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Wallentin, Lars
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Publications (10 of 587) Show all publications
Hijazi, Z., Oldgren, J., Lindbäck, J., Alexander, J. H., Connolly, S. J., Eikelboom, J. W., . . . Wallentin, L. (2018). A biomarker-based risk score to predict death in patients with atrial fibrillation: the ABC (age, biomarkers, clinical history) death risk score. European Heart Journal, 39(6), 477-485
Open this publication in new window or tab >>A biomarker-based risk score to predict death in patients with atrial fibrillation: the ABC (age, biomarkers, clinical history) death risk score
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2018 (English)In: European Heart Journal, ISSN 0195-668X, E-ISSN 1522-9645, Vol. 39, no 6, p. 477-485Article in journal (Refereed) Published
Abstract [en]

Aims: In atrial fibrillation (AF), mortality remains high despite effective anticoagulation. A model predicting the risk of death in these patients is currently not available. We developed and validated a risk score for death in anticoagulated patients with AF including both clinical information and biomarkers.

Methods and results: The new risk score was developed and internally validated in 14 611 patients with AF randomized to apixaban vs. warfarin for a median of 1.9 years. External validation was performed in 8548 patients with AF randomized to dabigatran vs. warfarin for 2.0 years. Biomarker samples were obtained at study entry. Variables significantly contributing to the prediction of all-cause mortality were assessed by Cox-regression. Each variable obtained a weight proportional to the model coefficients. There were 1047 all-cause deaths in the derivation and 594 in the validation cohort. The most important predictors of death were N-terminal pro B-type natriuretic peptide, troponin-T, growth differentiation factor-15, age, and heart failure, and these were included in the ABC (Age, Biomarkers, Clinical history)-death risk score. The score was well-calibrated and yielded higher c-indices than a model based on all clinical variables in both the derivation (0.74 vs. 0.68) and validation cohorts (0.74 vs. 0.67). The reduction in mortality with apixaban was most pronounced in patients with a high ABC-death score.

Conclusion: A new biomarker-based score for predicting risk of death in anticoagulated AF patients was developed, internally and externally validated, and well-calibrated in two large cohorts. The ABC-death risk score performed well and may contribute to overall risk assessment in AF.

Place, publisher, year, edition, pages
OXFORD UNIV PRESS, 2018
Keyword
Atrial fibrillation, Biomarkers, Mortality, NOAC, Oral anticoagulation, Risk score
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:uu:diva-348121 (URN)10.1093/eurheartj/ehx584 (DOI)000424876100015 ()29069359 (PubMedID)
Funder
Swedish Foundation for Strategic Research , RB13-0197Swedish Heart Lung Foundation, 20090183
Available from: 2018-04-11 Created: 2018-04-11 Last updated: 2018-04-11Bibliographically approved
Batra, G., Friberg, L., Erlinge, D., James, S. K., Jernberg, T., Svennblad, B., . . . Oldgren, J. (2018). Antithrombotic therapy after myocardial infarction in patients with atrial fibrillation undergoing percutaneous coronary intervention. European Heart Journal - Cardiovascular Pharmacotherapy, 4(1), 36-45
Open this publication in new window or tab >>Antithrombotic therapy after myocardial infarction in patients with atrial fibrillation undergoing percutaneous coronary intervention
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2018 (English)In: European Heart Journal - Cardiovascular Pharmacotherapy, ISSN 2055-6837, E-ISSN 2055-6845, Vol. 4, no 1, p. 36-45Article in journal (Refereed) Published
Abstract [en]

Aims: Optimal antithrombotic therapy after percutaneous coronary intervention (PCI) in patients with myocardial infarction (MI) and atrial fibrillation is uncertain. In this study, we compared antithrombotic regimes with regard to a composite cardiovascular outcome of all-cause mortality, MI or ischaemic stroke, and major bleeds.

