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1.
  • Alsharari, Zayed, et al. (author)
  • Comparison of a 21-item food questionnaire with a 7-day dietary registration andbiomarkers of fat intake in a Swedish cohort of 60-year-old adults.
  • Other publication (other academic/artistic)abstract
    • AbstractPurpose. To evaluate a 21-item food frequency questionnaire (FFQ) in men participating in alarge cohort of Swedish 60-year-old adults (60YO).Methods. A self-reported FFQ (including 21 qualitative and semi-quantitative questions) was completed by >2000 men as part of a detailed baseline examination. A subsample of 301 men was included in a subsequent study in which detailed dietary habits were determined by a 7-day food record. Spearman rank correlations (r) and weighted Kappa (Kw) statistics were used to compare food intake categories in FFQ and 7-day food record. Furthermore, fatty acid (FA) composition in serum cholesteryl esters, assessed concurrent with the FFQ completion, was used to evaluate intakes of specific fat-rich foods from the FFQ.Results. We found good agreement between FFQ and food records for the reported intake ofalcohol (r=0.72, Kw=0.51), margarine (r=0.60, Kw=0.33), and fruit (r=0.49, Kw=0.31), reasonably good agreement for total fish (r=0.25, Kw=0.23), and egg (r=0.35, Kw=0.28), but poor agreement for other food groups such as bread, cheese, vegetables and cookies. In addition, serum proportions of long-chain n-3 polyunsaturated FAs and pentadecanoic acid were significantly higher in men with greater intakes of fish and cheese, respectively.Conclusion. In this evaluation of a short FFQ against 7-d food records and serum biomarkers of fat intake we found that the FFQ reasonably well reflected the intake of certain food groups (e.g. alcohol, fish, and margarine), but performed less accurate for other food groups. Firm and overallconclusions on validity are confined by the time-lag between the test and the reference method.
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3.
  • Alsharari, Zayed, et al. (author)
  • Serum Fatty Acids, Desaturase Activities and Abdominal Obesity - A Population-Based Study of 60-Year Old Men and Women
  • 2017
  • In: PLOS ONE. - : PUBLIC LIBRARY SCIENCE. - 1932-6203. ; 12:1
  • Journal article (peer-reviewed)abstract
    • Abdominal obesity is a key contributor of metabolic disease. Recent trials suggest that dietary fat quality affects abdominal fat content, where palmitic acid and linoleic acid influence abdominal obesity differently, while effects of n-3 polyunsaturated fatty acids are less studied. Also, fatty acid desaturation may be altered in abdominal obesity. We aimed to investigate cross-sectional associations of serum fatty acids and desaturases with abdominal obesity prevalence in a population-based cohort study. Serum cholesteryl ester fatty acids composition was measured by gas chromatography in 60-year old men (n = 1883) and women (n = 2015). Cross-sectional associations of fatty acids with abdominal obesity prevalence and anthropometric measures (e.g., sagittal abdominal diameter) were evaluated in multivariable-adjusted logistic and linear regression models, respectively. Similar models were employed to investigate relations between desaturase activities (estimated by fatty acid ratios) and abdominal obesity. In logistic regression analyses, palmitic acid, stearoyl-CoA- desaturase and Delta 6-desaturase indices were associated with abdominal obesity; multivariable-adjusted odds ratios (95% confidence intervals) for highest versus lowest quartiles were 1.45 (1.19-1.76), 4.06 (3.27-5.05), and 3.07 (2.51-3.75), respectively. Linoleic acid, alpha-linolenic acid, docohexaenoic acid, and Delta 5-desaturase were inversely associated with abdominal obesity; multivariable-adjusted odds ratios (95% confidence intervals): 0.39 (0.32-0.48), 0.74 (0.61-0.89), 0.76 (0.62-0.93), and 0.40 (0.33-0.49), respectively. Eicosapentaenoic acid was not associated with abdominal obesity. Similar results were obtained from linear regression models evaluating associations with different anthropometric measures. Sex-specific and linear associations were mainly observed for n3-polyunsaturated fatty acids, while associations of the other exposures were generally non-linear and similar across sexes. In accordance with findings from short-term trials, abdominal obesity was more common among individuals with relatively high proportions of palmitic acid, whilst the contrary was true for linoleic acid. Further trials should examine the potential role of linoleic acid and its main dietary source, vegetable oils, in abdominal obesity prevention.
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4.
  • Broadaway, K Alaine, et al. (author)
  • Loci for insulin processing and secretion provide insight into type 2 diabetes risk.
  • 2023
  • In: American Journal of Human Genetics. - : Elsevier. - 0002-9297 .- 1537-6605. ; 110:2, s. 284-299
  • Journal article (peer-reviewed)abstract
    • Insulin secretion is critical for glucose homeostasis, and increased levels of the precursor proinsulin relative to insulin indicate pancreatic islet beta-cell stress and insufficient insulin secretory capacity in the setting of insulin resistance. We conducted meta-analyses of genome-wide association results for fasting proinsulin from 16 European-ancestry studies in 45,861 individuals. We found 36 independent signals at 30 loci (p value < 5 × 10-8), which validated 12 previously reported loci for proinsulin and ten additional loci previously identified for another glycemic trait. Half of the alleles associated with higher proinsulin showed higher rather than lower effects on glucose levels, corresponding to different mechanisms. Proinsulin loci included genes that affect prohormone convertases, beta-cell dysfunction, vesicle trafficking, beta-cell transcriptional regulation, and lysosomes/autophagy processes. We colocalized 11 proinsulin signals with islet expression quantitative trait locus (eQTL) data, suggesting candidate genes, including ARSG, WIPI1, SLC7A14, and SIX3. The NKX6-3/ANK1 proinsulin signal colocalized with a T2D signal and an adipose ANK1 eQTL signal but not the islet NKX6-3 eQTL. Signals were enriched for islet enhancers, and we showed a plausible islet regulatory mechanism for the lead signal in the MADD locus. These results show how detailed genetic studies of an intermediate phenotype can elucidate mechanisms that may predispose one to disease.
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5.
  • Carlsson, Axel C., et al. (author)
  • Financial stress in late adulthood and diverse risks of incident cardiovascular disease and all-cause mortality in women and men
  • 2014
  • In: BMC Public Health. - : BioMed Central. - 1471-2458. ; 14
  • Journal article (peer-reviewed)abstract
    • Background: Financial stress may have adverse health effects. The main aim of this study was to investigate whether having a cash margin and living alone or cohabiting is associated with incident cardiovascular disease (CVD) and all-cause mortality. Methods: Representative population-based prospective cohort study of 60-year-old women (n = 2065) and men (n = 1939) in Stockholm County, Sweden. National registers were used to identify cases of incident CVD (n = 375) and all-cause mortality (n = 385). The presence of a cash margin was determined in the questionnaire with the following question: Would you, if an unexpected situation occurred, be able to raise 10 000 SEK within a week? (This was equivalent to US$ 1250 in 1998). Results: Compared with cohabiting women with a cash margin, the risk of all-cause mortality was higher among cohabiting women without a cash margin, with hazard ratios (HRs) of 1.97 (95% confidence interval (CI) 1.06-3.66). Using cohabiting men with cash margin as referent, single men without a cash margin were at an increased risk of both incident CVD and all-cause mortality: HR 2.84 (95% CI 1.61-4.99) and 2.78 (95% CI 1.69-4.56), respectively. Single men with cash margins still had an increased risk of all-cause mortality when compared with cohabiting men with a cash margin: HR 1.67 (95% CI 1.22-2.28). Conclusions: Financial stress may increase the risks of incident CVD and all-cause mortality, especially among men. Furthermore these risks are likely to be greater in men living in single households and in women without cash margins. Living with a partner seems to protect men, but not women, from ill-health associated with financial stress due to the lack of a cash margin.
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7.
  • Carlsson, Axel, et al. (author)
  • Differences in anthropometric measures in immigrants and Swedish-born individuals : results from two community-based cohort studies
  • 2014
  • In: Preventive Medicine. - : Elsevier BV. - 0091-7435 .- 1096-0260. ; 69, s. 151-156
  • Journal article (peer-reviewed)abstract
    • AIM: To study differences in body mass index (BMI), waist-hip ratio (WHR), waist circumference (WC), sagittal abdominal diameter (SAD), waist-hip-height ratio (WHHR) and percent body fat in immigrants and Swedish-born men and women in two large population-based samples.METHODS: A cross-sectional analysis of 60-year-old individuals, n=4 232. To replicate the results, we also assessed another large independent cohort cross-sectionally, the Malmö Diet and Cancer Study (MDC, n=26 777). The data from both cohorts were collected in the 1990s in Sweden.RESULTS: Significant differences between Finnish-born, Middle Eastern and women from the rest of the world were seen for all anthropometric measures, using Swedish-born women as referent. However, WHHR was the only anthropometric measure that identified all these three groups of immigrant women as different from Swedish-born women with high statistical certainty (p<0.001). Apart from WHHR that identified differences in anthropometry in all immigrant groups of men using Swedish-born men as referent, few significant differences were seen in anthropometry among groups of immigrant men. These finding were observed in both cohorts, and remained after adjustments for smoking, physical activity and educational level.CONCLUSION: The present study confirms previous findings of more obesity among immigrants and is the first to report that WHHR measurements may detect anthropometric differences between different ethnic groups better than other anthropometrical measures.
