SwePub - search: WFRF:(Helgadottir H.)

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1.	Aad, G., et al. (author) 2015 In: Journal of High Energy Physics. - 1029-8479 .- 1126-6708. ; :3 Journal article (peer-reviewed)
2.	Ramdas, S., et al. (author) A multi-layer functional genomic analysis to understand noncoding genetic variation in lipids 2022 In: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 109:8, s. 1366-1387 Journal article (peer-reviewed)abstract A major challenge of genome-wide association studies (GWASs) is to translate phenotypic associations into biological insights. Here, we integrate a large GWAS on blood lipids involving 1.6 million individuals from five ancestries with a wide array of functional genomic datasets to discover regulatory mechanisms underlying lipid associations. We first prioritize lipid-associated genes with expression quantitative trait locus (eQTL) colocalizations and then add chromatin interaction data to narrow the search for functional genes. Polygenic enrichment analysis across 697 annotations from a host of tissues and cell types confirms the central role of the liver in lipid levels and highlights the selective enrichment of adipose-specific chromatin marks in high-density lipoprotein cholesterol and triglycerides. Overlapping transcription factor (TF) binding sites with lipid-associated loci identifies TFs relevant in lipid biology. In addition, we present an integrative framework to prioritize causal variants at GWAS loci, producing a comprehensive list of candidate causal genes and variants with multiple layers of functional evidence. We highlight two of the prioritized genes, CREBRF and RRBP1, which show convergent evidence across functional datasets supporting their roles in lipid biology.
3.	Graham, SE, et al. (author) Author Correction: The power of genetic diversity in genome-wide association studies of lipids 2023 In: Nature. - 1476-4687. ; 618:7965, s. E19-E20 Journal article (other academic/artistic)
4.	Graham, SE, et al. (author) The power of genetic diversity in genome-wide association studies of lipids 2021 In: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 600:7890, s. 675- Journal article (peer-reviewed)
5.	Lumbers, R. T., et al. (author) The genomics of heart failure: design and rationale of the HERMES consortium 2021 In: Esc Heart Failure. - : Wiley. - 2055-5822. ; 8:6, s. 5531-5541 Journal article (peer-reviewed)abstract Aims The HERMES (HEart failure Molecular Epidemiology for Therapeutic targets) consortium aims to identify the genomic and molecular basis of heart failure. Methods and results The consortium currently includes 51 studies from 11 countries, including 68 157 heart failure cases and 949 888 controls, with data on heart failure events and prognosis. All studies collected biological samples and performed genome-wide genotyping of common genetic variants. The enrolment of subjects into participating studies ranged from 1948 to the present day, and the median follow-up following heart failure diagnosis ranged from 2 to 116 months. Forty-nine of 51 individual studies enrolled participants of both sexes; in these studies, participants with heart failure were predominantly male (34-90%). The mean age at diagnosis or ascertainment across all studies ranged from 54 to 84 years. Based on the aggregate sample, we estimated 80% power to genetic variant associations with risk of heart failure with an odds ratio of >1.10 for common variants (allele frequency > 0.05) and >1.20 for low-frequency variants (allele frequency 0.01-0.05) at P < 5 x 10(-8) under an additive genetic model. Conclusions HERMES is a global collaboration aiming to (i) identify the genetic determinants of heart failure; (ii) generate insights into the causal pathways leading to heart failure and enable genetic approaches to target prioritization; and (iii) develop genomic tools for disease stratification and risk prediction.
6.	Kanoni, Stavroula, et al. (author) Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis. 2022 In: Genome biology. - : Springer Science and Business Media LLC. - 1474-760X .- 1465-6906 .- 1474-7596. ; 23:1 Journal article (peer-reviewed)abstract Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery.To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N=1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3-5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism.Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.