Methods and results: Patients between October 2005 and December 2012 were identified in Swedish registries, n = 7116. Landmark 0-90 and 91-365 days of outcome were evaluated with Cox-regressions, with dual antiplatelet therapy as reference. At discharge, 16.2% received triple therapy (aspirin, clopidogrel, and warfarin), 1.9% aspirin plus warfarin, 7.3% clopidogrel plus warfarin, and 60.8% dual antiplatelets. For cardiovascular outcome, adjusted hazard ratio with 95% confidence interval (HR) for triple therapy was 0.86 (0.70-1.07) for 0-90 days and 0.78 (0.58-1.05) for 91-365 days. A HR of 2.16 (1.48-3.13) and 1.61 (0.98-2.66) during 0-90 and 91-365 days, respectively, was observed for major bleeds. For aspirin plus warfarin, HR 0.82 (0.54-1.26) and 0.62 (0.48-0.79) was observed for cardiovascular outcome and 1.30 (0.60-2.85) and 1.01 (0.63-1.62) for major bleeds during 0-90 and 91-365 days, respectively. For clopidogrel plus warfarin, HR of 0.90 (0.68-1.19) and 0.68 (0.49-0.95) was observed for cardiovascular outcome and 1.28 (0.71-2.32) and 1.08 (0.57-2.04) for major bleeds during 0-90 and 91-365 days, respectively.

Conclusion: Compared to dual antiplatelets, aspirin or clopidogrel plus warfarin therapy was associated with similar 0-90 days and lower 91-365 days of risk of the cardiovascular outcome, without higher risk of major bleeds. Triple therapy was associated with non-significant lower risk of cardiovascular outcome and higher risk of major bleeds.

National Category
Clinical Medicine
Identifiers
urn:nbn:se:uu:diva-320310 (URN)10.1093/ehjcvp/pvx033 (DOI)000419693700010 ()29126156 (PubMedID)
Funder
Swedish Foundation for Strategic Research , KF10-0024
Available from: 2017-04-19 Created: 2017-04-19 Last updated: 2018-02-20Bibliographically approved
Sherwood, M. W., Lopes, R. D., Sun, J. L., Liaw, D., Harrington, R. A., Wallentin, L., . . . Alexander, J. H. (2018). Apixaban following acute coronary syndromes in patients with prior stroke: Insights from the APPRAISE-2 trial. American Heart Journal, 197, 1-8
Open this publication in new window or tab >>Apixaban following acute coronary syndromes in patients with prior stroke: Insights from the APPRAISE-2 trial
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2018 (English)In: American Heart Journal, ISSN 0002-8703, E-ISSN 1097-6744, Vol. 197, p. 1-8Article in journal (Refereed) Published
Abstract [en]

BACKGROUND AND PURPOSE: Patients with prior stroke are at greater risk for recurrent cardiovascular events post-acute coronary syndromes (ACS) and may have a different risk/benefit profile with antithrombotic therapy than patients without prior stroke.

METHODS: We studied 7391 patients with ACS from APPRAISE-2, stratified by the presence or absence of prior stroke. Baseline characteristics and outcomes of cardiovascular death, myocardial infarction (MI), or stroke were compared between groups. Interactions between prior stroke, treatment assignment (apixaban vs placebo), and outcomes were tested before and after multivariable adjustment with Cox proportional hazards models.

RESULTS: A total of 902 patients (12%) had prior stroke. Those with prior stroke were older (69 vs 67 years), had more hypertension (91% vs 77%), peripheral vascular disease (22% vs18%), and impaired renal function (38% vs 30%) but less diabetes (44% vs 48%) than those without prior stroke. Patients with prior stroke vs no prior stroke had higher unadjusted rates of cardiovascular death (4.8% vs 4.0%), MI (11.2% vs 7.1%), and ischemic stroke (3.2% vs 0.9%). Patients with prior stroke assigned to apixaban had similar rates of the composite of cardiovascular death, MI, or stroke compared with those assigned to placebo (HR 1.39; 95% CI 0.92-2.08). Patients without prior stroke assigned to apixaban had similar rates of cardiovascular death, MI, or ischemic stroke compared with those assigned to placebo (HR 0.87; 95% CI 0.73-1.04; P-interaction=.041). Median follow-up was 240 days.

