| 1. |
- Hägg, Sara, 1977-, et al.
(författare)
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Multi-Organ Expression Profiling Uncovers a Gene Module in Coronary Artery Disease Involving Transendothelial Migration of Leukocytes and LIM Domain Binding 2 : The Stockholm Atherosclerosis Gene Expression (STAGE) Study
- 2009
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Ingår i: PLoS Genetics. - : PLoS Genetics. - 1553-7390 .- 1553-7404. ; 5:12, s. e1000754-
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Tidskriftsartikel (refereegranskat)abstract
- Environmental exposures filtered through the genetic make-up of each individual alter the transcriptional repertoire in organs central to metabolic homeostasis, thereby affecting arterial lipid accumulation, inflammation, and the development of coronary artery disease (CAD). The primary aim of the Stockholm Atherosclerosis Gene Expression (STAGE) study was to determine whether there are functionally associated genes (rather than individual genes) important for CAD development. To this end, two-way clustering was used on 278 transcriptional profiles of liver, skeletal muscle, and visceral fat (n=66/tissue) and atherosclerotic and unaffected arterial wall (n=40/tissue) isolated from CAD patients during coronary artery bypass surgery. The first step, across all mRNA signals (n=15,042/12,621 RefSeqs/genes) in each tissue, resulted in a total of 60 tissue clusters (n=3958 genes). In the second step (performed within tissue clusters), one atherosclerotic lesion (n=49/48) and one visceral fat (n=59) cluster segregated the patients into two groups that differed in the extent of coronary stenosis (P=0.008 and P=0.00015). The associations of these clusters with coronary atherosclerosis were validated by analyzing carotid atherosclerosis expression profiles. Remarkably, in one cluster (n=55/54) relating to carotid stenosis (P=0.04), 27 genes in the two clusters relating to coronary stenosis were confirmed (n=16/17, P<10-27and-30). Genes in the transendothelial migration of leukocytes (TEML) pathway were overrepresented in all three clusters, referred to as the atherosclerosis module (A-module). In a second validation step, using three independent cohorts, the A-module was found to be genetically enriched with CAD risk by 1.8-fold (P<0.004). The transcription co-factor LIM domain binding 2 (LDB2) was identified as a potential high-hierarchy regulator of the A-module, a notion supported by subnetwork analysis, cellular and lesion expression of LDB2, and the expression of 13 TEML genes in Ldb2-deficient arterial wall. Thus, the A-module appears to be important for atherosclerosis development and together with LDB2 merits further attention in CAD research.
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| 2. |
- Leander, Karin
(författare)
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Family history in relation to myocardial infarction, and analyses of gene-environment interactions involving factors of haemostasis
- 2005
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Family history of coronary heart disease (CHD) has frequently been shown to increase the risk of MI. However, the mechanisms are not well understood. Probably, both genetic- and environmental effects contribute. It is possible that family history in combination with other cardiovascular risk factors is of particular importance in the aetiology of myocardial infarction (MI). Haemostatic factors seem to contribute in the causation of MI, although this is not established. Plasma fibrinogen and plasminogen activator inhibitor-1 (PAI-1) are two potentially important risk factors, with their genetic variants possibly influencing effects. The potential involvements of these factors in interactions with other cardiovascular risk factors are poorly understood. The aims of the present thesis were to assess the influence of family history of CHD on risk of first non-fatal MI in men and women, respectively, and to explore its potential role as a biologically interacting factor. The thesis also aimed to study the importance of fibrinogen and the G-455 A polymorphism, and PAI-1 and the 4G/5G polymorphism, in relation to risk of MI. Here a particular aim was also to explore potential synergistic effects for exposure combinations involving these factors regarding risk of MI. A final aim was to explore which cardiovascular risk factors may be most important for the long-term prognosis after a non-fatal MI. Data are derived from the Stockholm Heart Epidemiology Program (SHEEP), a populationbased case-control study of MI performed between 1992 and 1994 at the ten emergency hospitals within the county of Stockholm. The present analyses were restricted to 1643 men and women who had suffered a first-time non-fatal MI, and 2339 controls. Data on exposures were available from questionnaires, anthropometric measurements, blood samples, and medical records. A family history of CHD (defined as >=1 first-degree relative affected before the age of 65) was observed to be associated with risk of MI in both men and women. Synergistic effects were observed in women exposed to family history of CHD in combination with current smoking and with a high LDL/HDL quotient, respectively. In men, family history of CHD and diabetes mellitus seemed to act in synergy. High level of plasma fibrinogen was associated with increased risk of MI in both men and women, although the OR decreased after adjusting for other cardiovascular risk factors. Presence of the A-455 allele was associated with increased fibrinogen level but not with increased risk of MI. No clear synergistic effects were observed. High plasma PAI-1 activity was associated with increased risk of MI, and in men it also interacted with smoking in increasing the risk synergistically. In women, presence of the 4G allele was associated although weakly with increased risk of MI. Diabetes mellitus, job strain and abdominal adiposure had an impact on prognosis after MI in men. In women, prognostic importance was particularly noted for diabetes mellitus and for low level of Apolipoprotein AI. In both men and women the size of the initial infarction also had a prognostic value. In male survivors of MI, family history of CHD increased the risk of death from CHD during follow-up. In conclusion, this thesis suggests the occurrence of several biological interactions between risk factors for MI. The involvement of family history in such interactions indicates that gene-environment interaction may be in operation. After MI, several primary and secondary exposures have an influence on the prognosis.
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| 3. |
- Leander, Karin, et al.
