Search PubMed⌕ Search

Biomedical subjects

Gudmundur Thorgeirsson

Publications and source records attributed to Gudmundur Thorgeirsson.

At least 19 recordsLinked to original sources
PubMed2006

Familial aggregation of atrial fibrillation in Iceland.

AIMS: To examine the heritability of atrial fibrillation (AF) in Icelanders, utilizing a nationwide genealogy database and population-based data on AF. AF is a disorder with a high prevalence, which has been known to cluster in families, but the heritability of the common form has not been well defined. METHODS AND RESULTS: The study population included 5269 patients diagnosed since 1987 and age-sex-matched controls randomly selected from the genealogy database. Kinship coefficients (KC), expressed as genealogical index of familiality (GIF = average KC x 100,000), were calculated before and after exclusion of relatives separated by one to five meiotic events. Risk ratios (RR) were calculated for first- to fifth-degree relatives. The average pairwise GIF among patients with AF was 15.9 (mean GIF for controls 13.9, 95%CI = 13.3, 14.4); this declined to 15.4 (mean GIF for controls 13.6, 95%CI = 13.1, 14.2) after exclusion of relatives separated by one meiosis and to 13.7 (mean GIF for controls 12.6, 95%CI = 12.1, 13.2), 12.7 (mean GIF for controls 11.9, 95%CI = 11.4, 12.4), and 11.3 (mean GIF for controls 10.6, 95%CI = 10.1, 11.1) after exclusion of relatives within two, three, and four meioses, respectively (all P<0.00001). RRs among relative pairs also declined incrementally, from 1.77 in first-degree relatives to 1.36, 1.18, 1.10, and 1.05 in second- through fifth-degree relatives (all P<0.001), consistent with the declining proportion of alleles shared identically by descent. When the analysis was limited to subjects diagnosed with AF before the age of 60, first-degree relatives of the AF cases were nearly five times more likely to have AF than the general population. CONCLUSION: AF shows strong evidence of heritability among unselected patients in Iceland, suggesting that there may be undiscovered genetic variants underlying the risk of the common form of AF.

Aged↗
PubMed2005

A variant of the gene encoding leukotriene A4 hydrolase confers ethnicity-specific risk of myocardial infarction.

Variants of the gene ALOX5AP (also known as FLAP) encoding arachidonate 5-lipoxygenase activating protein are known to be associated with risk of myocardial infarction. Here we show that a haplotype (HapK) spanning the LTA4H gene encoding leukotriene A4 hydrolase, a protein in the same biochemical pathway as ALOX5AP, confers modest risk of myocardial infarction in an Icelandic cohort. Measurements of leukotriene B4 (LTB4) production suggest that this risk is mediated through upregulation of the leukotriene pathway. Three cohorts from the United States also show that HapK confers a modest relative risk (1.16) in European Americans, but it confers a threefold larger risk in African Americans. About 27% of the European American controls carried at least one copy of HapK, as compared with only 6% of African American controls. Our analyses indicate that HapK is very rare in Africa and that its occurrence in African Americans is due to European admixture. Interactions with other genetic or environmental risk factors that are more common in African Americans are likely to account for the greater relative risk conferred by HapK in this group.

Black or African American↗
PubMed2005

Effects of a 5-lipoxygenase-activating protein inhibitor on biomarkers associated with risk of myocardial infarction: a randomized trial.