CONCLUSIONS: Patients with prior stroke are at higher risk for recurrent cardiovascular events post-ACS and had a differential risk/benefit profile with oral anticoagulation.

National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:uu:diva-342516 (URN)10.1016/j.ahj.2017.09.020 (DOI)29447769 (PubMedID)
Available from: 2018-02-21 Created: 2018-02-21 Last updated: 2018-03-08Bibliographically approved
Guimarães, P. O., Leonardi, S., Huang, Z., Wallentin, L., de Werf, F. V., Aylward, P. E., . . . Tricoci, P. (2018). Clinical features and outcomes of patients with type 2 myocardial infarction: Insights from the Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRACER) trial. American Heart Journal, 196, 28-35
Open this publication in new window or tab >>Clinical features and outcomes of patients with type 2 myocardial infarction: Insights from the Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRACER) trial
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2018 (English)In: American Heart Journal, ISSN 0002-8703, E-ISSN 1097-6744, Vol. 196, p. 28-35Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Type 2 myocardial infarction (MI) is characterized by an imbalance between myocardial blood supply and demand, leading to myocardial ischemia without coronary plaque rupture, but its diagnosis is challenging.

METHODS: In the TRACER trial, patients with non-ST-segment elevation acute coronary syndromes were included. We aimed to describe provoking factors, cardiac biomarker profiles, treatment patterns, and clinical outcomes of patients with type 2 MIs. MI events during trial follow-up were adjudicated by an independent clinical events classification committee (CEC) and were classified according to the Third Universal Definition of MI. Using available source documents retrieved as part of the CEC process, we performed a retrospective chart abstraction to collect details on the type 2 MIs. Cox regression models were used to explore the association between MI type (type 1 or type 2) and cardiovascular death.

RESULTS: Overall, 10.3% (n=1327) of TRACER participants had a total of 1579 adjudicated MIs during a median follow-up of 502 days (25th and 75th percentiles [IQR] 349-667). Of all MIs, 5.2% (n=82) were CEC-adjudicated type 2 MIs, occurring in 76 patients. The incidence of type 2 MI was higher in the first month following randomization, after which the distribution became more scattered. The most frequent potential provoking factors for type 2 MIs were tachyarrhythmias (38.2%), anemia/bleeding (21.1%), hypotension/shock (14.5%), and hypertensive emergencies (11.8%). Overall, 36.3% had a troponin increase >10× the upper limit of normal. Coronary angiography was performed in 22.4% (n=17) of patients during hospitalizations due to type 2 MIs. The hazard of cardiovascular death was numerically higher following type 2 MI (vs. no MI, adj. HR 11.82, 95% CI 5.71-24.46; P<.0001) than that of type 1 MI (vs. no MI, adj. HR 8.90, 95% CI 6.93-11.43; P<.0001).

CONCLUSIONS: Type 2 MIs were more prevalent in the first month after ACS, were characterized by the presence of triggers and infrequent use of an invasive strategy, and were associated with a high risk of death. Further efforts are needed to better define the role and implications of type 2 MI in both clinical practice and research.

National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:uu:diva-342889 (URN)10.1016/j.ahj.2017.10.007 (DOI)000424518000005 ()29421012 (PubMedID)
Available from: 2018-02-23 Created: 2018-02-23 Last updated: 2018-03-08Bibliographically approved
Rao, M. P., Vinereanu, D., Wojdyla, D. M., Alexander, J. H., Atar, D., Hylek, E. M., . . . Granger, C. B. (2018). Clinical Outcomes and History of Fall in Patients with Atrial Fibrillation Treated with Oral Anticoagulation: Insights From the ARISTOTLE Trial. American Journal of Medicine, 131(3), 269-275.e2
Open this publication in new window or tab >>Clinical Outcomes and History of Fall in Patients with Atrial Fibrillation Treated with Oral Anticoagulation: Insights From the ARISTOTLE Trial
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2018 (English)In: American Journal of Medicine, ISSN 0002-9343, E-ISSN 1555-7162, Vol. 131, no 3, p. 269-275.e2Article in journal (Refereed) Published
Abstract [en]

PURPOSE: We assessed outcomes among anticoagulated patients with atrial fibrillation and a history of falling, and whether the benefits of apixaban vs warfarin are consistent in this population.