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8.
  • Carrasquilla, Germán D, et al. (author)
  • Does menopausal hormone therapy reduce myocardial infarction risk if initiated early after menopause? : A population-based case-control study
  • 2014
  • In: Menopause. - 1072-3714 .- 1530-0374. ; 22:6, s. 598-606
  • Journal article (peer-reviewed)abstract
    • OBJECTIVE: This study aims to assess whether the timing of menopausal hormone therapy initiation in relation to onset of menopause and hormone therapy duration is associated with myocardial infarction risk.METHODS: This study was based on the Stockholm Heart Epidemiology Program, a population-based case-control study including 347 postmenopausal women who had experienced a nonfatal myocardial infarction and 499 female control individuals matched for age and residential area. Odds ratios (with 95% CIs) for myocardial infarction were calculated using logistic regression.RESULTS: Early initiation of hormone therapy (within 10 y of onset of menopause or before age 60 y), compared with never use, was associated with an odds ratio of 0.87 (95% CI, 0.58-1.30) after adjustments for lifestyle factors, body mass index, and socioeconomic status. For late initiation of hormone therapy, the corresponding odds ratio was 0.97 (95% CI, 0.53-1.76). For hormone therapy duration of 5 years or more, compared with never use, the adjusted odds ratio was 0.64 (95% CI, 0.35-1.18). For hormone therapy duration of less than 5 years, the odds ratio was 0.97 (95% CI, 0.63-1.48).CONCLUSIONS: Neither the timing of hormone therapy initiation nor the duration of therapy is significantly associated with myocardial infarction risk.
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9.
  • Chen, Qiao Sen, et al. (author)
  • A machine learning based approach to identify carotid subclinical atherosclerosis endotypes
  • 2023
  • In: Cardiovascular Research. - : OXFORD UNIV PRESS. - 0008-6363 .- 1755-3245. ; 119:16, s. 2594-2606
  • Journal article (peer-reviewed)abstract
    • Aims To define endotypes of carotid subclinical atherosclerosis. Methods and results We integrated demographic, clinical, and molecular data (n = 124) with ultrasonographic carotid measurements from study participants in the IMPROVE cohort (n = 3340). We applied a neural network algorithm and hierarchical clustering to identify carotid atherosclerosis endotypes. A measure of carotid subclinical atherosclerosis, the c-IMTmean-max, was used to extract atherosclerosis-related features and SHapley Additive exPlanations (SHAP) to reveal endotypes. The association of endotypes with carotid ultrasonographic measurements at baseline, after 30 months, and with the 3-year atherosclerotic cardiovascular disease (ASCVD) risk was estimated by linear (& beta;, SE) and Cox [hazard ratio (HR), 95% confidence interval (CI)] regression models. Crude estimates were adjusted by common cardiovascular risk factors, and baseline ultrasonographic measures. Improvement in ASCVD risk prediction was evaluated by C-statistic and by net reclassification improvement with reference to SCORE2, c-IMTmean-max, and presence of carotid plaques. An ensemble stacking model was used to predict endotypes in an independent validation cohort, the PIVUS (n = 1061). We identified four endotypes able to differentiate carotid atherosclerosis risk profiles from mild (endotype 1) to severe (endotype 4). SHAP identified endotype-shared variables (age, biological sex, and systolic blood pressure) and endotype-specific biomarkers. In the IMPROVE, as compared to endotype 1, endotype 4 associated with the thickest c-IMT at baseline (& beta;, SE) 0.36 (0.014), the highest number of plaques 1.65 (0.075), the fastest c-IMT progression 0.06 (0.013), and the highest ASCVD risk (HR, 95% CI) (1.95, 1.18-3.23). Baseline and progression measures of carotid subclinical atherosclerosis and ASCVD risk were associated with the predicted endotypes in the PIVUS. Endotypes consistently improved measures of ASCVD risk discrimination and reclassification in both study populations. Conclusions We report four replicable subclinical carotid atherosclerosis-endotypes associated with progression of atherosclerosis and ASCVD risk in two independent populations. Our approach based on endotypes can be applied for precision medicine in ASCVD prevention.
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10.
  • Chernogubova, Ekaterina, et al. (author)
  • Common and Low-Frequency Genetic Variants in the PCSK9 Locus Influence Circulating PCSK9 Levels
  • 2012
  • In: Arteriosclerosis, Thrombosis and Vascular Biology. - 1079-5642 .- 1524-4636. ; 32:6, s. 1526-1534
  • Journal article (peer-reviewed)abstract
    • Objective- Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a circulating protein that influences plasma low-density lipoprotein concentration and susceptibility to coronary heart disease. Circulating PCSK9 levels show considerable interindividual differences, but the factors responsible for this variation are largely unknown. Methods and Results- We analyzed circulating PCSK9 levels in 4 cohorts of healthy, middle-aged Swedes (n=5722) and found that PCSK9 levels varied over approximate to 50-fold range, showed a positive relationship with plasma low-density lipoprotein-cholesterol concentration, and were associated with plasma triglyceride, fibrinogen, insulin, and glucose concentrations. A genome-wide association study conducted in 2 cohorts (n=1215) failed to uncover common genetic variants robustly associated with variation in circulating PCSK9 level. As expected, the minor allele of the PCSK9 R46L variant was in all cohorts associated with reduced PCSK9 levels and decreased plasma low-density lipoprotein-cholesterol concentrations, but no relationship was observed with the plasma triglyceride concentration. Further mapping of the PCSK9 locus revealed a common polymorphism (rs2479415, minor allele frequency 43.9%), located approximate to 6 kb upstream from PCSK9, which is independently associated with increased circulating PCSK9 levels. Conclusion- Common and low-frequency genetic variants in the PCSK9 locus influence the pronounced interindividual variation in circulating PCSK9 levels in healthy, middle-aged white (predominantly Swedish) subjects.
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11.
  • de las Fuentes, Lisa, et al. (author)
  • Gene-educational attainment interactions in a multi-ancestry genome-wide meta-analysis identify novel blood pressure loci
  • 2021
  • In: Molecular Psychiatry. - : Springer Nature. - 1359-4184 .- 1476-5578. ; 26:6, s. 2111-2125
  • Journal article (peer-reviewed)abstract
    • Educational attainment is widely used as a surrogate for socioeconomic status (SES). Low SES is a risk factor for hypertension and high blood pressure (BP). To identify novel BP loci, we performed multi-ancestry meta-analyses accounting for gene-educational attainment interactions using two variables, “Some College” (yes/no) and “Graduated College” (yes/no). Interactions were evaluated using both a 1 degree of freedom (DF) interaction term and a 2DF joint test of genetic and interaction effects. Analyses were performed for systolic BP, diastolic BP, mean arterial pressure, and pulse pressure. We pursued genome-wide interrogation in Stage 1 studies (N = 117 438) and follow-up on promising variants in Stage 2 studies (N = 293 787) in five ancestry groups. Through combined meta-analyses of Stages 1 and 2, we identified 84 known and 18 novel BP loci at genome-wide significance level (P < 5 × 10-8). Two novel loci were identified based on the 1DF test of interaction with educational attainment, while the remaining 16 loci were identified through the 2DF joint test of genetic and interaction effects. Ten novel loci were identified in individuals of African ancestry. Several novel loci show strong biological plausibility since they involve physiologic systems implicated in BP regulation. They include genes involved in the central nervous system-adrenal signaling axis (ZDHHC17, CADPS, PIK3C2G), vascular structure and function (GNB3, CDON), and renal function (HAS2 and HAS2-AS1, SLIT3). Collectively, these findings suggest a role of educational attainment or SES in further dissection of the genetic architecture of BP.
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12.