CONTEXT: Myocardial infarction (MI) is the leading cause of death in the world. Variants in the 5-lipoxygenase-activating protein (FLAP) gene are associated with risk of MI. OBJECTIVE: To determine the effect of an inhibitor of FLAP on levels of biomarkers associated with MI risk. DESIGN, SETTING, AND PATIENTS: A randomized, prospective, placebo-controlled, crossover trial of an inhibitor of FLAP (DG-031) in MI patients who carry at-risk variants in the FLAP gene or in the leukotriene A4 hydrolase gene. Of 268 patients screened, 191 were carriers of at-risk variants in FLAP (87%) or leukotriene A4 hydrolase (13%). Individuals were enrolled in April 2004 and were followed up by designated cardiologists from a university hospital in Iceland until September 2004. INTERVENTIONS: Patients were first randomized to receive 250 mg/d of DG-031, 500 mg/d of DG-031, 750 mg/d of DG-031, or placebo. After a 2-week washout period, patients received DG-031 if they had received placebo first or placebo if they had received DG-031 first. Treatment periods lasted for 4 weeks. MAIN OUTCOME MEASURES: Changes in levels of biomarkers associated with risk of MI. RESULTS: In response to 750 mg/d of DG-031, production of leukotriene B4 was significantly reduced by 26% (95% confidence interval [CI], 10%-39%; P = .003) and myeloperoxidase was significantly reduced by 12% (95% CI, 2%-21%; P = .02). The higher 2 doses of DG-031 produced a nonsignificant reduction in C-reactive protein (16%; 95% CI, -2% to 31%; P = .07) at 2 weeks. However, there was a more pronounced reduction (25%; 95% CI, 5%-40%; P = .02) in C-reactive protein at the end of the washout period that persisted for another 4 weeks thereafter. The FLAP inhibitor DG-031 was well tolerated and was not associated with any serious adverse events. CONCLUSION: In patients with specific at-risk variants of 2 genes in the leukotriene pathway, DG-031 led to significant and dose-dependent suppression of biomarkers that are associated with increased risk of MI events.

5-Lipoxygenase-Activating Proteins↗
PubMed2005

Risk factors for out-of-hospital cardiac arrest: the Reykjavik Study.

AIMS: To examine risk factors for out-of-hospital cardiac arrest in the Reykjavik Study, a long-term, prospective, population-based cohort study that started in 1967. METHODS AND RESULTS: From 1987 to 1996, 137 men and 44 women out of the 8006 men and 9435 women in the study sustained out-of-hospital cardiac arrest due to cardiac causes. Determinants included coronary artery disease (CAD), its classical risk factors, and age, body mass index (BMI), heart rate, cardiomegaly, and erythrocyte sedimentation rate. Electrocardiograms (ECGs) were examined for various abnormalities. Significance was determined by Cox regression analysis. In multivariable analysis, the risk in men was significantly associated with age, diastolic blood pressure, cholesterol, current smoking, and previous diagnosis of myocardial infarction (MI). In women, the risk was associated with diastolic blood pressure, elevated levels of cholesterol and triglycerides, and increased voltage on ECG. Increased BMI was inversely related to women's risk of out-of-hospital cardiac arrest. CONCLUSION: In this prospective, population-based cohort study previous MI and the classical risk factors for CAD significantly increased the risk of out-of-hospital cardiac arrest, the endpoint of this study. Increased voltage on ECG additionally increased women's risk.

Age Factors↗
PubMed2005

Hypertension control as predictor of mortality in treated men and women, followed for up to 30 years.

PURPOSE: To examine the prognosis of treated, hypertensive individuals in the Reykjavik Study. METHODS: A population-based longitudinal study of 9328 men and 10 062 women. Subjects were included in the study during the period 1967-1996. Two groups of treated, hypertensive subjects were defined at baseline: with controlled blood pressure and with uncontrolled blood pressure. Main outcome measures were cardiovascular disease (CVD) mortality and all-cause mortality. RESULTS: Of the hypertensive men 24.8% were treated, and of those 38.3% were controlled, and of the hypertensive women 45.3% were treated, and of those 52.7% were controlled. Comparing treated and uncontrolled (systolic blood pressure (SBP) > or =160 mmHg and/or diastolic blood pressure (DBP) > or =95 mmHg) versus treated and controlled hypertensive subjects, followed for up to 30 years, the uncontrolled men and women were at significantly higher risk of CVD mortality, hazard ratio (HR) = 1.47 (95% confidence interval (CI): 1.06-2.02) and HR 1.70 (CI: 1.23-2.36), respectively, showing the benefit of hypertension control. The risk of all-cause mortality was increased for treated, uncontrolled men and women, compared with those who were treated and controlled, but did not reach significance. When analyzing blood pressure as a continuous variable among treated, hypertensive subjects, SBP was a better predictor than DBP of CVD mortality and all-cause mortality in women. This was not the case in men. CONCLUSIONS: Control of blood pressure among hypertensive-treated subjects at baseline was associated with a lower risk of CVD mortality during follow-up. SBP was the single best predictor of CVD mortality and all-cause mortality in treated women. The uncontrolled women were at a higher risk than the uncontrolled men.

