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- Young, William J., et al.
(författare)
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Genetic analyses of the electrocardiographic QT interval and its components identify additional loci and pathways
- 2022
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- The QT interval is a heritable electrocardiographic measure associated with arrhythmia risk when prolonged. Here, the authors used a series of genetic analyses to identify genetic loci, pathways, therapeutic targets, and relationships with cardiovascular disease. The QT interval is an electrocardiographic measure representing the sum of ventricular depolarization and repolarization, estimated by QRS duration and JT interval, respectively. QT interval abnormalities are associated with potentially fatal ventricular arrhythmia. Using genome-wide multi-ancestry analyses (>250,000 individuals) we identify 177, 156 and 121 independent loci for QT, JT and QRS, respectively, including a male-specific X-chromosome locus. Using gene-based rare-variant methods, we identify associations with Mendelian disease genes. Enrichments are observed in established pathways for QT and JT, and previously unreported genes indicated in insulin-receptor signalling and cardiac energy metabolism. In contrast for QRS, connective tissue components and processes for cell growth and extracellular matrix interactions are significantly enriched. We demonstrate polygenic risk score associations with atrial fibrillation, conduction disease and sudden cardiac death. Prioritization of druggable genes highlight potential therapeutic targets for arrhythmia. Together, these results substantially advance our understanding of the genetic architecture of ventricular depolarization and repolarization.
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- Komen, Joris J., et al.
(författare)
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Oral anticoagulants in patients with atrial fibrillation at low stroke risk : a multicentre observational study
- 2022
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Ingår i: European Heart Journal. - : OXFORD UNIV PRESS. - 0195-668X .- 1522-9645. ; 43:37, s. 3528-3538
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Tidskriftsartikel (refereegranskat)abstract
- Aims There is currently no consensus on whether atrial fibrillation (AF) patients at low risk for stroke (one non-sex-related CHA(2)DS(2)-VASc point) should be treated with an oral anticoagulant. Methods and results We conducted a multi-country cohort study in Sweden, Denmark, Norway, and Scotland. In total, 59 076 patients diagnosed with AF at low stroke risk were included. We assessed the rates of stroke or major bleeding during treatment with a non-vitamin K antagonist oral anticoagulant (NOAC), a vitamin K antagonist (VKA), or no treatment, using inverse probability of treatment weighted (IPTW) Cox regression. In untreated patients, the rate for ischaemic stroke was 0.70 per 100 person-years and the rate for a bleed was also 0.70 per 100 person-years. Comparing NOAC with no treatment, the stroke rate was lower [hazard ratio (HR) 0.72; 95% confidence interval (CI) 0.56-0.94], and the rate for intracranial haemorrhage (ICH) was not increased (HR 0.84; 95% CI 0.54-1.30). Comparing VKA with no treatment, the rate for stroke tended to be lower (HR 0.81; 95% CI 0.59-1.09), and the rate for ICH tended to be higher during VKA treatment (HR 1.37; 95% CI 0.88-2.14). Comparing NOAC with VKA treatment, the rate for stroke was similar (HR 0.92; 95% CI 0.70-1.22), but the rate for ICH was lower during NOAC treatment (HR 0.63; 95% CI 0.42-0.94). Conclusion These observational data suggest that NOAC treatment may be associated with a positive net clinical benefit compared with no treatment or VKA treatment in patients at low stroke risk, a question that can be tested through a randomized controlled trial. Key question What is the association between anticoagulant treatment and stroke and bleeding rate, in patients with one non-sex-related risk factor for stroke? Key findings Non-vitamin K antagonist oral anticoagulant (NOAC) treatment was associated with a lower stroke rate compared with no treatment. Non-vitamin K antagonist oral anticoagulant treatment was associated with a lower rate of intracranial haemorrhage compared with vitamin K antagonist (VKA) treatment. Take-home message These observational data suggest that NOAC treatment may be associated with a positive net clinical benefit compared with no treatment or VKA treatment in patients at low stroke risk, a hypothesis that can be tested through a randomized controlled trial.
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- Hautakangas, H, et al.
(författare)
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Genome-wide analysis of 102,084 migraine cases identifies 123 risk loci and subtype-specific risk alleles
- 2022
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Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 54:2, s. 152-
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Tidskriftsartikel (refereegranskat)abstract
- Migraine affects over a billion individuals worldwide but its genetic underpinning remains largely unknown. Here, we performed a genome-wide association study of 102,084 migraine cases and 771,257 controls and identified 123 loci, of which 86 are previously unknown. These loci provide an opportunity to evaluate shared and distinct genetic components in the two main migraine subtypes: migraine with aura and migraine without aura. Stratification of the risk loci using 29,679 cases with subtype information indicated three risk variants that seem specific for migraine with aura (in HMOX2, CACNA1A and MPPED2), two that seem specific for migraine without aura (near SPINK2 and near FECH) and nine that increase susceptibility for migraine regardless of subtype. The new risk loci include genes encoding recent migraine-specific drug targets, namely calcitonin gene-related peptide (CALCA/CALCB) and serotonin 1F receptor (HTR1F). Overall, genomic annotations among migraine-associated variants were enriched in both vascular and central nervous system tissue/cell types, supporting unequivocally that neurovascular mechanisms underlie migraine pathophysiology.
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- Sandvik, R. M., et al.
(författare)
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Contemporary N-2 and SF6 multiple breath washout in infants and toddlers with cystic fibrosis
- 2022
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Ingår i: Pediatric Pulmonology. - : Wiley. - 8755-6863 .- 1099-0496.
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Tidskriftsartikel (refereegranskat)abstract
- Introduction Multiple breath washout (MBW) is used for early detection of cystic fibrosis (CF) lung disease, with SF6MBW commonly viewed as the reference method. The use of N2MBW in infants and toddlers has been questioned for technical and physiological reasons, but a new correction of the N(2 )signal has minimized the technical part. The present study aimed to assess the remaining differences and the contributing mechanisms for the differences between SF6 and N2MBW,corrected-such as tidal volume reduction during N-2 washout with pure O-2. Method This was a longitudinal multicenter cohort study. SF6MBW and N2MBW were performed prospectively at three CF centers in the same visits on 154 test occasions across 62 children with CF (mean age: 22.7 months). Offline analysis using identical algorithms to the commercially available program provided outcomes of N-2,N-original and N-2,N-corrected for comparison with SF6MBW. Results Mean functional residual capacity, FRCN2,corrected was 14.3% lower than FRCN2, original, and 1.0% different from FRCSF6. Lung clearance index, LCIN2,corrected was 25.2% lower than LCIN2,original, and 7.3% higher than LCISF6. Mean (SD) tidal volume decreased significantly during N2MBWcorrected, compared to SF6MBW (-13.1 ml [-30.7; 4.6], p < 0.0001, equal to -12.0% [-25.7; 1.73]), but this tidal volume reduction did not correlate to the differences between LCIN2,corrected and LCISF6. The absolute differences in LCI increased significantly with higher LCISF6 (0.63/LCISF6) and (0.23/LCISF6), respectively, for N-2,N-original and N-2,N-corrected, but the relative differences were stable across disease severity for N-2,N-corrected, but not for N-2,N-original. Conclusion Only minor residual differences between FRCN2,corrected and FRCSF6 remained to show that the two methods measure gas volumes very similar in this age range. Small differences in LCI were found. Tidal volume reduction during N2MBW did not affect differences. The corrected N2MBW can now be used with confidence in young children with CF, although not interchangeably with SF6.
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