  • Do, Ron, et al. (author)
  • Common variants associated with plasma triglycerides and risk for coronary artery disease
  • 2013
  • In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:11, s. 1345-
  • Journal article (peer-reviewed)abstract
    • Triglycerides are transported in plasma by specific triglyceride-rich lipoproteins; in epidemiological studies, increased triglyceride levels correlate with higher risk for coronary artery disease (CAD). However, it is unclear whether this association reflects causal processes. We used 185 common variants recently mapped for plasma lipids (P < 5 x 10(-8) for each) to examine the role of triglycerides in risk for CAD. First, we highlight loci associated with both low-density lipoprotein cholesterol (LDL-C) and triglyceride levels, and we show that the direction and magnitude of the associations with both traits are factors in determining CAD risk. Second, we consider loci with only a strong association with triglycerides and show that these loci are also associated with CAD. Finally, in a model accounting for effects on LDL-C and/or high-density lipoprotein cholesterol (HDL-C) levels, the strength of a polymorphism's effect on triglyceride levels is correlated with the magnitude of its effect on CAD risk. These results suggest that triglyceride-rich lipoproteins causally influence risk for CAD.
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  • Ekblom Bak, Elin, 1981-, et al. (author)
  • Physical activity attenuates cardiovascular risk and mortality in men and women with and without the metabolic syndrome - a 20-year follow-up of a population-based cohort of 60-year-olds.
  • 2021
  • In: European Journal of Preventive Cardiology. - : Sage Publications. - 2047-4873 .- 2047-4881. ; 8:12, s. 1376-1385
  • Journal article (peer-reviewed)abstract
    • AimsThe purpose of this study was to analyse the association of leisure-time physical activity of different intensities at baseline, and cardiovascular disease incidence, cardiovascular disease mortality and all-cause mortality in a population-based sample of 60-year-old men and women with and without established metabolic syndrome, for more than 20 years of follow-up. A secondary aim was to study which cardiometabolic factors may mediate the association between physical activity and long-term outcomes.MethodsA total of 3693 participants (53% women) underwent physical examination and laboratory tests, completed an extensive questionnaire at baseline 1997–1999 and were followed until their death or until 31 December 2017. First-time cardiovascular disease events and death from any cause were ascertained through regular examinations of national registers.ResultsMetabolic syndrome prevalence was 23.0%. In metabolic syndrome participants, light physical activity attenuated cardiovascular disease incidence (hazard ratio = 0.71; 95% confidence interval 0.50–1.00) compared to sedentary (reference) after multi-adjustment. Moderate/high physical activity was inversely associated with both cardiovascular disease and all-cause mortality, but became non-significant after multi-adjustment. Sedentary non-metabolic syndrome participants had lower cardiovascular disease incidence (0.47; 0.31–0.72) but not significantly different cardiovascular disease (0.61; 0.31–1.19) and all-cause mortality (0.92; 0.64–1.34) compared to sedentary metabolic syndrome participants. Both light and moderate/high physical activity were inversely associated with cardiovascular disease and all-cause mortality in non-metabolic syndrome participants (p<0.05). There were significant variations in several central cardiometabolic risk factors with physical activity level in non-metabolic syndrome participants. Fibrinogen mediated the protective effects of physical activity in non-metabolic syndrome participants.ConclusionPhysical activity of different intensities attenuated cardiovascular risk and mortality in 60-year old men and women with metabolic syndrome during a 20-year follow-up.
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14.
  • Engström, Gunnar, et al. (author)
  • Pulmonary function and atherosclerosis in the general population : causal associations and clinical implications
  • 2024
  • In: European Journal of Epidemiology. - : Springer Nature. - 0393-2990 .- 1573-7284. ; 39:1, s. 35-49
  • Journal article (peer-reviewed)abstract
    • Reduced lung function is associated with cardiovascular mortality, but the relationships with atherosclerosis are unclear. The population-based Swedish CArdioPulmonary BioImage study measured lung function, emphysema, coronary CT angiography, coronary calcium, carotid plaques and ankle-brachial index in 29,593 men and women aged 50–64 years. The results were confirmed using 2-sample Mendelian randomization. Lower lung function and emphysema were associated with more atherosclerosis, but these relationships were attenuated after adjustment for cardiovascular risk factors. Lung function was not associated with coronary atherosclerosis in 14,524 never-smokers. No potentially causal effect of lung function on atherosclerosis, or vice versa, was found in the 2-sample Mendelian randomization analysis. Here we show that reduced lung function and atherosclerosis are correlated in the population, but probably not causally related. Assessing lung function in addition to conventional cardiovascular risk factors to gauge risk of subclinical atherosclerosis is probably not meaningful, but low lung function found by chance should alert for atherosclerosis.
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15.
  • Feitosa, Mary F., et al. (author)
  • Novel genetic associations for blood pressure identified via gene-alcohol interaction in up to 570K individuals across multiple ancestries
  • 2018
  • In: PLOS ONE. - : Public library science. - 1932-6203. ; 13:6
  • Journal article (peer-reviewed)abstract
    • Heavy alcohol consumption is an established risk factor for hypertension; the mechanism by which alcohol consumption impact blood pressure (BP) regulation remains unknown. We hypothesized that a genome-wide association study accounting for gene-alcohol consumption interaction for BP might identify additional BP loci and contribute to the understanding of alcohol-related BP regulation. We conducted a large two-stage investigation incorporating joint testing of main genetic effects and single nucleotide variant (SNV)-alcohol consumption interactions. In Stage 1, genome-wide discovery meta-analyses in approximate to 131 K individuals across several ancestry groups yielded 3,514 SNVs (245 loci) with suggestive evidence of association (P <1.0 x 10(-5)). In Stage 2, these SNVs were tested for independent external replication in individuals across multiple ancestries. We identified and replicated (at Bonferroni correction threshold) five novel BP loci (380 SNVs in 21 genes) and 49 previously reported BP loci (2,159 SNVs in 109 genes) in European ancestry, and in multi-ancestry meta-analyses (P < 5.0 x 10(-8)). For African ancestry samples, we detected 18 potentially novel BP loci (P< 5.0 x 10(-8)) in Stage 1 that warrant further replication. Additionally, correlated meta-analysis identified eight novel BP loci (11 genes). Several genes in these loci (e.g., PINX1, GATA4, BLK, FTO and GABBR2 have been previously reported to be associated with alcohol consumption. These findings provide insights into the role of alcohol consumption in the genetic architecture of hypertension.
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  • Gaulton, Kyle J, et al. (author)
  • Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci.
  • 2015
  • In: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 47:12, s. 1415-1415
  • Journal article (peer-reviewed)abstract
    • We performed fine mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in or near KCNQ1. 'Credible sets' of the variants most likely to drive each distinct signal mapped predominantly to noncoding sequence, implying that association with T2D is mediated through gene regulation. Credible set variants were enriched for overlap with FOXA2 chromatin immunoprecipitation binding sites in human islet and liver cells, including at MTNR1B, where fine mapping implicated rs10830963 as driving T2D association. We confirmed that the T2D risk allele for this SNP increases FOXA2-bound enhancer activity in islet- and liver-derived cells. We observed allele-specific differences in NEUROD1 binding in islet-derived cells, consistent with evidence that the T2D risk allele increases islet MTNR1B expression. Our study demonstrates how integration of genetic and genomic information can define molecular mechanisms through which variants underlying association signals exert their effects on disease.
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17.
  • Gertow, Karl, et al. (author)
  • Identification of the BCAR1-CFDP1-TMEM170A Locus as a Determinant of Carotid Intima-Media Thickness and Coronary Artery Disease Risk
  • 2012
  • In: Circulation: Cardiovascular Genetics. - 1942-325X .- 1942-3268. ; 5:6, s. 656-665
  • Journal article (peer-reviewed)abstract
    • Background-Carotid intima-media thickness (cIMT) is a widely accepted marker of subclinical atherosclerosis. To date, large-scale investigations of genetic determinants of cIMT are sparse. Methods and Results-To identify cIMT-associated genes and genetic variants, a discovery analysis using the Illumina 200K CardioMetabochip was conducted in 3430 subjects with detailed ultrasonographic determinations of cIMT from the IMPROVE (Carotid Intima Media Thickness [IMT] and IMT-Progression as Predictors of Vascular Events in a High Risk European Population) study. Segment-specific IMT measurements of common carotid, bifurcation, and internal carotid arteries, and composite IMT variables considering the whole carotid tree (IMTmean, IMTmax, and IMTmean-max), were analyzed. A replication stage investigating 42 single-nucleotide polymorphisms for association with common carotid IMT was undertaken in 5 independent European cohorts (total n=11 590). A locus on chromosome 16 (lead single-nucleotide polymorphism rs4888378, intronic in CFDP1) was associated with cIMT at significance levels passing multiple testing correction at both stages (array-wide significant discovery P=6.75x10(-7) for IMTmax; replication P=7.24x10(-6) for common cIMT; adjustments for sex, age, and population substructure where applicable; minor allele frequency 0.43 and 0.41, respectively). The protective minor allele was associated with lower carotid plaque score in a replication cohort (P=0.04, n=2120) and lower coronary artery disease risk in 2 case-control studies of subjects with European ancestry (odds ratio [95% confidence interval] 0.83 [0.77-0.90], P=6.53x10(-6), n=13 591; and 0.95 [0.92-0.98], P=1.83x10(-4), n= 82 297, respectively). Queries of human biobank data sets revealed associations of rs4888378 with nearby gene expression in vascular tissues (n=126-138). Conclusions-This study identified rs4888378 in the BCAR1-CFDP1-TMEM170A locus as a novel genetic determinant of cIMT and coronary artery disease risk in individuals of European descent. (Circ Cardiovasc Genet. 2012;5:656-665.)