7.	Thorgeirsson, T. E., et al. (author) A rare missense mutation in CHRNA4 associates with smoking behavior and its consequences 2016 In: Molecular Psychiatry. - : Springer Science and Business Media LLC. - 1359-4184 .- 1476-5578. ; 21:5, s. 594-600 Journal article (peer-reviewed)abstract Using Icelandic whole-genome sequence data and an imputation approach we searched for rare sequence variants in CHRNA4 and tested them for association with nicotine dependence. We show that carriers of a rare missense variant (allele frequency = 0.24%) within CHRNA4, encoding an R336C substitution, have greater risk of nicotine addiction than non-carriers as assessed by the Fagerstrom Test for Nicotine Dependence (P = 1.2 x 10(-4)). The variant also confers risk of several serious smoking-related diseases previously shown to be associated with the D398N substitution in CHRNA5. We observed odds ratios (ORs) of 1.7-2.3 for lung cancer (LC; P = 4.0 x 10(-4)), chronic obstructive pulmonary disease (COPD; P = 9.3 x 10(-4)), peripheral artery disease (PAD; P = 0.090) and abdominal aortic aneurysms (AAAs; P = 0.12), and the variant associates strongly with the early-onset forms of LC (OR = 4.49, P = 2.2 x 10(-4)), COPD (OR = 3.22, P = 2.9 x 10(-4)), PAD (OR = 3.47, P = 9.2 x 10(-3)) and AAA (OR = 6.44, P = 6.3 x 10(-3)). Joint analysis of the four smoking-related diseases reveals significant association (P = 6.8 x 10(-5)), particularly for early-onset cases (P = 2.1 x 10(-7)). Our results are in agreement with functional studies showing that the human alpha 4 beta 2 isoform of the channel containing R336C has less sensitivity for its agonists than the wild-type form following nicotine incubation.
8.	Stacey, Simon N, et al. (author) A germline variant in the TP53 polyadenylation signal confers cancer susceptibility. 2011 In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 43:11, s. 1098-103 Journal article (peer-reviewed)abstract To identify new risk variants for cutaneous basal cell carcinoma, we performed a genome-wide association study of 16 million SNPs identified through whole-genome sequencing of 457 Icelanders. We imputed genotypes for 41,675 Illumina SNP chip-typed Icelanders and their relatives. In the discovery phase, the strongest signal came from rs78378222[C] (odds ratio (OR) = 2.36, P = 5.2 × 10(-17)), which has a frequency of 0.0192 in the Icelandic population. We then confirmed this association in non-Icelandic samples (OR = 1.75, P = 0.0060; overall OR = 2.16, P = 2.2 × 10(-20)). rs78378222 is in the 3' untranslated region of TP53 and changes the AATAAA polyadenylation signal to AATACA, resulting in impaired 3'-end processing of TP53 mRNA. Investigation of other tumor types identified associations of this SNP with prostate cancer (OR = 1.44, P = 2.4 × 10(-6)), glioma (OR = 2.35, P = 1.0 × 10(-5)) and colorectal adenoma (OR = 1.39, P = 1.6 × 10(-4)). However, we observed no effect for breast cancer, a common Li-Fraumeni syndrome tumor (OR = 1.06, P = 0.57, 95% confidence interval 0.88-1.27).
9.	Gudbjartsson, Daniel F., et al. (author) Sequence variants affecting eosinophil numbers associate with asthma and myocardial infarction 2009 In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 41:3, s. 342-347 Journal article (peer-reviewed)abstract Eosinophils are pleiotropic multifunctional leukocytes involved in initiation and propagation of inflammatory responses and thus have important roles in the pathogenesis of inflammatory diseases. Here we describe a genome-wide association scan for sequence variants affecting eosinophil counts in blood of 9,392 Icelanders. The most significant SNPs were studied further in 12,118 Europeans and 5,212 East Asians. SNPs at 2q12 (rs1420101), 2q13 (rs12619285), 3q21 (rs4857855), 5q31 (rs4143832) and 12q24 (rs3184504) reached genome-wide significance (P = 5.3 x 10(-14), 5.4 x 10(-10), 8.6 x 10(-17), 1.2 x 10(-10) and 6.5 x 10(-19), respectively). A SNP at IL1RL1 associated with asthma (P = 5.5 x 10(-12)) in a collection of ten different populations (7,996 cases and 44,890 controls). SNPs at WDR36, IL33 and MYB that showed suggestive association with eosinophil counts were also associated with atopic asthma (P = 4.2 x 10(-6), 2.2 x 10(-5) and 2.4 x 10(-4), respectively). We also found that a nonsynonymous SNP at 12q24, in SH2B3, associated significantly (P = 8.6 x 10(-8)) with myocardial infarction in six different populations (6,650 cases and 40,621 controls).
