| 1. |
- Turcot, Valerie, et al.
(författare)
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Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity
- 2018
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 50:1, s. 26-41
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are similar to 10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed similar to 7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity.
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| 2. |
- Marouli, Eirini, et al.
(författare)
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Rare and low-frequency coding variants alter human adult height
- 2017
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 542:7640, s. 186-190
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Tidskriftsartikel (refereegranskat)abstract
- Height is a highly heritable, classic polygenic trait with approximately 700 common associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated coding variants with lower minor-allele frequencies (in the range of 0.1-4.8%) and effects of up to 2 centimetres per allele (such as those in IHH, STC2, AR and CRISPLD2), greater than ten times the average effect of common variants. In functional follow-up studies, rare height increasing alleles of STC2 (giving an increase of 1-2 centimetres per allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of IGFBP-4 in vitro, resulting in higher bioavailability of insulin-like growth factors. These 83 height-associated variants overlap genes that are mutated in monogenic growth disorders and highlight new biological candidates (such as ADAMTS3, IL11RA and NOX4) and pathways (such as proteoglycan and glycosaminoglycan synthesis) involved in growth. Our results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate-to-large effect associated with polygenic human phenotypes, and that these variants implicate relevant genes and pathways.
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| 3. |
- Carlsen, Esben A, et al.
(författare)
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The stability of myocardial area at risk estimated electrocardiographically in patients with ST elevation myocardial infarction.
- 2014
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Ingår i: Journal of Electrocardiology. - : Elsevier BV. - 1532-8430 .- 0022-0736. ; 47:4, s. 540-545
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Tidskriftsartikel (refereegranskat)abstract
- In patients with ST-elevation myocardial infarction (STEMI) the amount of myocardial area at risk (MaR) indicates the maximal potential loss of myocardium if the coronary artery remains occluded. During the time course of infarct evolution ischemic MaR is replaced by necrosis, which results in a decrease in ST segment elevation and QRS complex distortion. Recently it has been shown that combining the electrocardiographic (ECG) Aldrich ST and Selvester QRS scores result in a more accurate estimate of MaR than using either method alone. Therefore, we hypothesized that the combined Aldrich and Selvester score, indicating MaR, is stable until myocardial reperfusion therapy. In a retrospective analysis of a study population of 114 patients, 33 patients were included. The combined Aldrich and Selvester score was determined in ECGs recorded in the ambulance (ECG1) and in the hospital before reperfusion (ECG2). The combined Aldrich and Selvester score was considered stable if the difference between ECG1 and ECG2 was <4.5-percentage point. Stability of the combined Aldrich and Selvester score was observed in 12/33 patients (36.4%), and in regards to anterior and inferior ST elevation in 4/14 patients (28.6%) and 8/19 patients (42.1%), respectively. The median time between the recording of ECG1 and ECG2 was 75minutes, however the changes in ECG scores were independent of the time between ECG recordings. Patients not meeting the stability criterion either had a decrease (9 patients) or increase (12 patients) of the combined Aldrich and Selvester score. In conclusion, the ECG estimated MaR was stable between the earliest recording time and initiation of reperfusion treatment only in a subgroup of the patients with STEMI. The findings of this study may suggest heterogeneity in regards to the development of the MaR and could indicate a potential need for differentiation in the acute treatment.
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| 4. |
- Mahajan, Anubha, et al.
(författare)
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Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes
- 2018
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 50:4, s. 559-571
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Tidskriftsartikel (refereegranskat)abstract
- We aggregated coding variant data for 81,412 type 2 diabetes cases and 370,832 controls of diverse ancestry, identifying 40 coding variant association signals (P < 2.2 × 10−7); of these, 16 map outside known risk-associated loci. We make two important observations. First, only five of these signals are driven by low-frequency variants: even for these, effect sizes are modest (odds ratio ≤1.29). Second, when we used large-scale genome-wide association data to fine-map the associated variants in their regional context, accounting for the global enrichment of complex trait associations in coding sequence, compelling evidence for coding variant causality was obtained for only 16 signals. At 13 others, the associated coding variants clearly represent ‘false leads’ with potential to generate erroneous mechanistic inference. Coding variant associations offer a direct route to biological insight for complex diseases and identification of validated therapeutic targets; however, appropriate mechanistic inference requires careful specification of their causal contribution to disease predisposition.
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| 5. |
- Mohammad, Moman A., et al.