Blood Pressure↗
PubMed2005

Glucose abnormalities and heart failure predict poor prognosis in the population-based Reykjavík Study.

BACKGROUND: The risk of cardiovascular disease increases progressively with increasing blood glucose from levels well below the diabetic threshold. In the Reykjavík Study the relationship between heart failure and abnormal glucose regulation was already apparent at the level of impaired glucose tolerance. The aim of this study was to determine the prognosis of participants with any glucose abnormality and heart failure and to test whether the combination of these conditions may adversely affect the subsequent prognosis. DESIGN: A prospective population-based study. METHODS: Data from the first visit of 19 381 participants were used. Participants were divided into groups according to their glycaemic and heart failure level, and comparisons were made between the groups and disease-free participants serving as a reference group. The risk of mortality and morbidity was calculated with adjustments for main cardiovascular risk factors and ischaemic heart disease. RESULTS: Participants in the reference group were younger, had lower body mass indices and more seldom a history of myocardial infarction compared with diseased groups. Mortality was lowest in the reference group (P<0.0001) increasing to a maximum in participants with the combination of glucose abnormality and heart failure. Prognostically, the mortality risk associated with abnormal glucose regulation was increased but was lower than the risk of diabetes. The risk of a new myocardial infarction was highest in participants with diabetes [hazard ratio (HR) 1.6; 95% confidence interval (CI) 1.3-2.0] or diabetes in combination with heart failure (HR 1.8; CI 1.1-2.7). CONCLUSIONS: Heart failure or glucose abnormalities are related to increased morbidity and mortality. The combination of glucose abnormality and heart failure did, however, not add further to the unfavourable prognosis in the presence of ischaemic heart disease.

Adolescent↗
PubMed2005

Vaccinia virus complement control protein diminishes formation of atherosclerotic lesions: complement is centrally involved in atherosclerotic disease.

Complement is known to be activated in atherosclerotic lesions, but the importance of this event in disease pathology is a matter of debate. Studies of rabbits fed a high-fat diet have indicated complement activation as a rate-limiting step, whereas results from genetically modified mouse strains (ApoE-/- or LDLR-/-) have failed to support this finding. To resolve whether this reflects differences between species or between genetically driven and diet-induced disease, we studied the effect of a complement inhibitor, vaccinia virus complement control protein (VCP), on C57BL/6 mice, the background strain of ApoE-/- and LDLR-/- mice. Atherosclerosis was induced by a high-fat diet, and VCP (20 mg/kg) was injected once per week after the eighth week. Fatty streak development was monitored at 15 weeks by microscopic examination of oil red-O-stained sections from the root of the aorta. VCP injections led to significant (50%) reduction of lesion size (P = 0.004). Lesions were marked by gradual accumulation of lipids and macrophages but did not develop beyond the fatty streak stage. VCP activity disappeared from serum in 4 days, and the possibility therefore exists that a higher level of protection may be achieved by more frequent injections. We conclude that the development of fatty streaks in diet-induced atherosclerotic disease can be significantly retarded by prophylactic treatment with a complement inhibitor. These results support previous findings from complement-deficient rabbits and suggest that the pathogenesis of atherosclerosis in diet-induced disease differs from that induced by major defects in lipid metabolism.

Animals↗
PubMed2005

The association between glucose abnormalities and heart failure in the population-based Reykjavik study.

OBJECTIVE: Diabetes is an independent risk factor for heart failure, whereas the relation between heart failure and abnormal glucose regulation (AGR) needs further evaluation. We studied this combination in the Reykjavik Study. RESEARCH DESIGN AND METHODS: The Reykjavik Study, a population-based cohort study during 1967-1997, recruited 19,381 participants aged 33-84 years who were followed until 2002. Oral glucose tolerance tests and chest X-rays were obtained from all participants. Cases were defined in accordance with World Health Organization criteria for type 2 diabetes or AGR (impaired glucose tolerance or impaired fasting glucose) and European Society of Cardiology guidelines for heart failure. RESULTS: The overall prevalence of type 2 diabetes and heart failure was 0.5% in men and 0.4% in women, while AGR and heart failure were found in 0.7% of men and 0.6% of women. Among participants with normal glucose regulation, heart failure was diagnosed in 3.2% compared with 6.0 and 11.8% among those with AGR and type 2 diabetes, respectively. The prevalence of type 2 diabetes in the age-group 45-65 years increased in both sexes during the period (P for trend = 0.007). The odds ratio was 2.8 (95% CI 2.2-3.6) for the association between type 2 diabetes and heart failure and 1.7 (1.4-2.1) between AGR and heart failure. CONCLUSIONS: There is a strong association between any form of glucometabolic perturbation and heart failure. Future studies in this field should focus on all types of glucose abnormalities rather than previously diagnosed diabetes only.