10.	Rafnar, Thorunn, et al. (author) European genome-wide association study identifies SLC14A1 as a new urinary bladder cancer susceptibility gene. 2011 In: Human molecular genetics. - : Oxford University Press (OUP). - 1460-2083 .- 0964-6906. ; 20:21, s. 4268-81 Journal article (peer-reviewed)abstract Three genome-wide association studies in Europe and the USA have reported eight urinary bladder cancer (UBC) susceptibility loci. Using extended case and control series and 1000 Genomes imputations of 5 340 737 single-nucleotide polymorphisms (SNPs), we searched for additional loci in the European GWAS. The discovery sample set consisted of 1631 cases and 3822 controls from the Netherlands and 603 cases and 37 781 controls from Iceland. For follow-up, we used 3790 cases and 7507 controls from 13 sample sets of European and Iranian ancestry. Based on the discovery analysis, we followed up signals in the urea transporter (UT) gene SLC14A. The strongest signal at this locus was represented by a SNP in intron 3, rs17674580, that reached genome-wide significance in the overall analysis of the discovery and follow-up groups: odds ratio = 1.17, P = 7.6 × 10(-11). SLC14A1 codes for UTs that define the Kidd blood group and are crucial for the maintenance of a constant urea concentration gradient in the renal medulla and, through this, the kidney's ability to concentrate urine. It is speculated that rs17674580, or other sequence variants in LD with it, indirectly modifies UBC risk by affecting urine production. If confirmed, this would support the 'urogenous contact hypothesis' that urine production and voiding frequency modify the risk of UBC.
11.	Rafnar, T, et al. (author) Sequence variants at the TERT-CLPTM1L locus associate with many cancer types 2009 In: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 69 Journal article (peer-reviewed)
12.	Surendran, Praveen, et al. (author) Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals 2020 In: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 52:12, s. 1314-1332 Journal article (peer-reviewed)abstract Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to similar to 1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency <= 0.01) variant BP associations (P < 5 x 10(-8)), of which 32 were in new BP-associated loci and 55 were independent BP-associated single-nucleotide variants within known BP-associated regions. Average effects of rare variants (44% coding) were similar to 8 times larger than common variant effects and indicate potential candidate causal genes at new and known loci (for example, GATA5 and PLCB3). BP-associated variants (including rare and common) were enriched in regions of active chromatin in fetal tissues, potentially linking fetal development with BP regulation in later life. Multivariable Mendelian randomization suggested possible inverse effects of elevated systolic and diastolic BP on large artery stroke. Our study demonstrates the utility of rare-variant analyses for identifying candidate genes and the results highlight potential therapeutic targets.
13.	Walpole, S, et al. (author) Comprehensive Study of the Clinical Phenotype of Germline BAP1 Variant-Carrying Families Worldwide 2018 In: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 1460-2105 .- 0027-8874. ; 110:12, s. 1328-1341 Journal article (peer-reviewed)
14.	Aragam, KG, et al. (author) Discovery and systematic characterization of risk variants and genes for coronary artery disease in over a million participants 2022 In: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 54:12, s. 1803-1815 Journal article (peer-reviewed)abstract The discovery of genetic loci associated with complex diseases has outpaced the elucidation of mechanisms of disease pathogenesis. Here we conducted a genome-wide association study (GWAS) for coronary artery disease (CAD) comprising 181,522 cases among 1,165,690 participants of predominantly European ancestry. We detected 241 associations, including 30 new loci. Cross-ancestry meta-analysis with a Japanese GWAS yielded 38 additional new loci. We prioritized likely causal variants using functionally informed fine-mapping, yielding 42 associations with less than five variants in the 95% credible set. Similarity-based clustering suggested roles for early developmental processes, cell cycle signaling and vascular cell migration and proliferation in the pathogenesis of CAD. We prioritized 220 candidate causal genes, combining eight complementary approaches, including 123 supported by three or more approaches. Using CRISPR–Cas9, we experimentally validated the effect of an enhancer in MYO9B, which appears to mediate CAD risk by regulating vascular cell motility. Our analysis identifies and systematically characterizes >250 risk loci for CAD to inform experimental interrogation of putative causal mechanisms for CAD.
15.	Aragam, KG, et al. (author) Discovery and systematic characterization of risk variants and genes for coronary artery disease in over a million participants 2022 In: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 54:12, s. 1803-1815 Journal article (peer-reviewed)abstract The discovery of genetic loci associated with complex diseases has outpaced the elucidation of mechanisms of disease pathogenesis. Here we conducted a genome-wide association study (GWAS) for coronary artery disease (CAD) comprising 181,522 cases among 1,165,690 participants of predominantly European ancestry. We detected 241 associations, including 30 new loci. Cross-ancestry meta-analysis with a Japanese GWAS yielded 38 additional new loci. We prioritized likely causal variants using functionally informed fine-mapping, yielding 42 associations with less than five variants in the 95% credible set. Similarity-based clustering suggested roles for early developmental processes, cell cycle signaling and vascular cell migration and proliferation in the pathogenesis of CAD. We prioritized 220 candidate causal genes, combining eight complementary approaches, including 123 supported by three or more approaches. Using CRISPR–Cas9, we experimentally validated the effect of an enhancer in MYO9B, which appears to mediate CAD risk by regulating vascular cell motility. Our analysis identifies and systematically characterizes >250 risk loci for CAD to inform experimental interrogation of putative causal mechanisms for CAD.
