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| 2. |
- 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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| 3. |
- Olsen, Michael Hecht, et al.
(författare)
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Effects of losartan compared with atenolol on lipids in patients with hypertension and left ventricular hypertrophy : the losartan intervention for endpoint reduction in hypertension (LIFE) study
- 2009
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Ingår i: Journal of Hypertension. - 0263-6352 .- 1473-5598. ; 27:3, s. 567-574
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Beta-blockers and angiotensin II receptor blockers have different effects on lipids. Methods: We examined lipid levels in the Losartan Intervention For Endpoint reduction in hypertension study and their impact on the primary composite endpoint of cardiovascular death, myocardial infarction, or stroke. We measured total and high-density lipoprotein cholesterol at baseline and annually during 4.8 years of losartan-based compared with atenolol-based treatment in 8611 patients with hypertension and left ventricular hypertrophy. Results: Patients randomized to losartan-based or atenolol-based treatment had similar baseline total (6.04 ± 1.12 vs. 6.05 ± 1.13 mmol/l, NS) and high-density lipoprotein (HDL) cholesterol (1.50 ± 0.44 vs. 1.49 ± 0.44 mmol/l, NS). Total cholesterol decreased significantly but equally (-0.37 ± 1.05 vs. -0.34 ± 1.09 mmol/l, NS), whereas HDL cholesterol decreased less during the first 2 years in patients randomized to losartan compared with atenolol (-0.13 ± 0.24 vs. -0.19 ± 0.25 mmol/l) and remained higher each year (1.38, 1.37, 1.42, 1.47, and 1.48 mmol/l vs. 1.32, 1.30, 1.36, 1.40, and 1.42 mmol/l, all P < 0.001) independent of hydrochlorothiazide or statin treatment. In Cox regression analysis, baseline total cholesterol [hazard ratio (HR) = 1.08 (1.02–1.14) per mmol/l, P < 0.01], HDL cholesterol [HR = 0.56 (0.48–0.66) per mmol/l, P < 0.001], and treatment allocation [HR = 0.86 (0.76–0.98), P < 0.05] predicted composite endpoint independently. Using time-varying analyses, the predictive strength of HDL cholesterol was increased [HR = 0.36 (0.30–0.44) per mmol/l, P < 0.001], whereas that of total cholesterol [HR = 1.03 (0.97–1.09) per mmol/l, NS] and treatment allocation [HR = 0.91 (0.80–1.03), NS] were reduced. Conclusion: Losartan blunted the decrease in HDL cholesterol during antihypertensive treatment in the LIFE study. Higher intreatment HDL cholesterol was associated with fewer composite endpoints and may partly explain the better outcome of losartan-based treatment.
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- Sjögren, Per, et al.
(författare)
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Markers of endothelial activity are related to components of the metabolic syndrome, but not to circulating concentrations of the advanced glycation end-product N epsilon-carboxymethyl-lysine in healthy Swedish men
- 2007
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Ingår i: Atherosclerosis. - : Elsevier BV. - 0021-9150 .- 1879-1484. ; 195:2, s. e168-e175
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Tidskriftsartikel (refereegranskat)abstract
- Endothelial function is considered important in the development of cardiovascular diseases and type 2 diabetes. Circulating advanced glycation end-products (AGEs) and dietary components have been shown to affect endothelial function in type 2 diabetics, but determinants of endothelial function in a non-diabetic population are more poorly investigated. Therefore, we investigated relationships between dietary habits, AGEs and endothelial activation in men with isolated metabolic disturbances. Circulating markers of endothelial activation (soluble forms of vascular cell adhesion molecule-1, intercellular adhesion molecule-1, E-selectin and von Willebrand factor) and plasma N epsilon-carboxymethyl-lysine (CML, the predominant AGE in human plasma) were analyzed in a cross-sectional study of 294 healthy men. Individuals completed a 7-day dietary record, and metabolic and inflammatory parameters were determined. NCEP/ATPIII-criteria were used to define the metabolic syndrome. Endothelial activation was higher in individuals with the metabolic syndrome, and was positively related to certain features of the syndrome (insulin, glucose, inflammation and obesity), but not to others (triacylglycerol and blood pressure). Dietary factors were related to endothelial activation, but CML was not. Multivariate analysis revealed energy and alcohol intake, along with insulin and markers of oxidative stress and inflammation, to be positive predictors of endothelial activation. In this cohort of otherwise healthy men, endothelial activation was increased in individuals with the full metabolic syndrome, but not in those with only some of the components of the metabolic syndrome. Insulin resistance, inflammation, oxidative stress, the dietary intake of energy and alcohol, but not plasma CML, predicted endothelial activation in these men.
