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- 2019
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Tidskriftsartikel (refereegranskat)
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| 2. |
- Ashar, Foram N., et al.
(författare)
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A comprehensive evaluation of the genetic architecture of sudden cardiac arrest
- 2018
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Ingår i: European Heart Journal. - : Oxford University Press. - 0195-668X .- 1522-9645. ; 39:44, s. 3961-
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Tidskriftsartikel (refereegranskat)abstract
- Aims: Sudden cardiac arrest (SCA) accounts for 10% of adult mortality in Western populations. We aim to identify potential loci associated with SCA and to identify risk factors causally associated with SCA.Methods and results: We carried out a large genome-wide association study (GWAS) for SCA (n = 3939 cases, 25 989 non-cases) to examine common variation genome-wide and in candidate arrhythmia genes. We also exploited Mendelian randomization (MR) methods using cross-trait multi-variant genetic risk score associations (GRSA) to assess causal relationships of 18 risk factors with SCA. No variants were associated with SCA at genome-wide significance, nor were common variants in candidate arrhythmia genes associated with SCA at nominal significance. Using cross-trait GRSA, we established genetic correlation between SCA and (i) coronary artery disease (CAD) and traditional CAD risk factors (blood pressure, lipids, and diabetes), (ii) height and BMI, and (iii) electrical instability traits (QT and atrial fibrillation), suggesting aetiologic roles for these traits in SCA risk.Conclusions: Our findings show that a comprehensive approach to the genetic architecture of SCA can shed light on the determinants of a complex life-threatening condition with multiple influencing factors in the general population. The results of this genetic analysis, both positive and negative findings, have implications for evaluating the genetic architecture of patients with a family history of SCA, and for efforts to prevent SCA in high-risk populations and the general community.
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| 3. |
- Lahrouchi, Najim, et al.
(författare)
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Transethnic Genome-Wide Association Study Provides Insights in the Genetic Architecture and Heritability of Long QT Syndrome
- 2020
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Ingår i: Circulation. - : Lippincott Williams & Wilkins. - 0009-7322 .- 1524-4539. ; 142:4, s. 324-338
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Tidskriftsartikel (refereegranskat)abstract
- Background: Long QT syndrome (LQTS) is a rare genetic disorder and a major preventable cause of sudden cardiac death in the young. A causal rare genetic variant with large effect size is identified in up to 80% of probands (genotype positive) and cascade family screening shows incomplete penetrance of genetic variants. Furthermore, a proportion of cases meeting diagnostic criteria for LQTS remain genetically elusive despite genetic testing of established genes (genotype negative). These observations raise the possibility that common genetic variants with small effect size contribute to the clinical picture of LQTS. This study aimed to characterize and quantify the contribution of common genetic variation to LQTS disease susceptibility. Methods: We conducted genome-wide association studies followed by transethnic meta-analysis in 1656 unrelated patients with LQTS of European or Japanese ancestry and 9890 controls to identify susceptibility single nucleotide polymorphisms. We estimated the common variant heritability of LQTS and tested the genetic correlation between LQTS susceptibility and other cardiac traits. Furthermore, we tested the aggregate effect of the 68 single nucleotide polymorphisms previously associated with the QT-interval in the general population using a polygenic risk score. Results: Genome-wide association analysis identified 3 loci associated with LQTS at genome-wide statistical significance (P<5x10(-8)) nearNOS1AP,KCNQ1, andKLF12, and 1 missense variant inKCNE1(p.Asp85Asn) at the suggestive threshold (P<10(-6)). Heritability analyses showed that approximate to 15% of variance in overall LQTS susceptibility was attributable to common genetic variation (h2SNP0.148; standard error 0.019). LQTS susceptibility showed a strong genome-wide genetic correlation with the QT-interval in the general population (r(g)=0.40;P=3.2x10(-3)). The polygenic risk score comprising common variants previously associated with the QT-interval in the general population was greater in LQTS cases compared with controls (P<10-13), and it is notable that, among patients with LQTS, this polygenic risk score was greater in patients who were genotype negative compared with those who were genotype positive (P<0.005). Conclusions: This work establishes an important role for common genetic variation in susceptibility to LQTS. We demonstrate overlap between genetic control of the QT-interval in the general population and genetic factors contributing to LQTS susceptibility. Using polygenic risk score analyses aggregating common genetic variants that modulate the QT-interval in the general population, we provide evidence for a polygenic architecture in genotype negative LQTS.
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| 4. |
- Zijlstra, Jolande A, et al.
(författare)
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Different defibrillation strategies in survivors after out-of-hospital cardiac arrest.
- 2018
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Ingår i: Heart. - : BMJ. - 1355-6037 .- 1468-201X. ; 104:23, s. 1929-1936
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: In the last decade, there has been a rapid increase in the dissemination of automated external defibrillators (AEDs) for prehospital defibrillation of out-of-hospital cardiac arrest patients. The aim of this study was to study the association between different defibrillation strategies on survival rates over time in Copenhagen, Stockholm, Western Sweden and Amsterdam, and the hypothesis was that non-EMS defibrillation increased over time and was associated with increased survival.METHODS: We performed a retrospective analysis of four prospectively collected cohorts of out-of-hospital cardiac arrest patients between 2008 and 2013. Emergency medical service (EMS)-witnessed arrests were excluded.RESULTS: A total of 22 453 out-of-hospital cardiac arrest patients with known survival status were identified, of whom 2957 (13%) survived at least 30 days postresuscitation. Of all survivors with a known defibrillation status, 2289 (81%) were defibrillated, 1349 (59%) were defibrillated by EMS, 454 (20%) were defibrillated by a first responder AED and 429 (19%) were defibrillated by an onsite AED and 57 (2%) were unknown. The percentage of survivors defibrillated by first responder AEDs (from 13% in 2008 to 26% in 2013, p<0.001 for trend) and onsite AEDs (from 14% in 2008 to 30% in 2013, p<0.001 for trend) increased. The increased use of these non-EMS AEDs was associated with the increase in survival rate of patients with a shockable initial rhythm.CONCLUSION: Survivors of out-of-hospital cardiac arrest are increasingly defibrillated by non-EMS AEDs. This increase is primarily due to a large increase in the use of onsite AEDs as well as an increase in first-responder defibrillation over time. Non-EMS defibrillation accounted for at least part of the increase in survival rate of patients with a shockable initial rhythm.
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