16.	Ek, M, et al. (author) Genome sequencing with comprehensive variant calling identifies structural variants and repeat expansions in a large fraction of individuals with neuromuscular disorders 2024 In: EUROPEAN JOURNAL OF HUMAN GENETICS. - 1018-4813. ; 32, s. 523-524 Conference paper (other academic/artistic)
17.	Evangelou, Evangelos, et al. (author) A meta-analysis of genome-wide association studies identifies novel variants associated with osteoarthritis of the hip 2014 In: Annals of the Rheumatic Diseases. - : BMJ. - 1468-2060 .- 0003-4967. ; 73:12, s. 2130-2136 Journal article (peer-reviewed)abstract Objectives Osteoarthritis (OA) is the most common form of arthritis with a clear genetic component. To identify novel loci associated with hip OA we performed a meta-analysis of genome-wide association studies (GWAS) on European subjects. Methods We performed a two-stage meta-analysis on more than 78 000 participants. In stage 1, we synthesised data from eight GWAS whereas data from 10 centres were used for 'in silico' or 'de novo' replication. Besides the main analysis, a stratified by sex analysis was performed to detect possible sex-specific signals. Meta-analysis was performed using inverse-variance fixed effects models. A random effects approach was also used. Results We accumulated 11 277 cases of radiographic and symptomatic hip OA. We prioritised eight single nucleotide polymorphism (SNPs) for follow-up in the discovery stage (4349 OA cases); five from the combined analysis, two male specific and one female specific. One locus, at 20q13, represented by rs6094710 (minor allele frequency (MAF) 4%) near the NCOA3 (nuclear receptor coactivator 3) gene, reached genome-wide significance level with p=7.9x10(-9) and OR=1.28 (95% CI 1.18 to 1.39) in the combined analysis of discovery (p= 5.6x10(-8)) and follow-up studies (p=7.3x10(-4)). We showed that this gene is expressed in articular cartilage and its expression was significantly reduced in OA-affected cartilage. Moreover, two loci remained suggestive associated; rs5009270 at 7q31 (MAF 30%, p=9.9x10(-7), OR=1.10) and rs3757837 at 7p13 (MAF 6%, p=2.2x10(-6), OR=1.27 in male specific analysis). Conclusions Novel genetic loci for hip OA were found in this meta-analysis of GWAS.
18.	Gretarsdottir, S, et al. (author) Risk variants for atrial fibrillation on chromosome 4q25 associate with ischemic stroke 2008 In: Annals of neurology. - : Wiley. - 1531-8249 .- 0364-5134. ; 64:4, s. 402-409 Journal article (peer-reviewed)
19.	Gunnlaugsson, Eysteinn, et al. (author) End-to-end machine learning on raw eeg signals for sleep stage classification 2019 In: Sleep Medicine. - : ELSEVIER. - 1389-9457 .- 1878-5506. ; 64, s. S139-S139 Journal article (other academic/artistic)
20.	Lindstrand, A, et al. (author) Genome Sequencing is a sensitive first-line test to diagnose individuals with intellectual disability 2023 In: EUROPEAN JOURNAL OF HUMAN GENETICS. - 1018-4813. ; 31, s. 451-451 Conference paper (other academic/artistic)
21.	Volpe, G, et al. (author) Roadmap on Deep Learning for Microscopy 2023 In: ArXiv. - 2331-8422. Journal article (other academic/artistic)
22.	Ascierto, PA, et al. (author) Brain metastases and survival evaluation in the SECOMBIT trial 2023 In: ANNALS OF ONCOLOGY. - 0923-7534. ; 34, s. S653-S653 Conference paper (other academic/artistic)
23.	Ascierto, PA, et al. (author) Phase II study SECOMBIT (sequential combo immuno and target therapy study): A subgroup analysis with a longer follow-up. 2022 In: JOURNAL OF CLINICAL ONCOLOGY. - 0732-183X. ; 40:16 Conference paper (other academic/artistic)
24.	Ascierto, PA, et al. (author) Sequencing of Ipilimumab Plus Nivolumab and Encorafenib Plus Binimetinib for Untreated BRAF-Mutated Metastatic Melanoma (SECOMBIT): A Randomized, Three-Arm, Open-Label Phase II Trial 2023 In: Journal of clinical oncology : official journal of the American Society of Clinical Oncology. - 1527-7755. ; 41:2, s. 212-221 Journal article (peer-reviewed)
25.	Ascierto, PA, et al. (author) Sequencing of Ipilimumab Plus Nivolumab and Encorafenib Plus Binimetinib for Untreated BRAF-Mutated Metastatic Melanoma (SECOMBIT): A Randomized, Three-Arm, Open-Label Phase II Trial 2023 In: Journal of clinical oncology : official journal of the American Society of Clinical Oncology. - 1527-7755. ; 41:2, s. 212- Journal article (peer-reviewed)
26.	Ascierto, PA, et al. (author) Sequential immunotherapy and targeted therapy for metastatic BRAF V600 mutated melanoma: 4-year survival and biomarkers evaluation from the phase II SECOMBIT trial 2024 In: Nature communications. - 2041-1723. ; 15:1, s. 146- Journal article (peer-reviewed)