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| 5. |
- Warensjö, Eva, et al.
(författare)
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Associations between estimated fatty acid desaturase activities in serum lipids and adipose tissue in humans : links to obesity and insulin resistance
- 2009
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Ingår i: Lipids in Health and Disease. - 1476-511X. ; 8, s. 37-
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Tidskriftsartikel (refereegranskat)abstract
- Fatty acid composition of serum lipids and adipose tissue triacylglycerols (AT-TAG) partly reflect dietary fatty acid intake. The fatty acid composition is, besides the diet, also influenced by desaturating enzymes that can be estimated using product-to-precursor fatty acid ratios. The interrelationships between desaturase indices derived from different serum lipid fractions and adipose tissue are unclear, as well as their associations with obesity and insulin resistance. We aimed to investigate cross-sectional correlations between desaturase indices as measured in serum lipid fractions (phospholipids; PL and free fatty acids; FFA) and in adipose tissue (AT-TAG). In a population-based sample of 301 healthy 60-year-old men various desaturase indices were assessed: stearoyl-CoA-desaturase (16:1n-7/16:0; SCD-16 and 18:1n-9/18:0; SCD-18, respectively), delta-6-desaturase (20:3n-6/18:2n-6; D6D) and delta-5-desaturase (20:4n-6/20:3n-6; D5D). Correlations with BMI and insulin resistance (HOMA-IR) were also examined. SCD-16 and D5D were significantly correlated between fractions and tissues (all r > 0.30), whereas SCD-18 and D6D were not. Desaturase indices in serum FFA and AT-TAG were significantly correlated; SCD-16 (r = 0.63), SCD-18 (r = 0.37), and D5D (r = 0.43). In phospholipids, SCD-16 was positively correlated to BMI (r = 0.15), while D5D negatively to both BMI (r = -0.30) and HOMA-IR (r = -0.31), all p < 0.01. D6D in both phospholipids and AT-TAG was positively correlated to HOMA-IR and BMI (all p < 0.01). In conclusion, SCD-1 and D5D activity indices showed overall strong correlations between lipid pools. SCD-1 activity index in adipose tissue is best reflected by 16:1/16:0-ratio in serum FFA, but associations with obesity and insulin resistance differ between these pools. D5D in PL was inversely related to obesity and insulin resistance, whereas D6D index showed positive associations.
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| 6. |
- Bennet, Anna M., et al.
(författare)
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Decreased risk for myocardial infarction and lower tumor necrosis factor-alpha levels in carriers of variants of the PDCD1 gene
- 2006
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Ingår i: Human Immunology. - : Elsevier BV. - 0198-8859 .- 1879-1166. ; 67:9, s. 700-705
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Tidskriftsartikel (refereegranskat)abstract
- Increasing interest has been directed toward the inflammatory mechanisms involved in the pathogenesis of myocardial infarction (MI). In the search for genetic mechanisms underlying these inflammatory components, we studied variants of programmed cell death-1 (PDCD1), an immunoinhibitory receptor that inhibits lymphocyte activation and cytokine production, previously shown to be associated with several autoimmune disorders. The PD1.1, PD1.3, and PD1.6 polymorphisms of the PDCD1 gene were typed in the Stockholm Heart Epidemiology Program, a population-based clinical material consisting of 1179 first-time MI case patients and 1528 unaffected control subjects. Individual alleles and haplotypes were studied for association with levels of the inflammatory cytokines tumor necrosis factor-alpha (TNF-alpha), interleukin-6, and C-reactive protein and risk for MI. We observed a weak protective effect of PD1.3A allele for MI (odds ratio: 0.78, 95% confidence interval: 0.61-0.98). We also observed decreased levels of TNF-alpha in carriers of the PD1.1A/PD1.3G/PD1.6A haplotype, which is consistent with our previous observation that this haplotype may be protective from autoimmune conditions. Carriers of variants of the PDCD1 gene exhibit a decreased risk for nonfatal myocardial infarction, and PDCD1 mediates variation in TNF-alpha levels.
