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1.
  • Malik, R., et al. (författare)
  • Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes
  • 2018
  • Ingår i: Nature Genetics. - : NATURE PUBLISHING GROUP. - 1061-4036 .- 1546-1718. ; 50:D, Munich, Germany. [Chauhan, Ganesh] Indian Inst Sci, Ctr Brain Res, Bangalore, Karnataka, India. [Chauhan, Ganesh; Sargurupremraj, Muralidharan; Mishra, Aniket; Tzourio, Christophe; Debette, [Traylor, Matthew; Rutten-Jacobs, Loes; Markus, Hugh S.] Univ Cambridge, Div Clin Neurosci, Stroke [Sargurupremraj, Muralidharan; Mishra, Aniket; Debette, Stephanie] Bordeaux Univ Hosp, Inst [Okada, Yukinori; Kanai, Masahiro; Kamatani, Yoichiro] RIKEN Ctr Integrat Med Sci, Lab Stat Anal, [Okada, Yukinori; Kanai, Masahiro; Sakaue, Saori] Osaka Univ, Grad Sch Med, Dept Stat Genet, Osaka, [Okada, Yukinori] Osaka Univ, Immunol Frontier Res Ctr WPI IFReC, Lab Stat Immunol, Suita, Osaka, [Giese, Anne-Katrin; Rost, Natalia S.] Harvard Med Sch, MGH, Dept Neurol, Boston, MA USA. [van der Laan, Sander W.] Univ Utrecht, Univ Med Ctr Utrecht, Div Heart & Lungs, Lab Expt Cardiol,Dept [Gretarsdottir, Solveig; Thorleifsson, Gudmar; Thorsteinsdottir, Unnur; Stefansson, Kari] DeCODE Genet [Anderson, Christopher D.; Rosand, Jonathan] MGH, Ctr Genom Med, Boston, MA USA. [Anderson, Christopher D.; Ay, Hakan; Rost, Natalia S.; Rosand, Jonathan] MGH, J Philip Kistler Stroke [Anderson, Christopher D.; Rosand, Jonathan] Broad Inst, Program Med & Populat Genet, Cambridge, s. 524-
  • Tidskriftsartikel (refereegranskat)abstract
    • Stroke has multiple etiologies, but the underlying genes and pathways are largely unknown. We conducted a multiancestry genome-wide-association meta-analysis in 521,612 individuals (67,162 cases and 454,450 controls) and discovered 22 new stroke risk loci, bringing the total to 32. We further found shared genetic variation with related vascular traits, including blood pressure, cardiac traits, and venous thromboembolism, at individual loci (n = 18), and using genetic risk scores and linkage-disequilibrium-score regression. Several loci exhibited distinct association and pleiotropy patterns for etiological stroke sub-types. Eleven new susceptibility loci indicate mechanisms not previously implicated in stroke pathophysiology, with prioritization of risk variants and genes accomplished through bioinformatics analyses using extensive functional datasets. Stroke risk loci were significantly enriched in drug targets for antithrombotic therapy.
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2.
  • Lindgren, Stefan, et al. (författare)
  • Intravenous iron sucrose is superior to oral iron sulphate for correcting anaemia and restoring iron stores in IBD patients : A randomized, controlled, evaluator-blind, multicentre study
  • 2009
  • Ingår i: Scandinavian Journal of Gastroenterology. - : Taylor & Francis. - 0036-5521 .- 1502-7708. ; 44:7, s. 838-845
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective. Patients with inflammatory bowel disease (IBD) often have low iron stores or anaemia. There is controversy about whether iron should be supplemented orally or intravenously (i.v.). The purpose of this study was to investigate whether treatment with intravenous iron is superior to treatment with oral iron. The primary end-points were response and remaining anaemia at the end of treatment (EOT).Material and methods. Ninety-one patients with IBD and anaemia (B-Hb <115 g/L) were randomized to oral iron sulphate (n=46) or intravenous iron sucrose (n=45) treatment for 20 weeks.Results. Forty-three patients in the intravenous iron group completed the study compared to 35 patients in the oral iron group (p=0.0009). Only 22 patients (48%) tolerated the prescribed oral dose, and 52% reduced the dose or withdrew from treatment because of poor tolerance. At EOT, 47% patients in the oral iron group increased their B-Hb by ≥20 g/L, compared with 66% in the intravenous iron group (p=0.07). In the oral iron group, 41% still had anaemia versus 16% of the patients in the intravenous iron group (p=0.007), and 22% versus 42% reached their reference B-Hb level (p=0.04). Treatment with intravenous iron sucrose improved iron stores faster and more effectively than oral iron (p=0.002). Under treatment with intravenous iron, 74% of the patients had no anaemia and normal S-ferritin levels (>25 µg/L) at EOT compared with 48% of patients receiving oral iron (p=0.013).Conclusions. Treatment with intravenous iron sucrose is effective, safe, well tolerated and superior to oral iron in correcting haemoglobin and iron stores in patients with IBD.