27.	Chen, H.Y., et al. (author) Dyslipidemia, inflammation, calcification, and adiposity in aortic stenosis: a genome-wide study 2023 In: European Heart Journal. - : Oxford University Press. - 0195-668X .- 1522-9645. ; 44:21, s. 1927-1939 Journal article (peer-reviewed)abstract Aims Although highly heritable, the genetic etiology of calcific aortic stenosis (AS) remains incompletely understood. The aim of this study was to discover novel genetic contributors to AS and to integrate functional, expression, and cross-phenotype data to identify mechanisms of AS. Methods and results A genome-wide meta-analysis of 11.6 million variants in 10 cohorts involving 653 867 European ancestry participants (13 765 cases) was performed. Seventeen loci were associated with AS at P ≤ 5 × 10−8, of which 15 replicated in an independent cohort of 90 828 participants (7111 cases), including CELSR2–SORT1, NLRP6, and SMC2. A genetic risk score comprised of the index variants was associated with AS [odds ratio (OR) per standard deviation, 1.31; 95% confidence interval (CI), 1.26–1.35; P = 2.7 × 10−51] and aortic valve calcium (OR per standard deviation, 1.22; 95% CI, 1.08–1.37; P = 1.4 × 10−3), after adjustment for known risk factors. A phenome-wide association study indicated multiple associations with coronary artery disease, apolipoprotein B, and triglycerides. Mendelian randomization supported a causal role for apolipoprotein B-containing lipoprotein particles in AS (OR per g/L of apolipoprotein B, 3.85; 95% CI, 2.90–5.12; P = 2.1 × 10−20) and replicated previous findings of causality for lipoprotein(a) (OR per natural logarithm, 1.20; 95% CI, 1.17–1.23; P = 4.8 × 10−73) and body mass index (OR per kg/m2, 1.07; 95% CI, 1.05–1.9; P = 1.9 × 10−12). Colocalization analyses using the GTEx database identified a role for differential expression of the genes LPA, SORT1, ACTR2, NOTCH4, IL6R, and FADS. Conclusion Dyslipidemia, inflammation, calcification, and adiposity play important roles in the etiology of AS, implicating novel treatments and prevention strategies. © The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.
28.	Dalmasso, B, et al. (author) Germline ATM variants predispose to melanoma: a joint analysis across the GenoMEL and MelaNostrum consortia 2021 In: Genetics in medicine : official journal of the American College of Medical Genetics. - : Elsevier BV. - 1530-0366. ; 23:11, s. 2087-2095 Journal article (peer-reviewed)
29.	Ek, M, et al. (author) Genome sequencing with comprehensive variant calling identifies structural variants and repeat expansions in a large fraction of individuals with ataxia and/or neuromuscular disorders 2023 In: Frontiers in neurology. - 1664-2295. ; 14, s. 1170005- Journal article (peer-reviewed)
30.	Helgadottir, H, et al. (author) Efficacy of novel melanoma treatments in metastatic melanoma patients with germline CDKN2A mutations 2019 In: JOURNAL OF TRANSLATIONAL MEDICINE. - 1479-5876. ; 17 Conference paper (other academic/artistic)
31.	Helgadottir, H, et al. (author) Multiple primary melanoma incidence trends over five decades, a nationwide population-based study 2020 In: ANNALS OF ONCOLOGY. - : Elsevier BV. - 0923-7534. ; 31, s. S766-S766 Conference paper (other academic/artistic)
32.	Helgadottir, H, et al. (author) [Overview of immune-related side effects from immune checkpoint inhibitors. Part 2: Endocrine, rheumatologic and skin toxicity] 2021 In: Lakartidningen. - 1652-7518. ; 118 Journal article (peer-reviewed)
33.	Helgadottir, H, et al. (author) The common Scandinavian human leucocyte antigen ancestral haplotype 62.1 as prognostic factor in patients with advanced malignant melanoma 2009 In: Cancer immunology, immunotherapy : CII. - : Springer Science and Business Media LLC. - 1432-0851 .- 0340-7004. ; 58:10, s. 1599-1608 Journal article (peer-reviewed)
34.	Jespersen, H, et al. (author) Phase II multicenter open label study of pembrolizumab and entinostat in adult patients with metastatic uveal melanoma (PEMDAC study) 2019 In: ANNALS OF ONCOLOGY. - 0923-7534. ; 30, s. 907-907 Conference paper (other academic/artistic)
35.	Shah, S, et al. (author) Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure 2020 In: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1, s. 163- Journal article (peer-reviewed)abstract Heart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homoeostasis (BAG3), and cellular senescence (CDKN1A). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies.