Adult↗
PubMed2004

Genetic basis of tobacco smoking: strong association of a specific major histocompatibility complex haplotype on chromosome 6 with smoking behavior.

The genetic basis for addiction to tobacco smoking--particularly that of the perception of olfactory stimuli that may be important in reinforcing smoking addiction--is largely unknown. A cluster of genes for olfactory receptors is in close proximity to the MHC region on chromosome 6. Polymorphisms of MHC class III genes (RCCX modules, TNFA promoter polymorphisms) were determined in 101 healthy subjects and 232 coronary artery disease (CAD) patients from Hungary with defined tobacco smoking habits. A highly significant association between ever smoking (past + current smokers) and a specific MHC haplotype was observed (odds ratios = 2.14-4.13; P-values = 0.012 to <0.001). This haplotype is characterized by the presence of C4A null alleles and a solitary short C4B gene linked to the TNF2 allele of the promoter for TNFA gene. This haplotype occurred more frequently in the ever smokers than in the never smokers [odds ratio: 4.97 (1.96-12.62); P = 0.001], and such associations were stronger in women (odds ratio = 13.6) than in men (odds ratio = 2.79). An independent study of complement C4 protein polymorphism and smoking habits in Icelandic subjects (n = 351) yielded similar and confirmative results. Considering the documented link between olfactory stimuli and smoking in females, and the presence of a cluster of odorant receptor genes close to the MHC class I region, our findings implicate a potential role of the MHC-linked olfactory receptor genes in the initiation of smoking.

Adult↗
PubMed2004

Thrombin and histamine stimulate endothelial nitric-oxide synthase phosphorylation at Ser1177 via an AMPK mediated pathway independent of PI3K-Akt.

Histamine and thrombin cause phosphorylation and activation of endothelial NO-synthase (eNOS) on Ser1177. We tested the role of various protein kinases in mediating this effect in human umbilical vein endothelial cells. Inhibition of the Ca2+/calmodulin-dependent protein kinase II or phosphoinositide 3-kinase (PI3K) had no effect. H89, an inhibitor of both protein kinase A (PKA) and 5'-AMP-activated protein kinase (AMPK), strongly inhibited phosphorylation and activity of eNOS. Conversely, the PKA inhibitor Rp-adenosine 3 '5'-cyclic monophosphate (cAMPS) had no effect and eNOS was not phosphorylated by treatments that affect cAMP levels. Thrombin and histamine caused phosphorylation of AMPK on Thr172 as well as on its downstream target acetyl-CoA carboxylase. Activation of AMPK using AICAR or CCCP also resulted in eNOS phosphorylation. We conclude that histamine and thrombin cause eNOS phosphorylation in an AMPK mediated manner, independent of P13K-Akt.

AMP-Activated Protein Kinases↗
PubMed2004

The gene encoding 5-lipoxygenase activating protein confers risk of myocardial infarction and stroke.

We mapped a gene predisposing to myocardial infarction to a locus on chromosome 13q12-13. A four-marker single-nucleotide polymorphism (SNP) haplotype in this locus spanning the gene ALOX5AP encoding 5-lipoxygenase activating protein (FLAP) is associated with a two times greater risk of myocardial infarction in Iceland. This haplotype also confers almost two times greater risk of stroke. Another ALOX5AP haplotype is associated with myocardial infarction in individuals from the UK. Stimulated neutrophils from individuals with myocardial infarction produce more leukotriene B4, a key product in the 5-lipoxygenase pathway, than do neutrophils from controls, and this difference is largely attributed to cells from males who carry the at-risk haplotype. We conclude that variants of ALOX5AP are involved in the pathogenesis of both myocardial infarction and stroke by increasing leukotriene production and inflammation in the arterial wall.

5-Lipoxygenase-Activating Proteins↗
PubMed2003

The gene encoding phosphodiesterase 4D confers risk of ischemic stroke.