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| 7. |
- Farahmand, Bahman, et al.
(författare)
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Golf- a game of life and death : Reduced mortality in Swedish golf players
- 2009
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Ingår i: Scandinavian Journal of Medicine and Science in Sports. - : Wiley. - 0905-7188 .- 1600-0838. ; 19:3, s. 419-424
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Tidskriftsartikel (refereegranskat)abstract
- The specific health benefits achieved from different formsand patterns of leisure-time physical activity are not established.We analyzed the mortality in a cohort of Swedishgolf players. We used the Swedish Golf Federation’s membershipregistry and the nationwide Mortality Registry. Wecalculated standardized mortality ratios (SMR) with stratificationfor age, sex, and socioeconomic status. The cohortincluded 300 818 golfers, and the total number of deaths was1053. The overall SMR was 0.60 [95% confidence intervals(CIs): 0.57–0.64]. The mortality reduction was observed inmen and women, in all age groups, and in all socioeconomiccategories. Golfers with the lowest handicap (the mostskilled players) had the lowest mortality; SMR50.53(95% CI: 0.41–0.67) compared with 0.68 (95% CI: 0.61–0.75) for those with the highest handicap. While we cannotconclude with certainty that all the 40% decreased mortalityrates are explained by the physical activity associatedwith playing golf, we conclude that most likely this is part ofthe explanation. To put the observed mortality reduction incontext, it may be noted that a 40% reduction of mortalityrates corresponds to an increase in life expectancy of about5 years.
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| 10. |
- Grönlund, Hans, et al.
(författare)
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Low levels of IgM antibodies against phosphorylcholine predict development of acute myocardial infarction in a population-based cohort from northern Sweden.
- 2009
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Ingår i: European Journal of Cardiovascular Prevention & Rehabilitation. - : Sage. - 1741-8267 .- 1741-8275. ; 16:3, s. 382-386
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Phosphorylcholine (PC) is one important epitope on oxidized low-density lipoprotein that may play an important role by contributing to the atherogenicity of oxidized low-density lipoprotein. IgM antibodies against PC (anti-PC) are present ubiquitously in the population as natural antibodies. We here determine the association between anti-PC and incidence of myocardial infarction (MI). METHODS: We studied 462 incident cases of first events of MI and 888 age-matched and sex-matched controls identified through 13 years of follow-up (1987-1999) of participants in a population-based study from northern Sweden. Relative risks (RRs) with 95% confidence intervals (CIs) of incident MI with adjustments for age, sex, geographical region, hypertension, diabetes, BMI, smoking habits, s-cholesterol and high-sensitivity C-reactive protein were determined. Anti-PC levels were measured by enzyme-linked immunoassay. RESULTS: Low anti-PC values were associated with increased risk of MI. Significant associations were found for values below 26.8 U/ml, corresponding to the lowest 25th percentile, and the highest association was seen below 16.9 U/ml. These results remained almost the same after adjustment for confounding factors (RR crude: 1.56, CI: 1.07-2.28 and RR adjusted: 1.69, CI: 1.09-2.54). CONCLUSION: Low levels of natural IgM anti-PC could play an important role as risk markers for development of MI. Adjustment for common confounders only marginally affected the RR, suggesting that the addition of IgM anti-PC add independent information to the more traditional risk factors.
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