36.	Sigurdsson, Martin, I, et al. (author) Association Between Preoperative Opioid and Benzodiazepine Prescription Patterns and Mortality After Noncardiac Surgery 2019 In: JAMA Surgery. - : AMER MEDICAL ASSOC. - 2168-6254 .- 2168-6262. ; 154:8 Journal article (peer-reviewed)abstract ImportanceThe number of patients prescribed long-term opioids and benzodiazepines and complications from their long-term use have increased. Information regarding the perioperative outcomes of patients prescribed these medications before surgery is limited. ObjectiveTo determine whether patients prescribed opioids and/or benzodiazepines within 6 months preoperatively would have greater short- and long-term mortality and increased opioid consumption postoperatively. Design, Setting, and ParticipantsThis retrospective, single-center, population-based cohort study included all patients 18 years or older, undergoing noncardiac surgical procedures at a national hospital in Iceland from December 12, 2005, to December 31, 2015, with follow-up through May 20, 2016. A propensity score-matched control cohort was generated using individuals from the group that received prescriptions for neither medication class within 6 months preoperatively. Data analysis was performed from April 10, 2018, to March 9, 2019. ExposuresPatients who filled prescriptions for opioids only, benzodiazepines only, both opioids and benzodiazepines, or neither medication within 6 months preoperatively. Main Outcomes and MeasuresLong-term survival compared with propensity score-matched controls. Secondary outcomes were 30-day survival and persistent postoperative opioid consumption, defined as a prescription filled more than 3 months postoperatively. ResultsAmong 41170 noncardiac surgical cases in 27787 individuals (16004 women [57.6%]; mean [SD] age, 56.3 [18.8] years), a preoperative prescription for opioids only was filled for 7460 cases (17.7%), benzodiazepines only for 3121 (7.4%), and both for 2633 (6.2%). Patients who filled preoperative prescriptions for either medication class had a greater comorbidity burden compared with patients receiving neither medication class (Elixhauser comorbidity index >0 for 16% of patients filling prescriptions for opioids only, 22% for benzodiazepines only, and 21% for both medications compared with 14% for patients filling neither). There was no difference in 30-day (opioids only: 1.3% vs 1.0%; P=.23; benzodiazepines only: 1.9% vs 1.5%; P=.32) or long-term (opioids only: hazard ratio [HR], 1.12 [95% CI, 1.01-1.24]; P=.03; benzodiazepines only: HR, 1.11 [95% CI, 0.98-1.26]; P=.11) survival among the patients receiving opioids or benzodiazepines only compared with controls. However, patients prescribed both opioids and benzodiazepines had greater 30-day mortality (3.2% vs 1.8%; P=.004) and a greater hazard of long-term mortality (HR, 1.41; 95% CI, 1.22-1.64; P<.001). The rate of persistent postoperative opioid consumption was higher for patients filling prescriptions for opioids only (43%), benzodiazepines only (23%), or both (66%) compared with patients filling neither (12%) (P<.001 for all). Conclusions and RelevanceThe findings suggest that opioid and benzodiazepine prescription fills in the 6 months before surgery are associated with increased short-and long-term mortality and an increased rate of persistent postoperative opioid consumption. These patients should be considered for early referral to preoperative clinic and medication optimization to improve surgical outcomes.