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3.
  • Andsberg, Gunnar, et al. (författare)
  • PreHospital Ambulance Stroke Test - pilot study of a novel stroke test
  • 2017
  • Ingår i: Scandinavian Journal of Trauma, Resuscitation and Emergency Medicine. - : BioMed Central (BMC). - 1757-7241. ; 25:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: There is a need for a prehospital stroke test that in addition to high sensitivity for stroke, also is able to communicate stroke severity similar to the National Institute of Health Stroke Scale (NIHSS). Methods: The PreHospital Ambulance Stroke Test (PreHAST), an eight item test based on NIHSS, which scores stroke severity from 0-19 points, was designed and adapted for the ambulance services. In the pilot study the ambulance nurses used PreHAST to assess patients with suspected stroke in the prehospital setting. Regardless of the results after PreHAST testing the patients were triaged with a provisional stroke diagnosis. The PreHAST scores were compared with the final diagnosis and the ability to differentiate stroke and transient ischemic attacks (TIA) with ongoing symptoms at evaluation from non-stroke patients was analysed. Results: 69 patients were included in the study, 26 had stroke/TIA and 43 other diagnoses. All stroke/TIA patients were identified by PreHAST (sensitivity 100% (95% CI; 87-100%)). The specificity increased with higher PreHAST scores and the discriminative capacity for PreHAST for different cut off values showed an area under the curve of 0.77 (95%CI; 0.66-0.88) in the receiver operating characteristic (ROC) analysis. Discussion: PreHAST is designed for high sensitivity, screening for a broad range of stroke symptoms including most key components of NIHSS. The promising sensitivity between 87 and 100% in our study has to be confirmed in a larger study also including multiple centres. Higher PreHAST scores implied more typical patterns of stroke and accordingly the proportion of stroke mimics decrease with higher scores. However, also stroke mimics with epilepsy/seizure and patients with deficit after prior stroke could show higher PreHAST scores. Other prehospital stroke tests that evaluate stroke severity have been designed with the main purpose to screen for large vessel occlusion. The advantage of PreHAST is the dual purpose not only to evaluate stroke severity but also to screen for stroke in general. Conclusions: PreHAST is a new screening test of stroke adapted for ambulance services that in addition to high sensitivity for stroke, provides a grading system with increasing specificity with higher scores.
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4.