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18.
  • Gigante, Bruna, et al. (author)
  • Management of patients on antithrombotic therapy with severe infections : a joint clinical consensus statement of the ESC Working Group on Thrombosis, the ESC Working Group on Atherosclerosis and Vascular Biology, and the International Society on Thrombosis and Haemostasis
  • 2023
  • In: European Heart Journal. - : Oxford University Press. - 0195-668X .- 1522-9645. ; 44:32, s. 3040-3058
  • Journal article (peer-reviewed)abstract
    • Patients with severe infections and a pre-existing indication for antithrombotic therapy, i.e. antiplatelet agents, anticoagulant drugs, or their combinations, require integrated clinical counselling among coagulation, infectious disease, and cardiology specialists, due to sepsis-induced coagulopathy that frequently occurs. Bacterial and viral pathogens constitute an increasing threat to global public health, especially for patients with ongoing antithrombotic treatment who have a high risk of thrombotic recurrences and high susceptibility to severe infections with increased morbidity and mortality. Similarly, sepsis survivors are at increased risk for major vascular events. Coagulopathy, which often complicates severe infections, is associated with a high mortality and obligates clinicians to adjust antithrombotic drug type and dosing to avoid bleeding while preventing thrombotic complications. This clinical consensus statement reviews the best available evidence to provide expert opinion and statements on the management of patients hospitalized for severe bacterial or viral infections with a pre-existing indication for antithrombotic therapy (single or combined), in whom sepsis-induced coagulopathy is often observed. Balancing the risk of thrombosis and bleeding in these patients and preventing infections with vaccines, if available, are crucial to prevent events or improve outcomes and prognosis.
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19.
  • Harrison, Seamus C., et al. (author)
  • A gene-centric study of common carotid artery remodelling
  • 2013
  • In: Atherosclerosis. - : Elsevier BV. - 0021-9150 .- 1879-1484. ; 226:2, s. 440-446
  • Journal article (peer-reviewed)abstract
    • Background: Expansive remodelling is the process of compensatory arterial enlargement in response to atherosclerotic stimuli. The genetic determinants of this process are poorly characterized. Methods: Genetic association analyses of inter-adventitial common carotid artery diameter (ICCAD) in the IMPROVE study (n = 3427) using the Illumina 200k Metabochip was performed. Single nucleotide polymorphisms (SNPs) that met array-wide significance were taken forward for analysis in three further studies (n = 5704), and tested for association with Abdominal Aortic Aneurysm (AAA). Results: rs3768445 on Chromosome 1q24.3, in a cluster of protein coding genes (DNM3, PIGC, C1orf105) was associated with larger ICCAD in the IMPROVE study. For each copy of the rare allele carried, ICCAD was on average 0.13 mm greater (95% CI 0.08-0.18 mm, P = 8.2 x 10(-8)). A proxy SNP (rs4916251, R-2 = 0.99) did not, however, show association with ICCAD in three follow-up studies (P for replication = 0.29). There was evidence of interaction between carotid intima-media thickness (CIMT) and rs4916251 on ICCAD in two of the cohorts studies suggesting that it plays a role in the remodelling response to atherosclerosis. In meta-analysis of 5 case-control studies pooling data from 5007 cases and 43,630 controls, rs4916251 was associated with presence of AAA 1.10, 95% CI 1.03-1.17, p = 2.8 x 10(-3), I-2 = 18.8, Q = 0.30). A proxy SNP, rs4916251 was also associated with increased expression of PIGC in aortic tissue, suggesting that this may the mechanism by which this locus affects vascular remodelling. Conclusions: Common variation at 1q24.3 is associated with expansive vascular remodelling and risk of AAA. These findings support a hypothesis that pathways involved in systemic vascular remodelling play a role in AAA development.
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20.
  • Hägg, Sara, 1977-, et al. (author)
  • 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
  • In: PLoS Genetics. - : PLoS Genetics. - 1553-7390 .- 1553-7404. ; 5:12, s. e1000754-
  • Journal article (peer-reviewed)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.
  •  
21.
  • Ibsen, Daniel B., et al. (author)
  • The DASH diet is associated with a lower risk of heart failure : a cohort study
  • 2022
  • In: European Journal of Preventive Cardiology. - : OXFORD UNIV PRESS. - 2047-4873 .- 2047-4881. ; 29:7, s. 1114-1123
  • Journal article (peer-reviewed)abstract
    • Aims Trials demonstrate that following the DASH diet lowers blood pressure, which may prevent the development of heart failure (HF). We investigated the association between long-term adherence to the DASH diet and food substitutions within the DASH diet on the risk of HF. Methods and results Men and women aged 45-83 years without previous HF, ischaemic heart disease or cancer at baseline in 1998 from the Cohort of Swedish Men (n = 41 118) and the Swedish Mammography Cohort (n = 35 004) were studied. The DASH diet emphasizes intake of fruit, vegetables, whole grains, nuts and legumes, and low-fat dairy and deemphasizes red and processed meat, sugar-sweetened beverages, and sodium. DASH diet scores were calculated based on diet assessed by food frequency questionnaires in late 1997 and 2009. Incidence of HF was ascertained using the Swedish Patient Register. Multivariable Cox proportional hazards models were used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs). During the median 22 years of follow-up (1998-2019), 12 164 participants developed HF. Those with the greatest adherence to the DASH diet had a lower risk of HF compared to those with the lowest adherence (HR 0.85, 95% CI: 0.80, 0.91 for baseline diet and HR 0.83, 95% CI: 0.78, 0.89 for long-term diet, comparing quintiles). Replacing 1 serving/day of red and processed meat with emphasized DASH diet foods was associated with an 8-12% lower risk of HF. Conclusion Long-term adherence to the DASH diet and relevant food substitutions within the DASH diet were associated with a lower risk of HF.
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22.
  • Klaric, Lucija, et al. (author)
  • Mendelian randomisation identifies alternative splicing of the FAS death receptor as a mediator of severe COVID-19.
  • 2021
  • In: medRxiv : the preprint server for health sciences. - : Cold Spring Harbor Laboratory. ; , s. 1-28
  • Other publication (other academic/artistic)abstract
    • Severe COVID-19 is characterised by immunopathology and epithelial injury. Proteomic studies have identified circulating proteins that are biomarkers of severe COVID-19, but cannot distinguish correlation from causation. To address this, we performed Mendelian randomisation (MR) to identify proteins that mediate severe COVID-19. Using protein quantitative trait loci (pQTL) data from the SCALLOP consortium, involving meta-analysis of up to 26,494 individuals, and COVID-19 genome-wide association data from the Host Genetics Initiative, we performed MR for 157 COVID-19 severity protein biomarkers. We identified significant MR results for five proteins: FAS, TNFRSF10A, CCL2, EPHB4 and LGALS9. Further evaluation of these candidates using sensitivity analyses and colocalization testing provided strong evidence to implicate the apoptosis-associated cytokine receptor FAS as a causal mediator of severe COVID-19. This effect was specific to severe disease. Using RNA-seq data from 4,778 individuals, we demonstrate that the pQTL at the FAS locus results from genetically influenced alternate splicing causing skipping of exon 6. We show that the risk allele for very severe COVID-19 increases the proportion of transcripts lacking exon 6, and thereby increases soluble FAS. Soluble FAS acts as a decoy receptor for FAS-ligand, inhibiting apoptosis induced through membrane-bound FAS. In summary, we demonstrate a novel genetic mechanism that contributes to risk of severe of COVID-19, highlighting a pathway that may be a promising therapeutic target.
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23.