METHODS: Of the 18,201 patients in the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) study, 16,491 had information about history of falling-753 with history of falling and 15,738 without history of falling. The primary efficacy outcome was stroke or systemic embolism; the primary safety outcome was major bleeding.

RESULTS: -VASc (Congestive heart failure, Hypertension, Age ≥75 years, Diabetes mellitus, prior Stroke or TIA or thromboembolism, Vascular disease, Age 65-74 years, Sex category female) and HAS-BLED (Hypertension, Abnormal renal and liver function, Stroke, Bleeding, Labile international normalized ratio, Elderly, Drugs or alcohol) scores. Patients with a history of falling had higher rates of major bleeding (adjusted hazard ratio [HR] 1.39; 95% confidence interval [CI], 1.05-1.84; P = .020), including intracranial bleeding (adjusted HR 1.87; 95% CI, 1.02-3.43; P = .044) and death (adjusted HR 1.70; 95% CI, 1.36-2.14; P < .0001), but similar rates of stroke or systemic embolism and hemorrhagic stroke. There was no evidence of a differential effect of apixaban compared with warfarin on any outcome, regardless of history of falling. Among those with a history of falling, subdural bleeding occurred in 5 of 367 patients treated with warfarin and 0 of 386 treated with apixaban.

CONCLUSIONS: Patients with atrial fibrillation and a history of falling receiving anticoagulation have a higher risk of major bleeding, including intracranial, and death. The efficacy and safety of apixaban compared with warfarin were consistent, irrespective of history of falling.

Keyword
Anticoagulation, Apixaban, Atrial fibrillation, Bleeding, History of falls, Stroke, Warfarin
National Category
General Practice Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:uu:diva-342519 (URN)10.1016/j.amjmed.2017.10.036 (DOI)000425092300038 ()29122636 (PubMedID)
Available from: 2018-02-21 Created: 2018-02-21 Last updated: 2018-03-08Bibliographically approved
Proietti, M., Hijazi, Z., Andersson, U., Connolly, S. J., Eikelboom, J. W., Ezekowitz, M. D., . . . Wallentin, L. (2018). Comparison of bleeding risk scores in patients with atrial fibrillation: insights from the RE-LY trial. Journal of Internal Medicine, 283(3), 282-292
Open this publication in new window or tab >>Comparison of bleeding risk scores in patients with atrial fibrillation: insights from the RE-LY trial
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2018 (English)In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 283, no 3, p. 282-292Article in journal (Refereed) Published
Abstract [en]

Background: Oral anticoagulation is the mainstay of stroke prevention in atrial fibrillation (AF), but must be balanced against the associated bleeding risk. Several risk scores have been proposed for prediction of bleeding events in patients with AF.

Objectives: To compare the performance of contemporary clinical bleeding risk scores in 18113 patients with AF randomized to dabigatran 110 mg, 150 mg or warfarin in the RE-LY trial.

Methods: HAS-BLED, ORBIT, ATRIA and HEMORR(2)HAGES bleeding risk scores were calculated based on clinical information at baseline. All major bleeding events were centrally adjudicated.

Results: There were 1182 (6.5%) major bleeding events during a median follow-up of 2.0 years. For all the four schemes, high-risk subgroups had higher risk of major bleeding (all P<0.001). The ORBIT score showed the best discrimination with c-indices of 0.66, 0.66 and 0.62, respectively, for major, life-threatening and intracranial bleeding, which were significantly better than for the HAS-BLED score (difference in c-indices: 0.050, 0.053 and 0.048, respectively, all P<0.05). The ORBIT score also showed the best calibration compared with previous data. Significant treatment interactions between the bleeding scores and the risk of major bleeding with dabigatran 150 mg BD versus warfarin were found for the ORBIT (P=0.0019), ATRIA (P<0.001) and HEMORR(2)HAGES (P<0.001) scores. HAS-BLED score showed a nonsignificant trend for interaction (P=0.0607).

