| 1. |
- Pattaro, Cristian, et al.
(författare)
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Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function
- 2016
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways.
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| 2. |
- Folkersen, Lasse, et al.
(författare)
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Genomic and drug target evaluation of 90 cardiovascular proteins in 30,931 individuals.
- 2020
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Ingår i: Nature metabolism. - : Springer Science and Business Media LLC. - 2522-5812. ; 2:10, s. 1135-1148
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Tidskriftsartikel (refereegranskat)abstract
- Circulating proteins are vital in human health and disease and are frequently used as biomarkers for clinical decision-making or as targets for pharmacological intervention. Here, we map and replicate protein quantitative trait loci (pQTL) for 90 cardiovascular proteins in over 30,000 individuals, resulting in 451 pQTLs for 85 proteins. For each protein, we further perform pathway mapping to obtain trans-pQTL gene and regulatory designations. We substantiate these regulatory findings with orthogonal evidence for trans-pQTLs using mouse knockdown experiments (ABCA1 and TRIB1) and clinical trial results (chemokine receptors CCR2 and CCR5), with consistent regulation. Finally, we evaluate known drug targets, and suggest new target candidates or repositioning opportunities using Mendelian randomization. This identifies 11 proteins with causal evidence of involvement in human disease that have not previously been targeted, including EGF, IL-16, PAPPA, SPON1, F3, ADM, CASP-8, CHI3L1, CXCL16, GDF15 and MMP-12. Taken together, these findings demonstrate the utility of large-scale mapping of the genetics of the proteome and provide a resource for future precision studies of circulating proteins in human health.
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| 3. |
- Gilljam, Thomas, et al.
(författare)
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Heart transplantation in arrhythmogenic right ventricular cardiomyopathy - Experience from the Nordic ARVC Registry
- 2018
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Ingår i: International Journal of Cardiology. - : Elsevier BV. - 0167-5273 .- 1874-1754. ; 250, s. 201-206
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Tidskriftsartikel (refereegranskat)abstract
- Objective: There is a paucity of data on heart transplantation (HTx) in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC), and specific recommendations on indications for listing ARVC patients for HTx are lacking. In order to delineate features pertinent to HTx assessment, we explored the pre-HTx characteristics and clinical history in a cohort of ARVC patients who received heart transplants. Methods: Data from 31 ARVC/HTx patients enrolled in the Nordic ARVC Registry, transplanted between 1988 and 2014 at a median age of 46. years (14-65), were compared with data from 152 non-transplanted probands with Definite ARVC according to 2010 Task Force Criteria from the same registry. Results: The HTx patients were younger at presentation, median 31 vs. 38. years (p = 0.001). There was no difference in arrhythmia-related events. The indication for HTx was heart failure in 28 patients (90%) and ventricular arrhythmias in 3 patients (10%). During median follow-up of 4.9. years (0.04-28), there was one early death and two late deaths. Survival was 91% at 5. years after HTx. Age at first symptoms under 35. years independently predicted HTx in our cohort (OR = 7.59, 95% CI 2.69-21.39, p <. 0.001). Conclusion: HTx in patients with ARVC is performed predominantly due to heart failure. This suggests that current 2016 International Society for Heart and Lung Transplantation heart transplant listing recommendations for other cardiomyopathies could be applicable in many cases when taking into account the haemodynamic consequences of right ventricular failure in conjunction with ventricular arrhythmia.
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| 4. |
- Irving-Pease, Evan K., et al.
(författare)
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The selection landscape and genetic legacy of ancient Eurasians
- 2024
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Ingår i: Nature. - 0028-0836 .- 1476-4687. ; 625, s. 312-320
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Tidskriftsartikel (refereegranskat)abstract
- The Holocene (beginning around 12,000 years ago) encompassed some of the most significant changes in human evolution, with far-reaching consequences for the dietary, physical and mental health of present-day populations. Using a dataset of more than 1,600 imputed ancient genomes 1, we modelled the selection landscape during the transition from hunting and gathering, to farming and pastoralism across West Eurasia. We identify key selection signals related to metabolism, including that selection at the FADS cluster began earlier than previously reported and that selection near the LCT locus predates the emergence of the lactase persistence allele by thousands of years. We also find strong selection in the HLA region, possibly due to increased exposure to pathogens during the Bronze Age. Using ancient individuals to infer local ancestry tracts in over 400,000 samples from the UK Biobank, we identify widespread differences in the distribution of Mesolithic, Neolithic and Bronze Age ancestries across Eurasia. By calculating ancestry-specific polygenic risk scores, we show that height differences between Northern and Southern Europe are associated with differential Steppe ancestry, rather than selection, and that risk alleles for mood-related phenotypes are enriched for Neolithic farmer ancestry, whereas risk alleles for diabetes and Alzheimer’s disease are enriched for Western hunter-gatherer ancestry. Our results indicate that ancient selection and migration were large contributors to the distribution of phenotypic diversity in present-day Europeans.