  • Krychtiuk, Konstantin A., et al. (author)
  • Biomarkers of coagulation and fibrinolysis in acute myocardial infarction : a joint position paper of the Association for Acute Cardio Vascular Care and the European Society of Cardiology Working Group on Thrombosis
  • 2021
  • In: European Heart Journal. - : Oxford University Press. - 2048-8726 .- 2048-8734. ; 10:3, s. 343-355
  • Research review (peer-reviewed)abstract
    • The formation of a thrombus in an epicardial artery may result in an acute myocardial infarction (AMI). Despite major advances in acute treatment using network approaches to allocate patients to timely reperfusion and optimal antithrombotic treatment, patients remain at high risk for thrombotic complications. Ongoing activation of the coagulation system as well as thrombin-mediated platelet activation may both play a crucial role in this context. Whether measurement of circulating biomarkers of coagulation and fibrinolysis could be useful for risk stratification in secondary prevention is currently not fully understood. In addition, measurement of such biomarkers could be helpful to identify thrombus formation as the leading mechanism for AMI. The introduction of biomarkers of myocardial injury such as high-sensitivity cardiac troponins made rule-out of AMI even more precise. However, elevated markers of myocardial injury cannot provide proof of a type 1 AMI, let alone thrombus formation. The combined measurement of markers of myocardial injury with biomarkers reflecting ongoing thrombus formation might be helpful for the fast and correct diagnosis of an atherothrombotic type 1 AMI. This position paper gives an overview of the current knowledge and possible role of biomarkers of coagulation and fibrinolysis for the diagnosis of AMI, risk stratification, and individualized treatment strategies in patients with AMI.
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24.
  • Larsson, Susanna C., et al. (author)
  • Chocolate consumption and risk of myocardial infarction : a prospective study and meta-analysis.
  • 2016
  • In: Heart. - : BMJ. - 1355-6037 .- 1468-201X. ; 102:13, s. 1017-22
  • Journal article (peer-reviewed)abstract
    • OBJECTIVE: To examine whether chocolate consumption is associated with a reduced risk of ischaemic heart disease, we used data from a prospective study of Swedish adults and we performed a meta-analysis of available prospective data.METHODS AND RESULTS: The Swedish prospective study included 67 640 women and men from the Cohort of Swedish Men and the Swedish Mammography Cohort who had completed a food-frequency questionnaire and were free of cardiovascular disease at baseline. Myocardial infarction (MI) cases were ascertained through linkage with the Swedish National Patient and Cause of Death Registers. PubMed and EMBASE databases were searched from inception until 4 February 2016 to identify prospective studies on chocolate consumption and risk of ischaemic heart disease.RESULTS: The results from eligible studies were combined using a random-effects model. During follow-up (1998-2010), 4417 MI cases were ascertained in the Swedish study. Chocolate consumption was inversely associated with MI risk. Compared with non-consumers, the multivariable relative risk for those who consumed ≥3-4 servings/week of chocolate was 0.87 (95% CI 0.77 to 0.98; p for trend =0.04). Five prospective studies on chocolate consumption and ischaemic heart disease were identified. Together with the Swedish study, the meta-analysis included six studies with a total of 6851 ischaemic heart disease cases. The overall relative risk for the highest versus lowest category of chocolate consumption was 0.90 (95% CI 0.82 to 0.97), with little heterogeneity among studies (I(2)=24.3%).CONCLUSIONS: Chocolate consumption is associated with lower risk of MI and ischaemic heart disease.
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25.
  • Larsson, Susanna C., et al. (author)
  • Healthy Lifestyle and Risk of Heart Failure : Results From 2 Prospective Cohort Studies
  • 2016
  • In: Circulation Heart Failure. - 1941-3289 .- 1941-3297. ; 9:4
  • Journal article (peer-reviewed)abstract
    • BACKGROUND: The joint impact of multiple healthy lifestyle factors on heart failure (HF) risk is unclear. We investigated the separate and collective associations of healthy lifestyle factors with HF incidence in 2 population-based prospective cohort studies.METHODS AND RESULTS: This study consisted of 33,966 men (Cohort of Swedish Men) and 30,713 women (Swedish Mammography Cohort) who were 45 to 83 years of age and free of HF and ischemic heart disease at baseline. A healthy lifestyle was defined as being a nonsmoker and physically active (≥150 min/wk), and having body mass index between 18.5 and 25 kg/m(2) and a healthy diet (defined as adherence to a modified Mediterranean diet). Incident HF cases were ascertained by linkage with the Swedish National Patient Register and the Swedish Cause of Death Register. Cox proportional hazards regression was used to analyze the data. During 13 years of follow-up, HF was diagnosed in 1488 men and 1096 women. Each healthy lifestyle factor was associated with a statistically significant lower risk of HF in both men and women, and the risk decreased with increasing number of healthy behaviors. The greatest reduction in HF risk was observed for combinations that included nonsmoking. Compared with men and women with none of the healthy lifestyle factors, the multivariable relative risks (95% confidence interval) of HF for those with all 4 healthy behaviors were 0.38 (0.28-0.53) in men and 0.28 (0.19-0.41) in women.CONCLUSIONS: Adhering to a healthy lifestyle is associated with a substantially lower HF risk.CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifiers: NCT01127698 and NCT01127711.
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26.
  • Lind, Lars, et al. (author)
  • Plasma Protein Profile of Carotid Artery Atherosclerosis and Atherosclerotic Outcomes : Meta-Analyses and Mendelian Randomization Analyses
  • 2021
  • In: Arteriosclerosis, Thrombosis and Vascular Biology. - : Lippincott Williams & Wilkins. - 1079-5642 .- 1524-4636. ; 41:5, s. 1777-1788
  • Journal article (peer-reviewed)abstract
    • OBJECTIVE: To identify causal pathophysiological mechanisms for atherosclerosis and incident cardiovascular events using protein measurements.APPROACH AND RESULTS: Carotid artery atherosclerosis was assessed by ultrasound, and 86 cardiovascular-related proteins were measured using the Olink CVD-I panel in 7 Swedish prospective studies (11 754 individuals). The proteins were analyzed in relation to intima-media thickness in the common carotid artery (IMT-CCA), plaque occurrence, and incident cardiovascular events (composite end point of myocardial infarction or ischemic stroke) using a discovery/replication approach in different studies. After adjustments for traditional cardiovascular risk factors, 11 proteins remained significantly associated with IMT-CCA in the replication stage, whereas 9 proteins were replicated for plaque occurrence and 17 proteins for incident cardiovascular events. NT-proBNP (N-terminal pro-B-type natriuretic peptide) and MMP (matrix metalloproteinase)-12 were associated with both IMT-CCA and incident events, but the overlap was considerably larger between plaque occurrence and incident events, including MMP-12, TIM-1 (T-cell immunoglobulin and mucin domain 1), GDF (growth/differentiation factor)-15, IL (interleukin)-6, U-PAR (urokinase plasminogen activator surface receptor), LOX-1 (lectin-like oxidized LDL [low-density lipoprotein] receptor 1), and TRAIL-R2 (TNF [tumor necrosis factor]-related apoptosis-inducing ligand receptor 2). Only MMP-12 was associated with IMT-CCA, plaque, and incident events with a positive and concordant direction of effect. However, a 2-sample Mendelian randomization analysis suggested that increased MMP-12 may be protective against ischemic stroke (P=5.5x10(-7)), which is in the opposite direction of the observational analyses.CONCLUSIONS: The present meta-analysis discovered several proteins related to carotid atherosclerosis that partly differed in their association with IMT-CCA, plaque, and incident atherosclerotic disease. Mendelian randomization analysis for the top finding, MMP-12, suggests that the increased levels of MMP-12 could be a consequence of atherosclerotic burden rather than the opposite chain of events.
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27.