Conclusions: Amongst the current clinical bleeding risk scores, the ORBIT score demonstrated the best discrimination and calibration. All the scores demonstrated, to a variable extent, an interaction with bleeding risk associated with dabigatran or warfarin.

Place, publisher, year, edition, pages
WILEY, 2018
Keyword
anticoagulation treatment, atrial fibrillation, bleeding risk scores, dabigatran, major bleeding
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-347538 (URN)10.1111/joim.12702 (DOI)000425521000005 ()29044861 (PubMedID)
Available from: 2018-04-04 Created: 2018-04-04 Last updated: 2018-04-04Bibliographically approved
Verdecchia, P., Reboldi, G., Angeli, F., Mazzotta, G., Lip, G. Y. H., Brueckmann, M., . . . Di Pasquale, G. (2018). Dabigatran vs. warfarin in relation to the presence of left ventricular hypertrophy in patients with atrial fibrillation-the Randomized Evaluation of Long-term anticoagulation therapY (RE-LY) study. Europace, 20(2), 253-262
Open this publication in new window or tab >>Dabigatran vs. warfarin in relation to the presence of left ventricular hypertrophy in patients with atrial fibrillation-the Randomized Evaluation of Long-term anticoagulation therapY (RE-LY) study
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2018 (English)In: Europace, ISSN 1099-5129, E-ISSN 1532-2092, Vol. 20, no 2, p. 253-262Article in journal (Refereed) Published
Abstract [en]

Aim: We tested the hypothesis that left ventricular hypertrophy (LVH) interferes with the antithrombotic effects of dabigatran and warfarin in patients with atrial fibrillation (AF).

Methods and results: This is a post-hoc analysis of the Randomized Evaluation of Long-term anticoagulation therapY (RE-LY) Study. We defined LVH by electrocardiography (ECG) and included patients with AF on the ECG tracing at entry. Hazard ratios (HR) for each dabigatran dose vs. warfarin were calculated in relation to LVH. LVH was present in 2353 (22.7%) out of 10 372 patients. In patients without LVH, the rates of primary outcome were 1.59%/ year with warfarin, 1.60% with dabigatran 110 mg (HR vs. warfarin 1.01, 95% confidence interval (CI) 0.75-1.36) and 1.08% with dabigatran 150 mg (HR vs. warfarin 0.68, 95% CI 0.49-0.95). In patients with LVH, the rates of primary outcome were 3.21%/ year with warfarin, 1.69% with dabigatran 110 mg (HR vs. warfarin 0.52, 95% CI 0.32-0.84) and 1.55% with 150 mg (HR vs. warfarin 0.48, 95% CI 0.29-0.78). The interaction between LVH status and dabigatran 110 mg vs. warfarin was significant for the primary outcome (P = 0.021) and stroke (P = 0.016). LVH was associated with a higher event rate with warfarin, not with dabigatran. In the warfarin group, the time in therapeutic range was significantly lower in the presence than in the absence of LVH.

Conclusions: LVH was associated with a lower antithrombotic efficacy of warfarin, but not of dabigatran, in patients with AF. Consequently, the relative benefit of the lower dose of dabigatran compared to warfarin was enhanced in patients with LVH. The higher dose of dabigatran was superior to warfarin regardless of LVH status.

