COX7A2L genetic variants determine cardiorespiratory fitness in mice and human

Benegiamo et al. identify genetic variants of the mitochondrial supercomplex assembly factor COX7A2L in the skeletal muscle of mice and humans that promote cardiorespiratory fitness.Mitochondrial respiratory complexes form superassembled structures called supercomplexes. COX7A2L is a supercomplex-specific assembly factor in mammals, although its implication for supercomplex formation and cellular metabolism remains controversial. Here we identify a role for COX7A2L for mitochondrial supercomplex formation in humans. By using human cis-expression quantitative trait loci data, we highlight genetic variants in the COX7A2L gene that affect its skeletal muscle expression specifically. The most significant cis-expression quantitative trait locus is a 10-bp insertion in the COX7A2L 3 ' untranslated region that increases messenger RNA stability and expression. Human myotubes harboring this insertion have more supercomplexes and increased respiration. Notably, increased COX7A2L expression in the muscle is associated with lower body fat and improved cardiorespiratory fitness in humans. Accordingly, specific reconstitution of Cox7a2l expression in C57BL/6J mice leads to higher maximal oxygen consumption, increased lean mass and increased energy expenditure. Furthermore, Cox7a2l expression in mice is induced specifically in the muscle upon exercise. These findings elucidate the genetic basis of mitochondrial supercomplex formation and function in humans and show that COX7A2L plays an important role in cardiorespiratory fitness, which could have broad therapeutic implications in reducing cardiovascular mortality.Peer reviewe

Hemodynamic-based Assessment and Management of Cardiogenic Shock

Cardiogenic shock (CS) remains a deadly disease entity challenging patients, caregivers, and communities across the globe. CS can rapidly lead to the development of hypoperfusion and end-organ dysfunction, transforming a predictable hemodynamic event into a potential high-resource, intense, hemometabolic clinical catastrophe. Based on the scalable heterogeneity from a cellular level to healthcare systems in the hemodynamic-based management of patients experiencing CS, we present considerations towards systematic hemodynamic-based transitions in which distinct clinical entities share the common path of early identification and rapid transitions through an adaptive longitudinal situational awareness model of care that influences specific management considerations. Future studies are needed to best understand optimal management of drugs and devices along with engagement of health systems of care for patients with CS

Whole-Genome Sequencing of Pharmacogenetic Drug Response in Racially Diverse Children with Asthma

RATIONALE: Albuterol, a bronchodilator medication, is the first-line therapy for asthma worldwide. There are significant racial/ethnic differences in albuterol drug response. OBJECTIVES: To identify genetic variants important for bronchodilator drug response (BDR) in racially diverse children. METHODS: We performed the first whole-genome sequencing pharmacogenetics study from 1,441 children with asthma from the tails of the BDR distribution to identify genetic association with BDR. MEASUREMENTS AND MAIN RESULTS: We identified population-specific and shared genetic variants associated with BDR, including genome-wide significant (P \u3c 3.53 × 10 CONCLUSIONS: The lack of minority data, despite a collaboration of eight universities and 13 individual laboratories, highlights the urgent need for a dedicated national effort to prioritize diversity in research. Our study expands the understanding of pharmacogenetic analyses in racially/ethnically diverse populations and advances the foundation for precision medicine in at-risk and understudied minority populations

Whole-genome sequencing of pharmacogenetic drug response in racially diverse children with asthma

RATIONALE: Albuterol, a bronchodilator medication, is the first-line therapy for asthma worldwide. There are significant racial/ethnic differences in albuterol drug response. OBJECTIVES: To identify genetic variants important for bronchodilator drug response (BDR) in racially diverse children. METHODS: We performed the first whole-genome sequencing pharmacogenetics study from 1,441 children with asthma from the tails of the BDR distribution to identify genetic association with BDR. MEASUREMENTS AND MAIN RESULTS: We identified population-specific and shared genetic variants associated with BDR, including genome-wide significant (P \u3c 3.53 × 10-7) and suggestive (P \u3c 7.06 × 10-6) loci near genes previously associated with lung capacity (DNAH5), immunity (NFKB1 and PLCB1), and β-adrenergic signaling (ADAMTS3 and COX18). Functional analyses of the BDR-associated SNP in NFKB1 revealed potential regulatory function in bronchial smooth muscle cells. The SNP is also an expression quantitative trait locus for a neighboring gene, SLC39A8. The lack of other asthma study populations with BDR and whole-genome sequencing data on minority children makes it impossible to perform replication of our rare variant associations. Minority underrepresentation also poses significant challenges to identify age-matched and population-matched cohorts of sufficient sample size for replication of our common variant findings. CONCLUSIONS: The lack of minority data, despite a collaboration of eight universities and 13 individual laboratories, highlights the urgent need for a dedicated national effort to prioritize diversity in research. Our study expands the understanding of pharmacogenetic analyses in racially/ethnically diverse populations and advances the foundation for precision medicine in at-risk and understudied minority populations

Analysis of Parkinson disease patients from Portugal for mutations in SNCA, PRKN, PINK1 and LRRK2