  • Lind, Lars, et al. (author)
  • The plasma protein profile and cardiovascular risk differ between intima-media thickness of the common carotid artery and the bulb : A meta-analysis and a longitudinal evaluation
  • 2020
  • In: Atherosclerosis. - : ELSEVIER IRELAND LTD. - 0021-9150 .- 1879-1484. ; 295, s. 25-30
  • Journal article (peer-reviewed)abstract
    • Background and aims: Genetic loci associated with CHD show different relationships with intima-media thickness in the common carotid artery (IMT-CCA) and in the bulb (IMT-bulb). We evaluated if IMT-CCA and IMT-bulb differ also with respect to circulating protein profiles and risk of incident atherosclerotic disease.Methods: In three Swedish cohorts (MDC, IMPROVE, PIVUS, total n > 7000), IMT-CCA and IMT-bulb were assessed by ultrasound at baseline, and 86 cardiovascular-related proteins were analyzed. In the PIVUS study only, IMT-CCA and IMT-bulb were investigated in relation to incident atherosclerotic disease over 10 years of follow-up.Results: In a meta-analysis of the analysis performed separately in the cohorts, three proteins, matrix metalloproteinase-12 (MMP-12), hepatocyte growth factor (HGF) and N-terminal pro-B-type natriuretic peptide (NT-proBNP), were associated with IMT-CCA when adjusted for traditional cardiovascular risk factors. Five proteins were associated with IMT-bulb (MMP-12, growth/differentiation factor 15 (GDF-15), osteoprotegerin, growth hormone and renin). Following adjustment for cardiovascular risk factors, IMT-bulb was significantly more closely related to incident stroke or myocardial infarction (total number of cases, 111) than IMT-CCA in the PIVUS study (HR 1.51 for 1 SD, 95%CI 1.21-1.87, p < 0.001 vs HR 1.17, 95%CI 0.93-1.47, p = 0.16). MMP-12 levels were related to this combined end-point (HR 1.30, 95%CI 1.08-1.56, p = 0.0061).Conclusions: Elevated levels of MMP-12 were associated with both IMT-CCA and IMT-bulb, but other proteins were significantly related to IMT in only one of these locations. The finding that IMT-bulb was more closely related to incident atherosclerotic disease than IMT-CCA emphasizes a difference between these measurements of IMT.
  •  
28.
  • Locke, Adam E, et al. (author)
  • Genetic studies of body mass index yield new insights for obesity biology.
  • 2015
  • In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 518:7538, s. 197-401
  • Journal article (peer-reviewed)abstract
    • Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.
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29.
  • Lundström, Annika, et al. (author)
  • High Thrombin Generation after Acute Ischemic Stroke or Transient Ischemic Attack Is Associated with a Reduced Risk of Recurrence : An Observational Cohort Study
  • 2021
  • In: Thrombosis and Haemostasis. - : Georg Thieme Verlag KG. - 0340-6245 .- 2567-689X. ; 121:05, s. 584-593
  • Journal article (peer-reviewed)abstract
    • Thrombin is increasingly recognized to be of importance for cardiovascular disease. The aim of this study was to investigate the prognostic value of thrombin generation variables in a cohort of patients with acute ischemic stroke (AIS) or transient ischemic attack (TIA). Thrombin generation potential measured by calibrated automated thrombogram (CAT) and prothrombin fragment F1+2 was determined in the acute and convalescent phases for a cohort of 190 patients with AIS/TIA. Microvesicle (MV)-induced thrombin generation potential was determined for a subset of patients using modified CAT. Primary outcome was a composite of fatal and nonfatal AIS or myocardial infarction as documented in Swedish registers during a total follow-up of 986 patient-years. Hazard ratios (HRs) were calculated using Cox regression based on variable median split. Peak thrombin and endogenous thrombin potential (ETP) above median in the acute phase were associated with a reduced risk of primary outcome after adjustment for cardiovascular risk factors, HR: 0.50 (0.27-0.92), p =0.026 and HR: 0.53 (0.28-0.99), p =0.048, respectively. F1+2 was lower in patients than in healthy controls but not associated with outcome. MV-induced peak thrombin above median in the acute phase was associated with recurrent AIS, unadjusted HR: 2.65 (1.03-6.44), p =0.044. Contrary to expectation, high thrombin generation potential is associated with a reduced risk of recurrent ischemic event in patients with AIS/TIA. Low ETP/peak thrombin combined with high MV-induced peak thrombin can potentially identify patients at high risk of recurrence.
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30.
  • Lundström, Annika, et al. (author)
  • Prognostic Value of Circulating Microvesicle Subpopulations in Ischemic Stroke and TIA
  • 2020
  • In: Translational Stroke Research. - : Springer Science and Business Media LLC. - 1868-4483 .- 1868-601X. ; 11:4, s. 708-719
  • Journal article (peer-reviewed)abstract
    • Platelet microvesicles (PMV) have previously been found elevated in acute ischemic stroke (IS) and could be biomarkers for risk of recurrence. PMV surface antigens such as P-selectin and phosphatidylserine (PS) reflect platelet activation and procoagulance. Tissue factor-positive microvesicles (TF+MV) are considered procoagulant, in particular if co-expressing PS. We enumerated MV subpopulations with these surface antigens in a cohort of 211 patients with primarily non-cardioembolic IS or transient ischemic attack (TIA) and investigated their association with long-term outcome. MV concentrations were determined by flow cytometry in the acute and convalescent phase. Primary outcome was a composite of fatal and non-fatal recurrent IS or myocardial infarction. Secondary outcomes were recurrent IS and all-cause mortality. Outcome events were obtained from Swedish registers during a follow-up of 1100 patient years. Concentrations of PS-positive and PS-negative MV populations were elevated in patients compared with healthy controls in both the acute and convalescent phase. PS+TF+PMV displayed pronounced elevations, median fold change 77 in the acute phase (p < 0.0001) but were not associated with outcome, neither were PS+P-selectin(+)PMV. The only subpopulation positively associated with primary outcome was PS-TF+PMV, with adjusted hazard ratio of 1.86 (1.04-3.31,p = 0.036) by Cox regression. Unexpectedly, several MV subpopulations tended to be associated with reduced risk of poor long-term outcome. Our results suggest that PS+TF+PMV may be a promising marker for cerebral ischemia, and that the in vivo generation of PS-MV after IS/TIA warrants further study. Future MV studies should ideally enumerate PS(+)and PS-MV subpopulations separately.
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31.
  • Marklund, Matti, et al. (author)
  • Biomarkers of Dietary Omega-6 Fatty Acids and Incident Cardiovascular Disease and Mortality : An Individual-Level Pooled Analysis of 30 Cohort Studies
  • 2019
  • In: Circulation. - : American Heart Association. - 0009-7322 .- 1524-4539. ; 139:21, s. 2422-2436
  • Journal article (peer-reviewed)abstract
    • Background:Global dietary recommendations for and cardiovascular effects of linoleic acid, the major dietary omega-6 fatty acid, and its major metabolite, arachidonic acid, remain controversial. To address this uncertainty and inform international recommendations, we evaluated how in vivo circulating and tissue levels of linoleic acid (LA) and arachidonic acid (AA) relate to incident cardiovascular disease (CVD) across multiple international studies.Methods:We performed harmonized, de novo, individual-level analyses in a global consortium of 30 prospective observational studies from 13 countries. Multivariable-adjusted associations of circulating and adipose tissue LA and AA biomarkers with incident total CVD and subtypes (coronary heart disease, ischemic stroke, cardiovascular mortality) were investigated according to a prespecified analytic plan. Levels of LA and AA, measured as the percentage of total fatty acids, were evaluated linearly according to their interquintile range (ie, the range between the midpoint of the first and fifth quintiles), and categorically by quintiles. Study-specific results were pooled using inverse-variance-weighted meta-analysis. Heterogeneity was explored by age, sex, race, diabetes mellitus, statin use, aspirin use, omega-3 levels, and fatty acid desaturase 1 genotype (when available).Results:In 30 prospective studies with medians of follow-up ranging 2.5 to 31.9 years, 15198 incident cardiovascular events occurred among 68659 participants. Higher levels of LA were significantly associated with lower risks of total CVD, cardiovascular mortality, and ischemic stroke, with hazard ratios per interquintile range of 0.93 (95% CI, 0.88-0.99), 0.78 (0.70-0.85), and 0.88 (0.79-0.98), respectively, and nonsignificantly with lower coronary heart disease risk (0.94; 0.88-1.00). Relationships were similar for LA evaluated across quintiles. AA levels were not associated with higher risk of cardiovascular outcomes; in a comparison of extreme quintiles, higher levels were associated with lower risk of total CVD (0.92; 0.86-0.99). No consistent heterogeneity by population subgroups was identified in the observed relationships.Conclusions:In pooled global analyses, higher in vivo circulating and tissue levels of LA and possibly AA were associated with lower risk of major cardiovascular events. These results support a favorable role for LA in CVD prevention.
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32.