37.	Steinthorsdottir, V, et al. (author) Genetic predisposition to hypertension is associated with preeclampsia in European and Central Asian women 2020 In: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1, s. 5976- Journal article (peer-reviewed)abstract Preeclampsia is a serious complication of pregnancy, affecting both maternal and fetal health. In genome-wide association meta-analysis of European and Central Asian mothers, we identify sequence variants that associate with preeclampsia in the maternal genome at ZNF831/20q13 and FTO/16q12. These are previously established variants for blood pressure (BP) and the FTO variant has also been associated with body mass index (BMI). Further analysis of BP variants establishes that variants at MECOM/3q26, FGF5/4q21 and SH2B3/12q24 also associate with preeclampsia through the maternal genome. We further show that a polygenic risk score for hypertension associates with preeclampsia. However, comparison with gestational hypertension indicates that additional factors modify the risk of preeclampsia.
38.	Styrkarsdottir, Unnur, et al. (author) Severe osteoarthritis of the hand associates with common variants within the ALDH1A2 gene and with rare variants at 1p31. 2014 In: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 46:5, s. 498-502 Journal article (peer-reviewed)abstract Osteoarthritis is the most common form of arthritis and is a major cause of pain and disability in the elderly. To search for sequence variants that confer risk of osteoarthritis of the hand, we carried out a genome-wide association study (GWAS) in subjects with severe hand osteoarthritis, using variants identified through the whole-genome sequencing of 2,230 Icelanders. We found two significantly associated loci in the Icelandic discovery set: at 15q22 (frequency of 50.7%, odds ratio (OR) = 1.51, P = 3.99 × 10(-10)) in the ALDH1A2 gene and at 1p31 (frequency of 0.02%, OR = 50.6, P = 9.8 × 10(-10)). Among the carriers of the variant at 1p31 is a family with several members in whom the risk allele segregates with osteoarthritis. The variants within the ALDH1A2 gene were confirmed in replication sets from The Netherlands and the UK, yielding an overall association of OR = 1.46 and P = 1.1 × 10(-11) (rs3204689).
39.	Svedman, F. C., et al. (author) Plasma Thymidine Kinase Activity as a Novel Biomarker in Metastatic Melanoma Patients Treated with Immune Checkpoint Inhibitors 2022 In: Cancers. - : MDPI AG. - 2072-6694. ; 14:3 Journal article (peer-reviewed)abstract Background. Immune checkpoint inhibitors (ICI) are effective in fractions of patients with disseminated melanoma. This study is the first to analyze the plasma activity of thymidine kinase (TK), an enzyme involved in DNA synthesis and repair, as a biomarker in melanoma patients. Meth-ods. Plasma samples were collected prior to treatment start in patients with unresectable metastatic cutaneous melanoma, treated with ICI (anti-CTLA-4 and/or anti-PD-1). Plasma TK activity (TKa) levels were determined using the DiviTum TKa ELISA assay. TKa levels were correlated with patients’ baseline characteristics, response rate (RR), progression-free survival (PFS), and overall survival (OS). Results. In the 90 study patients, the median TKa level was 42 Du/L (range <20–1787 Du/L). A significantly higher plasma TKa was found in patients with ECOG performance status ≥1 (p = 0.003), M1c-d disease (p = 0.015), and elevated lactate dehydrogenase levels (p < 0.001). The RR was 63.2% and 30.3% in those with low or high TKa, respectively (p = 0.022). The median PFS was 19.9 and 12.6 months in patients with low or high TKa, respectively (hazard ratio (HR) 1.83 (95% CI, 1.08–3.08), p = 0.024). The median OS was >60 months and 18.5 months in patients with low or high TKa, respectively (HR: 2.25 (95% CI, 1.25–4.05), p = 0.011. Conclusions. High pretreatment plasma TKa levels were significantly associated with worse baseline characteristics and poor response and survival in ICI-treated melanoma patients. TKa is hence a novel and interesting plasma biomarker in melanoma and should be further studied to define its role as a prognostic and predictive marker in this disease. © 2022 by the authors. Licensee MDPI, Basel, Switzerland.