Background: Mutations in the genes PRKN and LRRK2 are the most frequent known genetic lesions among Parkinson's disease patients. We have previously reported that in the Portuguese population the LRRK2 c.6055G > A; p.G2019S mutation has one of the highest frequencies in Europe.Methods: Here, we follow up on those results, screening not only LRRK2, but also PRKN, SNCA and PINK1 in a cohort of early-onset and late-onset familial Portuguese Parkinson disease patients. This series comprises 66 patients selected from a consecutive series of 132 patients. This selection was made in order to include only early onset patients (age at onset below 50 years) or late-onset patients with a positive family history (at least one affected relative). All genes were sequenced bi-directionally, and, additionally, SNCA, PRKN and PINK1 were subjected to gene dosage analysis.Results: We found mutations both in LRRK2 and PRKN, while the remaining genes yielded no mutations. Seven of the studied patients showed pathogenic mutations, in homozygosity or compound heterozygosity for PRKN, and heterozygosity for LRRK2.Conclusion: Mutations are common in Portuguese patients with Parkinson's disease, and these results clearly have implications not only for the genetic diagnosis, but also for the genetic counseling of these patients

The Early Growth Genetics (EGG) and EArly Genetics and Lifecourse Epidemiology (EAGLE) consortia : design, results and future prospects

The impact of many unfavorable childhood traits or diseases, such as low birth weight and mental disorders, is not limited to childhood and adolescence, as they are also associated with poor outcomes in adulthood, such as cardiovascular disease. Insight into the genetic etiology of childhood and adolescent traits and disorders may therefore provide new perspectives, not only on how to improve wellbeing during childhood, but also how to prevent later adverse outcomes. To achieve the sample sizes required for genetic research, the Early Growth Genetics (EGG) and EArly Genetics and Lifecourse Epidemiology (EAGLE) consortia were established. The majority of the participating cohorts are longitudinal population-based samples, but other cohorts with data on early childhood phenotypes are also involved. Cohorts often have a broad focus and collect(ed) data on various somatic and psychiatric traits as well as environmental factors. Genetic variants have been successfully identified for multiple traits, for example, birth weight, atopic dermatitis, childhood BMI, allergic sensitization, and pubertal growth. Furthermore, the results have shown that genetic factors also partly underlie the association with adult traits. As sample sizes are still increasing, it is expected that future analyses will identify additional variants. This, in combination with the development of innovative statistical methods, will provide detailed insight on the mechanisms underlying the transition from childhood to adult disorders. Both consortia welcome new collaborations. Policies and contact details are available from the corresponding authors of this manuscript and/or the consortium websites.Peer reviewe

When cardiology meets endocrinology: sustained atrial flutter associated with thyrotoxic periodic paralysis

Periodic paralysis is a rare muscle disease that manifests as episodes of painless muscle weakness, and the hypokalemic form is commonly associated with hyperthyroidism. Most tachyarrhythmias related with thyrotoxicosis include sinus tachycardia and atrial fibrillation, but an association between thyrotoxic hypokalemic periodic paralysis and typical atrial flutter has seldomly been documented. Here, we present the case of a young male who was diagnosed with thyrotoxic periodic paralysis causing cavotricuspid isthmus-dependent atrial flutter, successfully treated with diltiazem, propranolol, methimazole, potassium iodine (SSK) and rivaroxaban

Trends and Outcomes of Left Atrial Appendage Occlusion in Renal and Liver Transplant Recipients: Insights From the United States National Inpatient and Readmission Database

Left atrial appendage occlusion using the Watchman device has emerged as an alternative treatment strategy for preventing strokes in patients with atrial fibrillation. However, there is no data on its safety and clinical outcomes in prior renal or liver transplant recipients. We included a total of 61,995 patients from the National Inpatient Sample (NIS, in-hospital outcomes) and 55,048 patients from the National Readmission Database (NRD, 30-day outcomes) who underwent percutaneous left atrial appendage occlusion (LAAO). From this group, 0.65% (n=405) and 0.62% (n=339) were renal and liver transplant recipients in NIS and NRD respectively. Transplant recipients were younger compared with non-transplant recipients (mean age 69 vs 77 years, P=\u3c0.01). There was little difference in terms of in-hospital mortality (0% vs 0.2%, P=0.43), major complications (6.2% vs 5.6%, P=0.61), cardiovascular complications (2.5% vs 2.8%, P=0.73), neurological complications (1.2% vs 0.7%, P=0.21) or bleeding complications (1.2% vs 0.7%, P=0.99) between transplant vs. non-transplant patients. Based on the NRD database, 30-day readmission rate was not meaningfully different for transplant recipients undergoing LAAO (9.44%) when compared to non-transplant patients (8.12%, [log-rank, P=0.56]). There was no difference between 30-day major or cardiovascular complications, however vascular complication rates were significantly higher for transplant recipients (OR 2.56, 95% CI [(1.66-3.47]). Our study findings suggest that LAAO may be safe for patients with a prior renal or liver transplant in terms of major complications, cardiovascular complications, and all-cause readmission rates. However vascular complications may be higher in transplant recipients. Further large-scale studies are needed to confirm these findings