  • Chauhan, G., et al. (författare)
  • Genetic and lifestyle risk factors for MRI-defined brain infarcts in a population-based setting
  • 2019
  • Ingår i: Neurology. - : American Academy of Neurology. - 0028-3878 .- 1526-632X. ; 92:5, s. E486-E503
  • Tidskriftsartikel (refereegranskat)abstract
    • ObjectiveTo explore genetic and lifestyle risk factors of MRI-defined brain infarcts (BI) in large population-based cohorts.MethodsWe performed meta-analyses of genome-wide association studies (GWAS) and examined associations of vascular risk factors and their genetic risk scores (GRS) with MRI-defined BI and a subset of BI, namely, small subcortical BI (SSBI), in 18 population-based cohorts (n = 20,949) from 5 ethnicities (3,726 with BI, 2,021 with SSBI). Top loci were followed up in 7 population-based cohorts (n = 6,862; 1,483 with BI, 630 with SBBI), and we tested associations with related phenotypes including ischemic stroke and pathologically defined BI.ResultsThe mean prevalence was 17.7% for BI and 10.5% for SSBI, steeply rising after age 65. Two loci showed genome-wide significant association with BI: FBN2, p = 1.77 x 10(-8); and LINC00539/ZDHHC20, p = 5.82 x 10(-9). Both have been associated with blood pressure (BP)-related phenotypes, but did not replicate in the smaller follow-up sample or show associations with related phenotypes. Age- and sex-adjusted associations with BI and SSBI were observed for BP traits (p value for BI, p([BI]) = 9.38 x 10(-25); p([SSBI]) = 5.23 x 10(-14) for hypertension), smoking (p([BI]) = 4.4 x 10(-10); p([SSBI]) = 1.2 x 10(-4)), diabetes (p([BI]) = 1.7 x 10(-8); p([SSBI]) = 2.8 x 10(-3)), previous cardiovascular disease (p([BI]) = 1.0 x 10(-18); p([SSBI]) = 2.3 x 10(-7)), stroke (p([BI]) = 3.9 x 10(-69); p([SSBI]) = 3.2 x 10(-24)), and MRI-defined white matter hyperintensity burden (p([BI]) = 1.43 x 10(-157); p([SSBI]) = 3.16 x 10(-106)), but not with body mass index or cholesterol. GRS of BP traits were associated with BI and SSBI (p 0.0022), without indication of directional pleiotropy.ConclusionIn this multiethnic GWAS meta-analysis, including over 20,000 population-based participants, we identified genetic risk loci for BI requiring validation once additional large datasets become available. High BP, including genetically determined, was the most significant modifiable, causal risk factor for BI.
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5.
  • Ilinca, A., et al. (författare)
  • Whole-Exome Sequencing in 22 Young Ischemic Stroke Patients With Familial Clustering of Stroke
  • 2020
  • Ingår i: Stroke. - : American Heart Association. - 0039-2499 .- 1524-4628. ; 51:4, s. 1056-1063
  • Tidskriftsartikel (refereegranskat)abstract
    • Backgrounds and Purpose-Although new methods for genetic analyses are rapidly evolving, there are currently knowledge gaps in how to detect Mendelian forms of stroke. Methods-We performed whole-exome sequencing in 22 probands, under 56 years at their first ischemic stroke episode, from multi-incident stroke families. With the use of a comprehensive stroke-gene panel, we searched for variants in stroke-related genes. The probands' clinical stroke subtype was related to clinical characteristics previously associated with pathogenic variants in these genes. Relatives were genotyped in 7 families to evaluate stroke-gene variants of unknown significance. In 2 larger families with embolic stroke of unknown source, whole-exome sequencing was performed in additional members to examine the possibility of identifying new stroke genes. Results-Six of 22 probands carried pathogenic or possibly pathogenic variants in genes reported to be associated with their stroke subtype. A known pathogenic variant in NOTCH3 and a possibly pathogenic variant in ACAD9 gene were identified. A novel JAK2:c.3188G>A (p.Arg1063His) mutation was seen in a proband with embolic stroke of undetermined source and prothrombotic status. However, penetrance in the family was incomplete. COL4A2:c.3368A>G (p.Glu1123Gly) was detected in 2 probands but did not cosegregate with the disease in their families. Whole-exome sequencing in multiple members of 2 pedigrees with embolic stroke of undetermined source revealed possibly pathogenic variants in genes not previously associated with stroke, GPR142:c.148C>G (p.Leu50Val), and PTPRN2:c.2416A>G (p.Ile806Val); LRRC1 c.808A>G (p.Ile270Val), SLC7A10c.1294dupG (p.Val432fs), IKBKB: c.1070C>T (p.Ala357Val), and OXGR1 c.392G>A (p.Arg131His), respectively. Conclusions-Screening with whole-exome sequencing using a comprehensive stroke-gene panel may identify rare monogenic forms of stroke, but careful evaluation of clinical characteristics and potential pathogenicity of novel variants remain important. In our study, the majority of individuals with familial aggregation of stroke lacked any identified genetic causes.
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6.
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7.