  • Marklund, Matti, et al. (author)
  • Polyunsaturated Fat Intake Estimated by Circulating Biomarkers and Risk of Cardiovascular Disease and All-Cause Mortality in a Population-Based Cohort of 60-Year-Old Men and Women
  • 2015
  • In: Circulation. - 0009-7322 .- 1524-4539. ; 132:7, s. 586-594
  • Journal article (peer-reviewed)abstract
    • Background High intake of polyunsaturated fatty acids (PUFAs) may reduce the risk of cardiovascular disease (CVD) and mortality. Large, prospective studies including both sexes and circulating PUFAs as dietary biomarkers are needed. We investigated sex-specific associations of the major dietary PUFAs, eicosapentaenoic acid, docohexaenoic acid, linoleic acid, and -linolenic acid, with incident CVD and all-cause mortality in a population-based cohort. Methods and Results PUFAs in serum cholesterol esters were measured at baseline in 60-year-old Swedish women (n=2193) and men (n=2039). With the use of national registers, 484 incident CVD events (294 men and 190 women) and 456 all-cause deaths (265 men and 191 women) were identified during follow-up (median, 14.5 years) in individuals without prior CVD at baseline. Associations of PUFAs with CVD and mortality were evaluated with Cox proportional hazard models. In multivariable-adjusted models, 1-SD increases in eicosapentaenoic acid and docohexaenoic acid were associated with lower risk of incident CVD among women (hazard ratio [HR], 0.79 [95% confidence interval (CI), 0.64-0.97] and 0.74 [95% CI, 0.61-0.89], respectively). -Linolenic acid was associated with moderately increased CVD risk in women (HR, 1.16; 95% CI, 1.02-1.32). Inverse associations with all-cause mortality were observed for eicosapentaenoic acid and docohexaenoic acid among all participants (HR, 0.81 [95% CI, 0.72-0.91] and 0.80 [95% CI, 0.72-0.89], respectively) and for linoleic acid in men (HR, 0.73; 95% CI, 0.64-0.83). Conclusions Serum linoleic acid and very-long-chain n-3 PUFAs, partly reflecting vegetable oil and fish intake, respectively, were inversely associated with all-cause mortality. Inverse associations of eicosapentaenoic acid and docohexaenoic acid with incident CVD were observed only in women.
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33.
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34.
  • McGale, Paul, et al. (author)
  • Incidence of heart disease in 35,000 women treated with radiotherapy for breast cancer in Denmark and Sweden
  • 2011
  • In: Radiotherapy and Oncology. - Amsterdam : Elsevier. - 0167-8140 .- 1879-0887. ; 100:2, s. 167-175
  • Journal article (peer-reviewed)abstract
    • Purpose: To study incidence of radiation-related heart disease in a large population of breast cancer patients followed for up to 30 years. Material and methods: 72,134 women diagnosed with breast cancer in Denmark or Sweden during 1976-2006 and followed prospectively. Radiation-related risk was studied by comparing women with left-sided and right-sided tumours. Results: 34,825 women (48%) received radiotherapy. Among unirradiated women tumour laterality had little relevance to heart disease. Among irradiated women mean dose to the whole heart was 6.3 Gy for left-sided tumours and 2.7 Gy for right-sided tumours. Mortality was similar in irradiated women with left-sided and right-sided tumours, but incidence ratios, left-sided versus right-sided, were raised: acute myocardial infarction 1.22 (95% CI 1.06-1.42), angina 1.25 (1.05-1.49), pericarditis 1.61 (1.06-2.43), valvular heart disease 1.54 (1.11-2.13). Incidence ratios for all heart disease were as high for women irradiated since 1990 (1.09 [1.00-1.19]) as for women irradiated during 1976-1989 (1.08 [0.99-1.17]), and were higher for women diagnosed with ischaemic heart disease prior to breast cancer than for other women (1.58 [1.19-2.10] versus 1.08 [1.01-1.15], p for difference = 0.01). Conclusions: Breast cancer radiotherapy has, at least until recently, increased the risk of developing ischaemic heart disease, pericarditis and valvular disease. Women with ischaemic heart disease before breast cancer diagnosis may have incurred higher risks than others. (C) 2011 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology 100 (2011) 167-175
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35.
  • McLeod, Olga, et al. (author)
  • Plasma autoantibodies against apolipoprotein B-100 peptide 210 in subclinical atherosclerosis.
  • 2014
  • In: Atherosclerosis. - : Elsevier BV. - 1879-1484 .- 0021-9150. ; 232:1, s. 242-248
  • Journal article (peer-reviewed)abstract
    • Experimental studies have suggested that autoimmunity is involved in atherosclerosis and provided evidence that both protective and pro-atherogenic immune responses exist. This concept has received support from small clinical studies implicating autoantibodies directed against apolipoprotein B-100 (apoB-100) in human atherosclerosis. We examined circulating autoantibodies directed against native and malondialdehyde (MDA)-modified epitope p210 of apoB-100 (IgG-p210nat and IgM-p210MDA) in relation to early atherosclerosis in a large, European longitudinal cohort study of healthy high-risk individuals.
  •  
36.
  • Nystrom, Petter K., et al. (author)
  • Obesity, Metabolic Syndrome and Risk of Atrial Fibrillation : A Swedish, Prospective Cohort Study
  • 2015
  • In: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 10:5
  • Journal article (peer-reviewed)abstract
    • Aim We aimed to investigate whether different measures of obesity could similarly predict atrial fibrillation, and whether the atrial fibrillation risk associated with obesity is dependent on presence of metabolic syndrome. Material and Methods We performed our study in a population-based longitudinal cardiovascular study, comprising 1 924 men and 2 097 women, aged 60 years, from Stockholm. Body mass index, waist circumference, sagittal abdominal diameter and components of metabolic syndrome (systolic- and diastolic blood pressure, fasting glucose, triglycerides, high-density lipoprotein-cholesterol) were recorded at baseline. Participants were classified by their body mass index (normal weight, overweight or obese), waist circumference (normal, semi-elevated or elevated), and according to presence of metabolic syndrome. Atrial fibrillation risk was estimated by Cox proportional hazards regression models, adjusted for common atrial fibrillation risk factors, expressed as HR and 95% CI. Results During a mean follow-up of 13.6 years, 285 incident atrial fibrillation cases were recorded. One standard deviation increment of each obesity measure was associated with increased atrial fibrillation risk as: bodymass index 1.25 (1.12 - 1.40), waist circumference 1.35 (1.19 - 1.54) and sagittal abdominal diameter 1.28 (1.14 - 1.44). Compared to normal weight subjects without metabolic syndrome, increased atrial fibrillation risk was noted for overweight subjects with metabolic syndrome, 1.67 (1.16 - 2.41), obese subjects without metabolic syndrome, 1.75 (1.11 - 2.74) and obese subjects withmetabolic syndrome, 1.92 (1.34 - 2.74). Compared to subjects with normal waist circumference without metabolic syndrome, subjects with elevated waist circumference and metabolic syndrome suffered increased atrial fibrillation risk, 2.03 (1.44 - 2.87). Conclusions Body mass index, waist circumference and sagittal abdominal diameter could similarly predict atrial fibrillation. Obesity was associated with an increased atrial fibrillation risk regardless of metabolic syndrome, whereas overweight and elevated waist circumference was associated with increased atrial fibrillation risk only if metabolic syndrome was present.
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37.
  • Olsson, Bob, 1969, et al. (author)
  • Apolipoprotein C-I genotype and serum levels of triglycerides, C-reactive protein and coronary heart disease
  • 2010
  • In: Metabolism. - : Elsevier BV. - 0026-0495. ; 59:12, s. 1736-1741
  • Journal article (peer-reviewed)abstract
    • Apolipoprotein C-I (apoCI) is implicated in lipid metabolism and inflammatory response, both important risk factors for human heart disease. However, most findings come from in vitro or animal studies, whereas data on human apoCI are sparse. To elucidate the role of apoCI in human disease, we analyzed a functional polymorphism in the promoter region of the apoCI gene in relation to blood lipids, C-reactive protein (CRP), coronary artery disease (CAD), and myocardial infarction (MI). Rs11568822 is a 4-base pair insertion/deletion (Ins/Del) polymorphism, and the Ins allele leads to a higher transcription in vitro compared with the Del allele. This polymorphism was analyzed in the Intergene study, a case-control study for CAD (N = 1236), and the Stockholm Heart Epidemiology Program, a case-control study for MI (N = 2774). Subjects homozygous for the Ins genotype had significantly higher serum levels of triglycerides (P = .01 and P = .006) and lower serum levels of CRP (P = .02 and P < .0001) compared with all other subjects in both studies. Similar results were obtained when analyzing only the controls of both studies (P = .002 and P = .0002, triglycerides; P = .002 and P < .0001, CRP). However, apoCI was not associated with CAD or MI. In conclusion, our data show that apoCI genotype is associated with serum levels of triglycerides and CRP, confirming the role of apoCI in lipid metabolism and suggesting that it also influences inflammation.
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38.