(författare)
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Primary risk factors influence risk of recurrent myocardial infarction/death from coronary heart disease : result from the Stockholm Heart Epidemiology program (SHEEP).
- 2007
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Ingår i: European Journal of Cardiovascular Prevention & Rehabilitation. - 1741-8267 .- 1741-8275. ; 14:4, s. 532-537
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUNDPrognosis after a first myocardial infarction (MI) is influenced by primary risk factors as well as secondary risk factors. There is still a lack of follow-up studies of well-characterized patient cohorts assessing the relative importance of these factors. DESIGNA cohort of 1635 patients (aged 45-70 years) surviving at least 28 days after a first MI were followed for 6-9 years with regard to recurrent MI/fatal coronary heart disease (CHD). Data were collected through questionnaires, physical examinations, and medical records. METHODSHazard ratios (HR) with 95% confidence intervals (CI) for different risk factors were calculated using the Cox proportional hazard model. RESULTSOf the primary risk factors, diabetes in both sexes was the most important predictor of recurrent MI/fatal CHD, multivariate-adjusted HR in men 1.6 (95% CI; 1.0-2.4) and in women 2.5 (95% CI; 0.9-6.9). Other primary risk factors with prognostic influence were job strain, HR 1.5 (95% CI; 1.0-2.1), and central obesity, HR 1.4 (95% CI; 1.0-2.0), in men and a low level of apolipoprotein A1, HR 2.3 (95% CI; 1.1-5.0), and high-density lipoprotein cholesterol, HR 1.9 (95% CI; 0.9-4.1), in women. The secondary risk factors most detrimental for prognosis were heart failure in men, HR 2.2 (95% CI; 1.2-4.0), and a high peak acute cardiac enzyme level in women, HR 4.4 (95% CI; 2.0-9.7). CONCLUSIONSLong-term follow-up of patients who survived at least 28 days after a first MI shows that several primary cardiovascular risk factors, particularly diabetes, contribute to the increased risk of recurrent MI/fatal CHD.
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| 4. |
- Malmstedt, Jonas, et al.
(författare)
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Outcome after leg bypass surgery for critical limb ischemia is poor in patients with diabetes
- 2008
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Ingår i: Diabetes Care. - Alexandria, VA, United States : American Diabetes Association. - 0149-5992 .- 1935-5548. ; 31:5, s. 887-892
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE—Our aim was to assess the risk of major amputation or death after leg bypass surgery for critical limb ischemia in patients with diabetes versus those without.RESEARCH DESIGN AND METHODS—We did a population-based cohort study by linking nationwide databases in Sweden. We identified 1,840 patients in the Swedish Vascular Registry who had their first leg bypass procedure for critical lower-limb ischemia between 1 January 2001 and 31 December 2003—742 with and 1,098 without diabetes. Our primary end point was first major amputation of the limb on which bypass was done or death. Individuals were followed up until 31 December 2005 through the National Hospital Patient Registry and the Cause-of-Death Registry.RESULTS—Incidence of ipsilateral amputation or death was higher in patients with diabetes than in patients without (30.2 vs. 22 events/100 person-years; crude hazard ratio [HR] 1.32 [95% CI 1.17–1.50]). Similarly, individuals with diabetes had a shorter amputation-free survival period than individuals without (2.3 years, range 1.9–2.8 vs. 3.4 years, range 3.1–3.7). Adjustment for demographic characteristics, comorbidities, and risk factors for amputation or death did not substantially affect the risk (HR 1.46 [95% CI 1.26–1.69]). The effect was more pronounced in male (1.75 [1.47–2.08]) than in female (1.35 [1.11–1.64]) patients after adjustment for age.CONCLUSIONS—Diabetes is associated with lower amputation–free survival after leg bypass for critical limb ischemia. Patients with diabetes and limb ischemia need intensified treatment of diabetes-related risk factors to improve outcome.
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| 5. |
- Nordenhem, Arvid, et al.
(författare)
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The complex between tPA and PAI-1 : risk factor for myocardial infarction as studied in the SHEEP project
- 2005
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Ingår i: Thrombosis Research. - : Elsevier BV. - 0049-3848 .- 1879-2472. ; 116:3, s. 223-232
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION:The tPA/PAI-1 complex seems to be an important biochemical marker for myocardial reinfarction. Therefore we explored the distribution, correlation and interaction of plasma concentrations of tPA/PAI-1 complex in all available patients and matched controls in the Stockholm Heart Epidemiology Program (SHEEP).METHODS AND PATIENTS:The SHEEP study is a case control study of 2246 patients with a first myocardial infarction (MI), of which 1267 surviving patients were subjected to blood sampling about 3 months after MI and compared with a control group, matched for age, sex and living area within the Stockholm County. The study consists of 886 (591 men and 295 women) patients and 1198 (753 men and 445 women) matched controls, who were all analysed for plasma tPA/PAI-1 complex.RESULTS:The plasma concentration of tPA/PAI-1 complex was significantly associated with the risk for MI, for both genders. Synergistic interactions were observed in men for the co exposure to high plasma tPA/PAI-1 complex concentrations in combination with smoking (OR=4.6) or diabetes mellitus (OR=7.9). Synergism was also seen in combination with exposure to serum hypercholesterolemia or increased levels of apolipoprotein B. An antagonistic effect of the co exposure to high tPA/PAI-1 complex and hypertension was found among men with a similar tendency among women, but an antagonistic effect of increased waist/hip ratio was only observed among the women.CONCLUSIONS:Measuring the plasma concentration of tPA/PAI-1 complex might be of practical value in assessing risk of MI for both genders, especially in those who are smokers or in patients with manifest diabetes mellitus.
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