  • Marini, S., et al. (författare)
  • Association of Apolipoprotein E With Intracerebral Hemorrhage Risk by Race/Ethnicity A Meta-analysis
  • 2019
  • Ingår i: Jama Neurology. - : American Medical Association. - 2168-6149 .- 2168-6157. ; 76:4, s. 480-491
  • Tidskriftsartikel (refereegranskat)abstract
    • IMPORTANCE Genetic studies of intracerebral hemorrhage (ICH) have focused mainly on white participants, but genetic risk may vary or could be concealed by differing nongenetic coexposures in nonwhite populations. Transethnic analysis of risk may clarify the role of genetics in ICH risk across populations. OBJECTIVE To evaluate associations between established differences in ICH risk by race/ethnicity and the variability in the risks of apolipoprotein E (APOE) epsilon 4 alleles, the most potent genetic risk factor for ICH. DESIGN, SETTING, AND PARTICIPANTS This case-control study of primary ICH meta-analyzed the association of APOE allele status on ICH risk, applying a 2-stage clustering approach based on race/ethnicity and stratified by a contributing study. A propensity score analysis was used to model the association of APOE with the burden of hypertension across race/ethnic groups. Primary ICH cases and controls were collected from 3 hospital- and population-based studies in the United States and 8 in European sites in the International Stroke Genetic Consortium. Participants were enrolled from January 1, 1999, to December 31, 2017. Participants with secondary causes of ICH were excluded from enrollment. Controls were regionally matched within each participating study. MAIN OUTCOMES AND MEASURES Clinical variables were systematically obtained from structured interviews within each site. APOE genotype was centrally determined for all studies. RESULTS In total, 13 124 participants (7153 [54.5%] male with a median [interquartile range] age of 66 [56-76] years) were included. In white participants, APOE epsilon 2 (odds ratio [OR], 1.49; 95% CI, 1.24-1.80; P < .001) and APOE epsilon 4 (OR, 1.51; 95% CI, 1.23-1.85; P < .001) were associated with lobar ICH risk; however, within self-identified Hispanic and black participants, no associations were found. After propensity score matching for hypertension burden, APOE epsilon 4 was associated with lobar ICH risk among Hispanic (OR, 1.14; 95% CI, 1.03-1.28; P = .01) but not in black (OR, 1.02; 95% CI, 0.98-1.07; P = .25) participants. APOE epsilon 2 and epsilon 4 did not show an association with nonlobar ICH risk in any race/ethnicity. CONCLUSIONS AND RELEVANCE APOE epsilon 4 and epsilon 2 alleles appear to affect lobar ICH risk variably by race/ethnicity, associations that are confirmed in white individuals but can be shown in Hispanic individuals only when the excess burden of hypertension is propensity score-matched; further studies are needed to explore the interactions between APOE alleles and environmental exposures that vary by race/ethnicity in representative populations at risk for ICH.
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8.
  • Oudin, Anna, et al. (författare)
  • Hospital admissions for ischemic stroke : does long-term exposure to air pollution interact with major risk factors?
  • 2011
  • Ingår i: Cerebrovascular Diseases. - : S. Karger. - 1015-9770 .- 1421-9786. ; 31:3, s. 284-293
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: The aim was to investigate whether the effects of major risk factors for ischemic stroke were modified by long-term exposure to air pollution in Scania, southern Sweden.Methods: Cases were defined as first-ever ischemic strokes in patients born between 1923 and 1965 during 2001-2006 (n = 7,244). Data were collected from The Swedish National Stroke Register (Riks-stroke) and the Malmö and Lund Stroke Registers. Population controls were matched on age and sex. Modeled outdoor annual mean NO(x) concentrations were used as proxy for long-term exposure to air pollution. Heterogeneity across NO(x) categories was tested for smoking, hypertension, diabetes mellitus, atrial fibrillation and physical inactivity. Data were analyzed as case-control data and to some extent as case-only data, with logistic regression analysis.Results: The case-control odds ratios for ischemic stroke in association with diabetes were 1.3 [95% confidence interval (CI): 1.1-1.6] and 2.0 (95% CI: 1.2-3.4) in the lowest and highest NO(x) category, respectively (p value for testing heterogeneity across the categories = 0.056). The case-only approach gave further support for the risk associated with diabetes to increase with NO(x) (p for trend = 0.033). We observed no main effect of mean NO(x) or any conclusive effect modifications between NO(x) and smoking, hypertension, atrial fibrillation or physical inactivity.Conclusions: In a low-level air pollution area, the risk for ischemic stroke associated with diabetes seemed to increase with long-term exposure to air pollution.
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9.