We previously mapped susceptibility to stroke to chromosome 5q12. Here we finely mapped this locus and tested it for association with stroke. We found the strongest association in the gene encoding phosphodiesterase 4D (PDE4D), especially for carotid and cardiogenic stroke, the forms of stroke related to atherosclerosis. Notably, we found that haplotypes can be classified into three distinct groups: wild-type, at-risk and protective. We also observed a substantial disregulation of multiple PDE4D isoforms in affected individuals. We propose that PDE4D is involved in the pathogenesis of stroke, possibly through atherosclerosis, which is the primary pathological process underlying ischemic stroke.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2003

Inhibition of Akt phosphorylation by thrombin, histamine and lysophosphatidylcholine in endothelial cells. Differential role of protein kinase C.

The protein kinase Akt is involved in embryonic vascular development and neoangiogenesis as well as in several endothelial cell functions, including activation of endothelial NO-synthase (eNOS) and promotion of endothelial cell survival. We have examined the effects of G-protein activators thrombin and histamine as well as lysophosphatidylcholine (LPC) on Akt phosphorylation in cultured human umbilical vein endothelial cells (HUVEC). Akt phosphorylation was analyzed with the phosphospecific Akt (Ser473) antibody by Western blotting. While epidermal growth factor (EGF) was a potent stimulator of Akt phosphorylation histamine, thrombin and LPC blocked its activation when used in cotreatment with EGF. Following inhibition or downregulation of protein kinase C (PKC), the inhibitory effect of both histamine and thrombin on the endothelial response to EGF was prevented. Furthermore, stimulation of PKC, using short-term 12-O-tetradecanoylphorbol-13-acetate (TPA) treatment, markedly inhibited the stimulatory effects of EGF on Akt phosphorylation. Rottlerin, an inhibitor of the PKCdelta, but not Gö6976, which is an inhibitor of alpha, beta, gamma and isoforms, reversed the inhibitory effects of histamine. Conversely, inhibition or downregulation of PKC did not prevent the inhibitory effect of LPC. Akt phosphorylation was also increased by sphingosine 1-phosphate (S1P) treatment and this activity was influenced by the various cotreatments in the same way as the activation by EGF. Overall, this study demonstrated that the G-protein activators thrombin and histamine inhibited both EGF- and S1P-mediated Akt phosphorylation in HUVEC by activation of PKCdelta, while the inhibitory effects of LPC were independent of PKCdelta.

Cells, Cultured↗
PubMed2003

Primary prevention of cardiovascular diseases.

One of the tasks of primary health care is the prevention of disease. Cardiovascular disease is still the leading cause of death, and there are several sets of guidelines dealing with both primary and secondary prevention. The article overviews the risk factors for cardiovascular disease and the strategies for primary prevention.

Cardiovascular Diseases↗
PubMed2003

An age-associated decrease in the frequency of C4B*Q0 indicates that null alleles of complement may affect health or survival.

We studied the distribution of complement C4, C3, and factor B allotypes in 423 healthy Icelandic subjects from 17 to 89 years of age. A marked decrease was observed in the carrier frequency of variant alleles of complement C4B (C4B(*)Q0) and C3 (C3(*)F). These results confirm our previous observations on Hungarian subjects and suggest a negative effect of C4B(*)Q0 on health or survival.

Adolescent↗
PubMed2002

Localization of a susceptibility gene for common forms of stroke to 5q12.

Stroke is one of the most complex diseases, with several subtypes, as well as secondary risk factors, such as hypertension, hyperlipidemia, and diabetes, which, in turn, have genetic and environmental risk factors of their own. Here, we report the results of a genomewide search for susceptibility genes for the common forms of stroke. We cross-matched a population-based list of patients with stroke in Iceland with an extensive computerized genealogy database clustering 476 patients with stroke within 179 extended pedigrees. Linkage to 5q12 was detected, and the LOD score at this locus meets the criteria for genomewide significance (multipoint allele-sharing LOD score of 4.40, P=3.9 x 10(-6)). A 20-cM region on 5q was physically and genetically mapped to obtain accurate marker order and intermarker distances. This locus on 5q12, which we have designated as "STRK1," does not correspond to known susceptibility loci for stroke or for its risk factors and represents the first mapping of a locus for common stroke.

Alleles↗