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| 5. |
- Arvidsson, Anna K., 1971-, et al.
(författare)
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Åkkvalitet på vinterväg
- 2014
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Denna VTI-studie konstaterar att det går att mäta ojämnheter på vinterväg på samma sätt som på barmarksväg. Både ojämnheter och buller vid låga frekvenser ökar vid visst vinterväglag och är kopplade till hastighet. De mätningar som utförts inom projektets ramar visar att det går utmärkt att utföra mätningar på en snöklädd yta. Med vinterväglag menas här en snöklädd väg cirka ett dygn efter ett kraftigt snöfall. Baserat på de vägar som mättes visar studien att ojämnheter i våglängdsintervallet 0,05 till 1 meter påverkas allra mest av vinterväglaget. Ojämnheterna ökar cirka 5 gånger i medeltal för hela testslingan från barmarks- till vinterförhållanden. Det går även att se att ytans struktur, som beskrivs av de kortaste våglängderna som undersöktes, <10 mm, blir slätare på den snöklädda ytan vilket var en av hypoteserna och som indikerar att mätningen är pålitlig. Kopplingen mellan buller och ojämnheter är relaterade till hastighet. Den största ljudskillnaden mellan vinter- och sommarväg var vid låga frekvenser. Det uppfattade ljudet i bilen var då mellan 3 och 6 decibel högre för körningen på vinterväg. I de mer högfrekventa områdena var skillnaden i ljudnivå tvärtom, lägre för vintervägen än för sommarvägen och en trolig orsak till detta kan vara att ljudet absorberas av snön.
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| 6. |
- Ellinor, Patrick T., et al.
(författare)
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Meta-analysis identifies six new susceptibility loci for atrial fibrillation
- 2012
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 44:6, s. 88-670
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Tidskriftsartikel (refereegranskat)abstract
- Atrial fibrillation is a highly prevalent arrhythmia and a major risk factor for stroke, heart failure and death(1). We conducted a genome-wide association study (GWAS) in individuals of European ancestry, including 6,707 with and 52,426 without atrial fibrillation. Six new atrial fibrillation susceptibility loci were identified and replicated in an additional sample of individuals of European ancestry, including 5,381 subjects with and 10,030 subjects without atrial fibrillation (P < 5 x 10(-8)). Four of the loci identified in Europeans were further replicated in silico in a GWAS of Japanese individuals, including 843 individuals with and 3,350 individuals without atrial fibrillation. The identified loci implicate candidate genes that encode transcription factors related to cardiopulmonary development, cardiac-expressed ion channels and cell signaling molecules.
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| 7. |
- Halldén, Sara, et al.
(författare)
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Smoking and obesity associated BDNF gene variance predicts total and cardiovascular mortality in smokers
- 2013
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Ingår i: Heart. - : BMJ. - 1355-6037 .- 1468-201X. ; 99:13, s. 949-953
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Tidskriftsartikel (refereegranskat)abstract
- Objective The brain derived neurotrophic factor (BDNF) locus has been implicated in psychiatric and substance related disorders. Recent genome-wide association studies (GWAS) have shown strong associations between single nucleotide polymorphisms in BDNF, smoking behaviour and high body mass index (BMI). Our aim was to test whether genetic BDNF variation alters the risk of smoking related morbidity and mortality. Design Cox proportional hazards models were used to relate the BDNF rs4923461(A/G) polymorphisms to all-cause, cancer and cardiovascular mortality and cardiovascular disease (CVD) incidence adjusted for age, sex, BMI, and smoking quantity. Setting The Malmo Diet and Cancer Study (MDCS), a population based prospective cohort study (n=30 447). Patients We obtained complete data on 25 071 subjects, of whom 6507 were current smokers and 18 564 were non-smokers who underwent a baseline examination from 1991-1996. Main outcome measures During a mean follow-up time of 12 years, 1049 deaths (346 cardiovascular deaths and 492 cancer deaths) and 802 incident CVD events occurred among current smokers. Results The major allele (A) of rs4923461 was significantly associated with ever having smoked (p=0.03) and high BMI (p=0.001). The A-allele was associated with risk of all-cause (HR=1.12, 95% CI 1.00 to 1.25; p<0.05) and CVD (HR=1.23, 95% CI 1.01 to 1.49; p=0.04) mortality. There was no significant association between the rs4923461 and cancer mortality or CVD incidence. Conclusions Our data suggest that smoking-and obesity-associated variation of the BDNF gene affects the risk of death, especially due to cardiovascular causes, in smokers. Determination of the BDNF genotype in smokers may guide the need for smoking cessation interventions.
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| 8. |
- Lundberg, Thomas, 1965-, et al.