(författare)
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Usefulness of High Sensitivity Troponin T to Predict Long-Term Left Ventricular Dysfunction After ST-Elevation Myocardial Infarction
- 2020
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Ingår i: American Journal of Cardiology. - : Elsevier BV. - 0002-9149. ; 134, s. 8-13
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Tidskriftsartikel (refereegranskat)abstract
- Guidelines recommend the use of transthoracic echocardiography (TTE) and clinical scores to risk stratify patients after ST-elevation myocardial infarction (STEMI). High sensitivity troponin T (hs-cTnT) is predictive of outcome after STEMI but the predictive value of hs-cTnT relative to other risk assessment tools has not been established. We aimed to compare the predictive value of hs-cTnT to other risk assessment tools in patients with STEMI. A subset of 578 patients with STEMI were included in this post-hoc study from the Third DANish Study of Optimal Acute Treatment of Patients with ST-segment Elevation Myocardial Infarction trial. Patients underwent cardiac magnetic resonance imaging (CMR) during index hospitalization as well as TTE at 1 year after their STEMI. The predictive value of hs-cTnT was compared with CKMB, infarct size (IS)/left ventricular ejection fraction (LVEF) assessed with CMR, LVEF assessed at discharge with TTE and the Global Registry of Acute Coronary Events (GRACE) and Thrombolysis in Myocardial Infarction (TIMI) risk-scores. The primary outcome was LV systolic dysfunction defined as LVEF ≤40% after 1 year on TTE. The area under the receiver operating characteristic curve analyses showed no significant difference between hs-cTnT and early CMR-assessed IS or LVEF in predicting subsequent LVEF ≤40%. Area under the curve for hs-cTnT was 0.82, 0.85 for IS (p = 0.22), and 0.87 for LVEF (p = 0.23). For predischarge TTE-assessed LVEF, the value was 0.85 (p = 0.45), 0.63 for creatine kinase-MB (p <0.001), 0.61 for the GRACE score (p <0.001), and 0.70 for the TIMI score (p = 0.02). A peak hs-cTnT value <3,500 ng/L ruled out LVEF ≤40% with probability of 98%. In conclusion, in patients presenting with STEMI undergoing PCI, hs-cTnT level strongly predicted long-term LV dysfunction and could be used as a clinical risk stratification tool to identify patients at high risk of progressing to LV dysfunction due to its general availability and high-predictive accuracy.
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| 6. |
- Nepper-Christensen, Lars, et al.
(författare)
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Benefit From Reperfusion With Primary Percutaneous Coronary Intervention Beyond 12 Hours of Symptom Duration in Patients With ST-Segment-Elevation Myocardial Infarction
- 2018
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Ingår i: Circulation. Cardiovascular Interventions. - 1941-7632. ; 11:9, s. 006842-006842
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Guidelines recommend primary percutaneous coronary intervention (PCI) in patients with ST-segment-elevation myocardial infarction (STEMI) presenting ≥12 hours of symptom onset in the presence of ongoing ischemia. However, data supporting this recommendation are limited. We evaluated the effect of primary PCI on reperfusion success, using cardiac magnetic resonance, in STEMI patients with signs of ongoing ischemia presenting 12 to 72 hours after symptom onset compared with STEMI patients presenting <12 hours.METHODS AND RESULTS: We included 865 STEMI patients who underwent cardiac magnetic resonance just after index PCI and 3 months later. Despite equal area at risk (34±12% versus 33±12%; P=0.370), patients presenting late (n=58) had larger final infarct size (13% [interquartile range, 9-24] versus 11% [interquartile range, 4-19]; P=0.037) and smaller myocardial salvage index (0.58 [interquartile range, 0.39-0.71] versus 0.65 [interquartile range, 0.49-0.84]; P=0.021) compared with patients presenting <12 hours after symptom onset (n=807). However, 65% of late-presenting patients achieved substantial myocardial salvage ≥0.50, and area under the curve for symptom onset to PCI as predictor of a myocardial salvage index ≥0.50 was poor (0.58 [95% CI, 0.53-0.63]; P<0.001). In addition, final infarct size, salvage index and left ventricular function correlated weakly with duration from symptom onset to primary PCI ( R2 values <0.05).CONCLUSIONS: STEMI patients with signs of ongoing ischemia treated with primary PCI 12 to 72 hours after symptom onset had less myocardial salvage and developed larger infarcts. However, a large proportion achieved substantial myocardial salvage indicating a benefit from primary PCI in late-presenting patients.CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifiers: NCT01435408 and NCT01960933.
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| 7. |
- Rerup, Sofie Aagaard, et al.
(författare)
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The prevalence and prognostic importance of possible familial hypercholesterolemia in patients with myocardial infarction
- 2016
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Ingår i: American Heart Journal. - : Elsevier BV. - 0002-8703 .- 1097-6744. ; 181, s. 35-42
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Tidskriftsartikel (refereegranskat)abstract
- Aims: Familial hypercholesterolemia (FH) is a common genetic disorder causing accelerated atherosclerosis and premature cardiovascular disease. The aim of this study was to examine the prevalence and prognostic significance of possible FH in patients with myocardial infarction (MI).Methods and results: By individual-level linkage of data from the Eastern Danish Heart Registry and national administrative registries, a study population of patients referred for coronary angiography due to MI was selected. The study population was divided into "unlikely FH" and "possible FH" based on the Dutch Lipid Clinic Network criteria, which included a plasma low-density lipoprotein cholesterol (LDL-C) and age for onset of cardiac disease. A score of >= 3 points was used as the cutpoint between the 2 groups. Among the study population of 13,174 MI patients, 1,281 (9.7%) had possible FH. These patients were younger (59.1 vs 65.7 years, P <= .0001), had similar levels of comorbidities, and were treated more aggressively with cholesterol-lowering drugs compared with patients with unlikely FH. During a median of 3.3 years of follow-up, the unadjusted and adjusted event rates of recurrent MI were higher in patients with possible FH compared with unlikely FH (16% vs 11%, adjusted hazard ratio 1.28, 95% CI 1.09-1.51, P = .003.). Differences in adjusted all-cause mortality were not statistically significant (17% vs 23%, adjusted hazard ratio 0.89 [0.74-1.04], P = .1).Conclusion: We found that MI patients with possible FH have higher risk of recurrent MI but similar risk of mortality compared with unlikely FH patients. Further studies on secondary prevention are warranted.
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