Place, publisher, year, edition, pages
OXFORD UNIV PRESS, 2018
Keyword
Atrial fibrillation, Warfarin, Dabigatran, Stroke, Systemic embolism
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:uu:diva-348396 (URN)10.1093/europace/eux022 (DOI)000424924300008 ()28520924 (PubMedID)
Available from: 2018-04-16 Created: 2018-04-16 Last updated: 2018-04-16Bibliographically approved
Storey, R. F., Ardissino, D., Vignali, L., Cairns, R., Becker, R. C., Cannon, C. P., . . . Wallentin, L. (2018). Ischaemic Events and Stent Thrombosis following Planned Discontinuation of Study Treatment with Ticagrelor or Clopidogrel in the PLATO Study. Thrombosis and Haemostasis, 118(2), 427-429
Open this publication in new window or tab >>Ischaemic Events and Stent Thrombosis following Planned Discontinuation of Study Treatment with Ticagrelor or Clopidogrel in the PLATO Study
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2018 (English)In: Thrombosis and Haemostasis, ISSN 0340-6245, Vol. 118, no 2, p. 427-429Article in journal (Refereed) Published
Place, publisher, year, edition, pages
SCHATTAUER GMBH-VERLAG MEDIZIN NATURWISSENSCHAFTEN, 2018
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-346215 (URN)10.1160/TH17-05-0355 (DOI)000423998900018 ()29443375 (PubMedID)
Funder
AstraZeneca
Available from: 2018-03-19 Created: 2018-03-19 Last updated: 2018-03-19Bibliographically approved
Kopin, D., Jones, W. S., Sherwood, M. W., Wojdyla, D. M., Wallentin, L., Lewis, B. S., . . . Alexander, J. H. (2018). Percutaneous coronary intervention and antiplatelet therapy in patients with atrial fibrillation receiving apixaban or warfarin: Insights from the ARISTOTLE trial. American Heart Journal, 197, 133-141, Article ID S0002-8703(17)30360-5.
Open this publication in new window or tab >>Percutaneous coronary intervention and antiplatelet therapy in patients with atrial fibrillation receiving apixaban or warfarin: Insights from the ARISTOTLE trial
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2018 (English)In: American Heart Journal, ISSN 0002-8703, E-ISSN 1097-6744, Vol. 197, p. 133-141, article id S0002-8703(17)30360-5Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: We assessed antiplatelet therapy use and outcomes in patients undergoing percutaneous coronary intervention (PCI) during the ARISTOTLE trial.

METHODS: Patients were categorized based on the occurrence of PCI during follow-up (median 1.8 years); PCI details and outcomes post-PCI are reported. Of the 18,201 trial participants, 316 (1.7%) underwent PCI (152 in apixaban group, 164 in warfarin group).

RESULTS: inhibitor; 32% received antiplatelet agents without OAC. Post-PCI, patients assigned to apixaban versus warfarin had numerically similar rates of major bleeding (5.93 vs 6.73 events/100 patient-years; P = .95) and stroke (2.74 vs 1.84 events/100 patient-years; P = .62).

CONCLUSIONS: PCI occurred infrequently during follow-up. Most patients on study drug at the time of PCI remained on study drug in the peri-PCI period; 19% continued the study drug without interruption. Antiplatelet therapy use post-PCI was variable, although most patients received DAPT. Additional data are needed to guide the use of antithrombotics in patients undergoing PCI.

Place, publisher, year, edition, pages
New York: , 2018
National Category
Medical and Health Sciences Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:uu:diva-342515 (URN)10.1016/j.ahj.2017.11.005 (DOI)29447773 (PubMedID)
Available from: 2018-02-21 Created: 2018-02-21 Last updated: 2018-03-15Bibliographically approved
Turcot, V., Lu, Y., Highland, H. M., Schurmann, C., Justice, A. E., Fine, R. S., . . . Loos, R. J. F. (2018). Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity. Nature Genetics, 50(1), 26-+
Open this publication in new window or tab >>Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity
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2018 (English)In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 50, no 1, p. 26-+Article in journal (Refereed) Published
Abstract [en]

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 ~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 ~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.

National Category
Genetics
Identifiers
urn:nbn:se:uu:diva-343882 (URN)10.1038/s41588-017-0011-x (DOI)000423157400007 ()29273807 (PubMedID)
Funder
NIH (National Institute of Health), R01DK089256 R01DK101855 K99HL130580 R01DK106621 HL094535 HL109946 R01DK075787 R01HD057194 U01HG007416 1R01HL09257R01HL128914; K24HL105780; R01DK110113; U01HG007417; R01DK107786; K23HL114724EU, European Research Council, SZ-245 50371-GLUCOSEGENES-FP7-IDEAS-ERC; 323195; 293574
Available from: 2018-03-16 Created: 2018-03-16 Last updated: 2018-03-16Bibliographically approved
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