(författare)
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Makrotexturens möjlighet att identifiera låg friktion : tillståndsmätning av vägytan
- 2015
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Trafikverket vill kunna beskriva friktionen för hela det statliga vägnätet. En rikstäckande friktionsmätning är praktiskt svår att hantera och mycket kostsam medan vi redan idag mäter vägytans makrotextur. I projektet testar vi om makrotexturen (MPD, Mean Profile Depth) kan användas för att beskriva friktionstillståndet på vägnätet. Vi har inte kunnat visa på detta samband men vi redovisar andra intressanta iakttagelser som ger en pusselbit till hur Trafikverket kan och bör hantera friktionsfrågan. Vi ser bland annat att risken för låg friktion är större på vägavsnitt som har låga MPD-värden speciellt på lappade ytbehandlade vägar med blödningar. Vidare beskriver vi vilka friktionsrisker det finns med olika beläggningar och hur dessa kan hanteras.
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| 9. |
- Niemelä, Matti, et al.
(författare)
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Randomized Comparison of Final Kissing Balloon Dilatation Versus No Final Kissing Balloon Dilatation in Patients With Coronary Bifurcation Lesions Treated With Main Vessel Stenting : The nordic-baltic bifurcation study III
- 2011
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Ingår i: Circulation. - 0009-7322 .- 1524-4539. ; 123:1, s. 79-86
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Tidskriftsartikel (refereegranskat)abstract
- Background-It is unknown whether the preferred 1-stent bifurcation stenting approach with stenting of the main vessel (MV) and optional side branch stenting using drug-eluting stents should be finalized by a kissing balloon dilatation (FKBD). Therefore, we compared strategies of MV stenting with and without FKBD. Methods and Results-We randomized 477 patients with a bifurcation lesion to FKBD (n=238) or no FKBD (n=239) after MV stenting. The primary end point was major adverse cardiac events: cardiac death, non-procedure-related index lesion myocardial infarction, target lesion revascularization, or stent thrombosis within 6 months. The 6-month major adverse cardiac event rates were 2.1% and 2.5% (P=1.00) in the FKBD and no-FKBD groups, respectively. Procedure and fluoroscopy times were longer and more contrast media was needed in the FKBD group than in the no-FKBD group. Three hundred twenty-six patients had a quantitative coronary assessment. At 8 months, the rate of binary (re) stenosis in the entire bifurcation lesion (MV and side branch) was 11.0% versus 17.3% (P=0.11), in the MV was 3.1% versus 2.5% (P=0.68), and in the side branch was 7.9% versus 15.4% (P=0.039) in the FKBD versus no-FKBD groups, respectively. In patients with true bifurcation lesions, the side branch restenosis rate was 7.6% versus 20.0% (P=0.024) in the FKBD and no-FKBD groups, respectively. Conclusions-MV stenting strategies with and without FKBD were associated with similar clinical outcomes. FKBD reduced angiographic side branch (re) stenosis, especially in patients with true bifurcation lesions. The simple no-FKBD procedures resulted in reduced use of contrast media and shorter procedure and fluoroscopy times. Long-term data on stent thrombosis are needed. Clinical Trial Registration-URL: http://clinicaltrials.gov. Unique identifier: NCT00914199. (Circulation. 2011;123:79-86.)
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| 10. |
- Padmanabhan, Sandosh, et al.
(författare)
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Genome-Wide Association Study of Blood Pressure Extremes Identifies Variant near UMOD Associated with Hypertension
- 2010
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Ingår i: PLoS Genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 6:10
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Tidskriftsartikel (refereegranskat)abstract
- Hypertension is a heritable and major contributor to the global burden of disease. The sum of rare and common genetic variants robustly identified so far explain only 1%-2% of the population variation in BP and hypertension. This suggests the existence of more undiscovered common variants. We conducted a genome-wide association study in 1,621 hypertensive cases and 1,699 controls and follow-up validation analyses in 19,845 cases and 16,541 controls using an extreme case-control design. We identified a locus on chromosome 16 in the 59 region of Uromodulin (UMOD; rs13333226, combined P value of 3.6x10(-11)). The minor G allele is associated with a lower risk of hypertension (OR [95% CI]: 0.87 [0.84-0.91]), reduced urinary uromodulin excretion, better renal function; and each copy of the G allele is associated with a 7.7% reduction in risk of CVD events after adjusting for age, sex, BMI, and smoking status (H.R. = 0.923, 95% CI 0.860-0.991; p = 0.027). In a subset of 13,446 individuals with estimated glomerular filtration rate (eGFR) measurements, we show that rs13333226 is independently associated with hypertension (unadjusted for eGFR: 0.89 [0.83-0.96], p = 0.004; after eGFR adjustment: 0.89 [0.83-0.96], p = 0.003). In clinical functional studies, we also consistently show the minor G allele is associated with lower urinary uromodulin excretion. The exclusive expression of uromodulin in the thick portion of the ascending limb of Henle suggests a putative role of this variant in hypertension through an effect on sodium homeostasis. The newly discovered UMOD locus for hypertension has the potential to give new insights into the role of uromodulin in BP regulation and to identify novel drugable targets for reducing cardiovascular risk.
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