d./allele, P=0.040), but not with any of the remaining obesity-related traits (P>0.3).ConclusionOverall, these variants, which were identified in a GWAS for early onset and morbid obesity, do not seem to influence obesity-related traits in the general population
Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture
Get PDFApproaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups
The minimal incubation period from the onset of Barrett's oesophagus to symptomatic adenocarcinoma
Get PDFBackground:The interval between the onset of Barrett's oesophagus (BO) and oesophageal adenocarcinoma (OAC) can be termed the incubation period. However, the unrecorded onset of BO precludes its direct observation.Methods:Determining the range of intervals between BO diagnosis and OAC within the longest observational BO follow-up study. Exclusion criteria were presence of high-grade dysplasia (HGD) or OAC at baseline, death within <2 years of BO diagnosis, oesophagectomy without HGD/OAC and loss to follow-up. A total of 133 patients (M/F 73/60) were taken into account.Results:In 1967 person years of follow-up there were 13 cases of HGD/OAC, (0.66% p.a.; 95% CI 0.58-0.74), 96 patients died without HGD/OAC and 24 survived without HGD/OAC. The mean intervals between BO diagnosis and either HGD/OAC, death or end of follow-up were 10.8, 12.6 and 25.5 years, respectively, and the mean ages at endpoint were 72.5, 80.0 and 68.3 years, respectively. The survivors without HGD/OAC had a lower age at BO diagnosis (mean 42.8 vs 61.2 and 67.4 years, P=0.001). Baseline presence of low-grade dysplasia was associated with progression to HGD/OAC (log rank P=0.001).Conclusion:The Rotterdam BO follow-up cohort revealed a long incubation period between onset of BO and development of HGD/OAC, in patients without HGD/OAC at baseline as illustrated by 24 patients diagnosed with BO at a young age and followed for a mean period of 25.5 years. Their tumour-free survival established a minimum incubation period, suggesting a true incubation period of three decades or more
Relationship between perilipin gene polymorphisms and body weight and body composition during weight loss and weight maintenance
No full textBACKGROUND: Genetic variation in the perilipin (PLIN) gene may play a role in the etiology and treatment of obesity. Objective: To examine different polymorphisms in the PLIN gene in relation to body-weight regulation. METHODS: 118 subjects followed a 6 wk VLCD, followed by 1 year weight maintenance. Body-weight (BW), body composition, leptin concentration, and polymorphisms of the PLIN gene: PLIN1:rs2289487, PLIN4:rs894160, PLIN6:rs1052700, PLIN5:rs2304795 and PLIN7:rs 2304796 were determined. RESULTS: BW loss during VLCD was 7.0±3.1 kg (pb0.05), and BW regain was 3.7±1.4 kg (pb0.05), including changes in body mass index (BMI), waist-circumference, body-composition and leptin concentrations (pb0.05). Linkage disequilibria were observed between PLIN1 and PLIN4: D' N0.9, r2=0.72; PLIN5 and PLIN7: D' N0.9, r2=0.85. In men, body weight, BMI, waist circumference, body fat, leptin concentrations were significantly lower for the haplotype of PLIN1 (C-alleles) and PLIN4 (A-alleles). In women weight loss and loss of fat mass were larger for the haplotype of PLIN1 (C-alleles) and PLIN4 (A-alleles). For PLIN6 genotypes body weight and body fat were lower for homozygotes of the minor allele (T/T) in the men; in the women leptin concentrations were lower. The haplotype of PLIN5 and PLIN7 consisting of A/G and G/G of PLIN5 and A/A of PLIN7 showed a reduction in FM: 5.9±0.6 kg vs 3.1±0.4 kg, % body fat: 5.5±0.6% vs 2.2±0.2%, and leptin: 20.5±10.8 ng/ml vs 12.9±6.7 ng/ml over time in the women (pb0.05). CONCLUSION: Since the haplotype of the minor alleles PLIN1–4, PLIN5–7 and PLIN6, was related to body-weight regulation at a lower level of body-weight in the men as well in the women we conclude that the PLIN1–4, 6, and 5–7 locus appears as a genetic influencer of obesity risk in humans.Stijn Soenen, Edwin C.M. Mariman, Neeltje Vogels, Freek G. Bouwman, Marcel den Hoed, Louise Brown and Margriet S. Westerterp-Planteng
Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization.