  • Wild, Philipp S., et al. (författare)
  • Large-scale genome-wide analysis identifies genetic variants associated with cardiac structure and function
  • 2017
  • Ingår i: Journal of Clinical Investigation. - : Am Soc Clin Investig. - 0021-9738 .- 1558-8238. ; 127:5, s. 1798-1812
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND. Understanding the genetic architecture of cardiac structure and function may help to prevent and treat heart disease. This investigation sought to identify common genetic variations associated with inter-individual variability in cardiac structure and function. METHODS. A GWAS meta-analysis of echocardiographic traits was performed, including 46,533 individuals from 30 studies (EchoGen consortium). The analysis included 16 traits of left ventricular (LV) structure, and systolic and diastolic function. RESULTS. The discovery analysis included 21 cohorts for structural and systolic function traits (n = 32,212) and 17 cohorts for diastolic function traits (n = 21,852). Replication was performed in 5 cohorts (n = 14,321) and 6 cohorts (n = 16,308), respectively. Besides 5 previously reported loci, the combined meta-analysis identified 10 additional genome-wide significant SNPs: rs12541595 near MTSS1 and rs10774625 in ATXN2 for LV end-diastolic internal dimension; rs806322 near KCNRG, rs4765663 in CACNA1C, rs6702619 near PALMD, rs7127129 in TMEM16A, rs11207426 near FGGY, rs17608766 in GOSR2, and rs17696696 in CFDP1 for aortic root diameter; and rs12440869 in IQCH for Doppler transmitral A-wave peak velocity. Findings were in part validated in other cohorts and in GWAS of related disease traits. The genetic loci showed associations with putative signaling pathways, and with gene expression in whole blood, monocytes, and myocardial tissue. CONCLUSION. The additional genetic loci identified in this large meta-analysis of cardiac structure and function provide insights into the underlying genetic architecture of cardiac structure and warrant follow-up in future functional studies.
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10.
  • Andsberg, Gunnar, et al. (författare)
  • PreHospital Ambulance Stroke Test : pilot study of a novel stroke test
  • 2017
  • Ingår i: Scandinavian Journal of Trauma, Resuscitation and Emergency Medicine. - London, UK : BioMed Central. - 1757-7241 .- 1757-7241. ; 25:1
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: There is a need for a prehospital stroke test that in addition to high sensitivity for stroke, also is able to communicate stroke severity similar to the National Institute of Health Stroke Scale (NIHSS).METHODS: The PreHospital Ambulance Stroke Test (PreHAST), an eight item test based on NIHSS, which scores stroke severity from 0-19 points, was designed and adapted for the ambulance services. In the pilot study the ambulance nurses used PreHAST to assess patients with suspected stroke in the prehospital setting. Regardless of the results after PreHAST testing the patients were triaged with a provisional stroke diagnosis. The PreHAST scores were compared with the final diagnosis and the ability to differentiate stroke and transient ischemic attacks (TIA) with ongoing symptoms at evaluation from non-stroke patients was analysed.RESULTS: 69 patients were included in the study, 26 had stroke/TIA and 43 other diagnoses. All stroke/TIA patients were identified by PreHAST (sensitivity 100% (95% CI; 87-100%)). The specificity increased with higher PreHAST scores and the discriminative capacity for PreHAST for different cut off values showed an area under the curve of 0.77 (95%CI; 0.66-0.88) in the receiver operating characteristic (ROC) analysis.DISCUSSION: PreHAST is designed for high sensitivity, screening for a broad range of stroke symptoms including most key components of NIHSS. The promising sensitivity between 87 and 100% in our study has to be confirmed in a larger study also including multiple centres. Higher PreHAST scores implied more typical patterns of stroke and accordingly the proportion of stroke mimics decrease with higher scores. However, also stroke mimics with epilepsy/seizure and patients with deficit after prior stroke could show higher PreHAST scores. Other prehospital stroke tests that evaluate stroke severity have been designed with the main purpose to screen for large vessel occlusion. The advantage of PreHAST is the dual purpose not only to evaluate stroke severity but also to screen for stroke in general.CONCLUSIONS: PreHAST is a new screening test of stroke adapted for ambulance services that in addition to high sensitivity for stroke, provides a grading system with increasing specificity with higher scores.
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