40.	Villabona Lisa Villabona, L, et al. (author) [Overview of immune-related side effects from immune checkpoint inhibitors. Part 1: Gastrointestinal, lung and kidney toxicity] 2021 In: Lakartidningen. - 1652-7518. ; 118 Journal article (peer-reviewed)
41.	Ascierto, PA, et al. (author) First report of efficacy and safety from the phase II study SECOMBIT (SEquential COMBo Immuno and Targeted therapy study) 2020 In: ANNALS OF ONCOLOGY. - : Elsevier BV. - 0923-7534. ; 31, s. S1173-S1174 Conference paper (other academic/artistic)
42.	Ascierto, PA, et al. (author) Phase II study SECOMBIT (sequential combo immuno and target therapy study): 4-years OS data and preliminary biomarkers evaluation 2022 In: ANNALS OF ONCOLOGY. - : Elsevier BV. - 0923-7534. ; 33:7, s. S1408-S1409 Conference paper (other academic/artistic)
43.	Ascierto, PA, et al. (author) SECOMBIT: The best sequential approach with combo immunotherapy [ipilimumab (I) /nivolumab (N)] and combo target therapy [encorafenib (E)/binimetinib (B)] in patients with BRAF mutated metastatic melanoma: A phase II randomized study 2021 In: ANNALS OF ONCOLOGY. - : Elsevier BV. - 0923-7534. ; 32, s. S1316-S1317 Conference paper (other academic/artistic)
44.	Astiazaran-Symonds, E, et al. (author) Gene-Level Associations in Patients With and Without Pathogenic Germline Variants in CDKN2A and Pancreatic Cancer 2022 In: JCO precision oncology. - 2473-4284. ; 6, s. e2200145- Journal article (peer-reviewed)
45.	Astiazaran-Symonds, E, et al. (author) Gene-Level Associations in Patients With and Without Pathogenic Germline Variants in CDKN2A and Pancreatic Cancer 2022 In: JCO precision oncology. - 2473-4284. ; 6, s. e2200145- Journal article (peer-reviewed)
46.	Backlund, E, et al. (author) Radiotherapy with or without immunotherapy in metastatic melanoma: efficacy and Tolerability 2023 In: Acta oncologica (Stockholm, Sweden). - 1651-226X. ; , s. 1-10 Journal article (peer-reviewed)
47.	Backlund, E, et al. (author) Radiotherapy with or without immunotherapy in metastatic melanoma: efficacy and tolerability 2023 In: Acta oncologica (Stockholm, Sweden). - 1651-226X. ; 62:12, s. 1921-1930 Journal article (peer-reviewed)
48.	Bagge, RO, et al. (author) A phase I, randomized, controlled, multicentre trial of isolated hepatic perfusion in combination with ipilimumab and nivolumab in patients with uveal melanoma metastases (the SCANDIUM 2 trial). 2023 In: JOURNAL OF CLINICAL ONCOLOGY. - 0732-183X. ; 41:16 Conference paper (other academic/artistic)
49.	Bagge, RO, et al. (author) Isolated hepatic perfusion as a treatment for uveal melanoma liver metastases, first results from a phase III randomized controlled multicenter trial (the SCANDIUM trial). 2022 In: JOURNAL OF CLINICAL ONCOLOGY. - 0732-183X. ; 40:17 Conference paper (other academic/artistic)
50.	Bagge, R. Olofsson, et al. (author) A phase Ib randomized multicenter trial of isolated hepatic perfusion in combination with ipilimumab and nivolumab for uveal melanoma metastases (SCANDIUM II trial) 2024 In: ESMO Open. - : Elsevier. - 2059-7029. ; 9:7 Journal article (peer-reviewed)abstract Background:Uveal melanoma (UM) is a rare malignancy where 50% of patients develop metastatic disease primarily affecting the liver. Approximately 40% of patients with metastatic UM respond to one-time isolated hepatic perfusion (IHP) with high -dose melphalan. This phase I trial investigates the safety and clinical ef fi cacy of IHP combined with ipilimumab (IPI) and nivolumab (NIVO).Patients and methods:Immunotherapy-na & iuml;ve patients were randomized in this phase I trial to receive either IHP followed by IPI 3 mg/kg and NIVO 1 mg/kg (IPI3/NIVO1) for four cycles (post -operative arm), or one cycle of preoperative IPI3/NIVO1, IHP and then three cycles of IPI3/NIVO1 (pre-post-operative arm), followed by maintenance therapy with NIVO 480 mg for 1 year.Results:Eighteen patients were enrolled and randomized. Three patients did not undergo IHP as planned. In total, 11/ 18 patients (6 in the post -operative arm and 5 in the pre-post-operative arm) did not complete the planned four cycles of IPI3/NIVO1. Toxicity to IHP was similar in both groups, but the number of immune-related adverse events (AEs) was higher in the pre-post-operative arm. Among assessable patients, overall response rate was 57% in the post -operative arm (4/7) and 22% in the pre-post-operative arm (2/9).Conclusions:Combination therapy with IHP and IPI3/NIVO1 was associated with severe AEs. The efficacy of this combination is encouraging with high response rates. One cycle of preoperative IPI/NIVO before IHP did not show potential benefits in terms of safety or efficacy.

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