Get PDFThe QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD
Long-Term Effects of Structured Home-Based Exercise Program on Functional Capacity and Quality of Life in Patients With Intermittent Claudication
No full textFakhry F. Spronk S, de Ridder M, den Hoed PT, Hunink MGM. Long-term effects of structured home-based exercise program on functional capacity and quality of life in patients with intermittent claudication. Arch Phys Med Rehabil 2011;92:1066-73. Objectives: To evaluate effects of a structured home-based exercise program on functional capacity and quality of life (QoL) in patients with intermittent claudication (IC) after 1-year follow-up, and to compare these results with those from a concurrent control group who received supervised exercise training (SET). Design: Comparative longitudinal cohort study. Setting: Referral center. Participants: Patients (N = 142) with IC. Interventions: Structured home-based exercise training or SET. Main Outcome Measures: The maximum (pain-free) walking distance and the ankle-brachial index (ABI) (at rest and postexercise) were measured at baseline and after 6 and 12 months' follow-up. Additionally, QoL was evaluated using a self-administered questionnaire consisting of the Euroqol-5D (scale 0-1), rating scale (scale 0-100), Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36; scale 0-100), and the Vascular Quality of Life Questionnaire (VascuQol; scale 1-7). Comparison of the groups was performed with adjustment for the nonrandomized setting using propensity scoring. Results: One hundred forty-two patients with IC started the structured home-based exercise program, of whom 95 (67%) completed 12 months' follow-up. The mean relative improvement compared with baseline was statistically significant after 12 months' follow-up for the maximum and pain-free walking distance (342%, 95% confidence interval [CI], 169-516; P<.01 and 338%, 95% CI, 42-635; P=.03, respectively) and for the ABI postexercise (mean change, .06; 95% CI, .01.10; P=.02). For the QoL outcomes, the improvement compared with baseline was statistically significant after 12 months for the VascuQol (mean change, .42; 95% CI, .20.65; P<.01) and for the SF-36 physical functioning (mean change, 5.17; 95% CI, .77-9.56; P=.02). Compared with the structured home-based exercise program, patients in the control group showed significantly better results in the mean relative improvement of maximum and pain-free walking distance and change in the ABI at rest after 12 months' follow-up. Conclusions: Structured home-based exercise training is effective in improving both functional capacity and QoL in patients with IC and may be considered as a feasible and valuable alternative toSET, since supervised exercise programs are not often available
Test-retest variability of VO2max using total-capture indirect calorimetry reveals linear relationship of VO2 and Power
No full textThis study aimed to analyze the intra-individual variation in VO2max of human subjects using total-capture and free-flow indirect calorimetry. Twenty-seven men (27 ± 5 year; VO2max 49-79 mL•kg-1 •min-1) performed two maximal exertion tests (CPETs) on a cycle ergometer, separated by a 7 ± 2 day interval. VO2 and VCO2 were assessed using an indirect calorimeter (Omnical) with total capture of exhalation in a free-flow airstream. Thirteen subjects performed a third maximal exertion test using a breath-by-breath calorimeter (Oxycon Pro). On-site validation was deemed a requirement. For the Omnical, the mean within-subject CV for VO2max was 1.2 ± 0.9% (0.0%-4.4%) and for ergometer workload P max 1.3 ± 1.3% (0%-4.6%). VO2max values with the Oxycon Pro were significantly lower in comparison with Omnical (P< t 0.001; t test) with mean 3570 vs 4061 and difference SD 361 mL • min-1. Validation results for the Omnical with methanol combustion were -0.05 ± 0.70% (mean ± SD; n = 31) at the 225 mL • min-1 VO2 level and -0.23 ± 0.80% (n = 31) at the 150 mL • min-1 VCO2 level. Results using gas infusion were 0.04 ± 0.75% (n = 34) and -0.99 ± 1.05% (n = 24) over the respective 500-6000 mL • min-1 VO2 and VCO2 ranges. Validation results for the Oxycon Pro in breath-by-breath mode were - 2.2 ± 1.6% (n = 12) for VO2 and 5.7 ± 3.3% (n = 12) for VCO2 over the 1000-4000 mL •min-1 range. On a Visual analog scale, participants reported improved breathing using the free-flow indirect calorimetry (score 7.6 ± 1.2 vs 5.1 ± 2.7, P = 0.008). We conclude that total capturing free-flow indirect calorimetry is suitable for measuring VO2 even with the highest range. VO2max was linear with the incline in P max over the full range
Genetic and metabolic determinants of methotrexate-induced mucositis in pediatric acute lymphoblastic leukemia
No full textMethotrexate (MTX) is an effective and toxic chemotherapeutic drug in the treatment of pediatric acute lymphoblastic leukemia(ALL). In this prospective study, we aimed to identify metabolic and genetic determinants of MTX toxicity. One hundred and thirty-four Dutch pediatric ALL patients were treated with four high infusions MTX (HD-MTX: 5 g m -2) every other week according to the DCOG-ALL-10 protocol. Mucositis (National Cancer Institute grade ≥3) was the most frequent occurring toxicity during the HD-MTX phase (20%) and occurred especially after the first MTX course. Mucositis was not associated with plasma MTX, plasma folate or plasma homocysteine levels. Patients with mucositis had higher erythrocyte folate levels at the start of protocol M than patients without mucositis (median 1.4 vs 1.2 μmol l -1,
COVID-19 in liver transplant candidates: Pretransplant and post-transplant outcomes - An ELITA/ELTR multicentre cohort study
No full textObjective Explore the impact of COVID-19 on patients on the waiting list for liver transplantation (LT) and on their post-LT course. Design Data from consecutive adult LT candidates with COVID-19 were collected across Europe in a dedicated registry and were analysed. Results From 21 February to 20 November 2020, 136 adult cases with laboratory-confirmed SARS-CoV-2 infection from 33 centres in 11 European countries were collected, with 113 having COVID-19. Thirty-seven (37/113, 32.7%) patients died after a median of 18 (10-30) days, with respiratory failure being the major cause (33/37, 89.2%). The 60-day mortality risk did not significantly change between first (35.3%, 95% CI 23.9% to 50.0%) and second (26.0%, 95% CI 16.2% to 40.2%) waves. Multivariable Cox regression analysis showed Laboratory Model for End-stage Liver Disease (Lab-MELD) score of ≥15 (Model for End-stage Liver Disease (MELD) score 15-19, HR 5.46, 95% CI 1.81 to 16.50; MELD score≥20, HR 5.24, 95% CI 1.77 to 15.55) and dyspnoea on presentation (HR 3.89, 95% CI 2.02 to 7.51) being the two negative independent factors for mortality. Twenty-six patients underwent an LT after a median time of 78.5 (IQR 44-102) days, and 25 (96%) were alive after a median follow-up of 118 days (IQR 31-170). Conclusions Increased mortality in LT candidates with COVID-19 (32.7%), reaching 45% in those with decompensated cirrhosis (DC) and Lab-MELD score of ≥15, was observed, with no significant difference between first and second waves of the pandemic. Respiratory failure was the major cause of death. The dismal prognosis of patients with DC supports the adoption of strict preventative measures and the urgent testing of vaccination efficacy in this population. Prior SARS-CoV-2 symptomatic infection did not affect early post-transplant survival (96%)
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