  • Patel, Riyaz S., et al. (author)
  • Association of Chromosome 9p21 With Subsequent Coronary Heart Disease Events : A GENIUS-CHD Study of Individual Participant Data
  • 2019
  • In: Circulation. - 2574-8300. ; 12:4
  • Journal article (peer-reviewed)abstract
    • BACKGROUND: Genetic variation at chromosome 9p21 is a recognized risk factor for coronary heart disease (CHD). However, its effect on disease progression and subsequent events is unclear, raising questions about its value for stratification of residual risk.METHODS: A variant at chromosome 9p21 (rs1333049) was tested for association with subsequent events during follow-up in 103 357 Europeans with established CHD at baseline from the GENIUS-CHD (Genetics of Subsequent Coronary Heart Disease) Consortium (73.1% male, mean age 62.9 years). The primary outcome, subsequent CHD death or myocardial infarction (CHD death/myocardial infarction), occurred in 13 040 of the 93 115 participants with available outcome data. Effect estimates were compared with case/control risk obtained from the CARDIoGRAMplusC4D consortium (Coronary Artery Disease Genome-wide Replication and Meta-analysis [CARDIoGRAM] plus The Coronary Artery Disease [C4D] Genetics) including 47 222 CHD cases and 122 264 controls free of CHD.RESULTS: Meta-analyses revealed no significant association between chromosome 9p21 and the primary outcome of CHD death/myocardial infarction among those with established CHD at baseline (GENIUSCHD odds ratio, 1.02; 95% CI, 0.99-1.05). This contrasted with a strong association in CARDIoGRAMPlusC4D odds ratio 1.20; 95% CI, 1.18-1.22; P for interaction < 0.001 compared with the GENIUS-CHD estimate. Similarly, no clear associations were identified for additional subsequent outcomes, including all-cause death, although we found a modest positive association between chromosome 9p21 and subsequent revascularization (odds ratio, 1.07; 95% CI, 1.04-1.09).CONCLUSIONS: In contrast to studies comparing individuals with CHD to disease-free controls, we found no clear association between genetic variation at chromosome 9p21 and risk of subsequent acute CHD events when all individuals had CHD at baseline. However, the association with subsequent revascularization may support the postulated mechanism of chromosome 9p21 for promoting atheroma development.
  •  
39.
  • Patel, Riyaz S., et al. (author)
  • Subsequent Event Risk in Individuals With Established Coronary Heart Disease : Design and Rationale of the GENIUS-CHD Consortium
  • 2019
  • In: Circulation. - 2574-8300. ; 12:4
  • Journal article (peer-reviewed)abstract
    • BACKGROUND: The Genetics of Subsequent Coronary Heart Disease (GENIUS-CHD) consortium was established to facilitate discovery and validation of genetic variants and biomarkers for risk of subsequent CHD events, in individuals with established CHD.METHODS: The consortium currently includes 57 studies from 18 countries, recruiting 185 614 participants with either acute coronary syndrome, stable CHD, or a mixture of both at baseline. All studies collected biological samples and followed-up study participants prospectively for subsequent events.RESULTS: Enrollment into the individual studies took place between 1985 to present day with a duration of follow-up ranging from 9 months to 15 years. Within each study, participants with CHD are predominantly of self-reported European descent (38%-100%), mostly male (44%-91%) with mean ages at recruitment ranging from 40 to 75 years. Initial feasibility analyses, using a federated analysis approach, yielded expected associations between age (hazard ratio, 1.15; 95% CI, 1.14-1.16) per 5-year increase, male sex (hazard ratio, 1.17; 95% CI, 1.13-1.21) and smoking (hazard ratio, 1.43; 95% CI, 1.35-1.51) with risk of subsequent CHD death or myocardial infarction and differing associations with other individual and composite cardiovascular endpoints.CONCLUSIONS: GENIUS-CHD is a global collaboration seeking to elucidate genetic and nongenetic determinants of subsequent event risk in individuals with established CHD, to improve residual risk prediction and identify novel drug targets for secondary prevention. Initial analyses demonstrate the feasibility and reliability of a federated analysis approach. The consortium now plans to initiate and test novel hypotheses as well as supporting replication and validation analyses for other investigators.
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40.
  • Peden, John F., et al. (author)
  • A genome-wide association study in Europeans and South Asians identifies five new loci for coronary artery disease
  • 2011
  • In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 43:4, s. 339-344
  • Journal article (peer-reviewed)abstract
    • Genome-wide association studies have identified 11 common variants convincingly associated with coronary artery disease (CAD)(1-7), a modest number considering the apparent heritability of CAD(8). All of these variants have been discovered in European populations. We report a meta-analysis of four large genome-wide association studies of CAD, with similar to 575,000 genotyped SNPs in a discovery dataset comprising 15,420 individuals with CAD (cases) (8,424 Europeans and 6,996 South Asians) and 15,062 controls. There was little evidence for ancestry-specific associations, supporting the use of combined analyses. Replication in an independent sample of 21,408 cases and 19,185 controls identified five loci newly associated with CAD (P < 5 x 10(-8) in the combined discovery and replication analysis): LIPA on 10q23, PDGFD on 11q22, ADAMTS7-MORF4L1 on 15q25, a gene rich locus on 7q22 and KIAA1462 on 10p11. The CAD-associated SNP in the PDGFD locus showed tissue-specific cis expression quantitative trait locus effects. These findings implicate new pathways for CAD susceptibility.
  •  
41.
  • Persson, Jonas, et al. (author)
  • Sex-Specific Effects of Adiponectin on Carotid Intima-Media Thickness and Incident Cardiovascular Disease
  • 2015
  • In: Journal of the American Heart Association. - : WILEY-BLACKWELL. - 2047-9980. ; 4:8
  • Journal article (peer-reviewed)abstract
    • Background-Plasma adiponectin levels have previously been inversely associated with carotid intima-media thickness (IMT), a marker of subclinical atherosclerosis. In this study, we used a sex-stratified Mendelian randomization approach to investigate whether adiponectin has a causal protective influence on IMT. Methods and Results-Baseline plasma adiponectin concentrationwas tested for association with baseline IMT, IMT progression over 30 months, and occurrence of cardiovascular events within 3 years in 3430 participants (women, n=1777; men, n=1653) with high cardiovascular risk but no prevalent disease. Plasma adiponectin levels were inversely associated with baseline mean bifurcation IMT after adjustment for established risk factors (beta=-0.018, P<0.001) in men but not in women (beta=-0.006, P=0.185; P for interaction=0.061). Adiponectin levels were inversely associated with progression of mean common carotid IMT in men (beta=-0.0022, P=0.047), whereas no association was seen in women (0.0007, P=0.475; P for interaction=0.018). Moreover, we observed that adiponectin levels were inversely associated with coronary events in women (hazard ratio 0.57, 95% CI 0.37 to 0.87) but not in men (hazard ratio 0.82,95% CI0.54 to 1.25). Agenescore of adiponectin-raisingalleles in6loci, reported recently inalarge multi-ethnic metaanalysis, was inversely associated with baseline mean bifurcation IMT in men (beta=-0.0008, P=0.004) but not in women (beta=-0.0003, P=0.522; P for interaction=0.007). Conclusions-This report provides some evidence for adiponectin protecting against atherosclerosis, with effects being confined to men; however, compared with established cardiovascular risk factors, the effect of plasma adiponectin was modest. Further investigation involving mechanistic studies is warranted.
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42.
  • Qian, Frank, et al. (author)
  • Omega-3 Fatty Acid Biomarkers and Incident Atrial Fibrillation
  • 2023
  • In: Journal of the American College of Cardiology. - : Elsevier. - 0735-1097 .- 1558-3597. ; 82:4, s. 336-349
  • Journal article (peer-reviewed)abstract
    • BACKGROUND: The relationship between omega-3 fatty acids and atrial fibrillation (AF) remains controversial.OBJECTIVES: This study aimed to determine the prospective associations of blood or adipose tissue levels of eicosa-pentaenoic acid (EPA), docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA) with incident AF.METHODS: We used participant-level data from a global consortium of 17 prospective cohort studies, each with baseline data on blood or adipose tissue omega-3 fatty acid levels and AF outcomes. Each participating study conducted a de novo analyses using a prespecified analytical plan with harmonized definitions for exposures, outcome, covariates, and sub-groups. Associations were pooled using inverse-variance weighted meta-analysis.RESULTS: Among 54,799 participants from 17 cohorts, 7,720 incident cases of AF were ascertained after a median 13.3 years of follow-up. In multivariable analysis, EPA levels were not associated with incident AF, HR per interquintile range (ie, the difference between the 90th and 10th percentiles) was 1.00 (95% CI: 0.95-1.05). HRs for higher levels of DPA, DHA, and EPA+DHA, were 0.89 (95% CI: 0.83-0.95), 0.90 (95% CI: 0.85-0.96), and 0.93 (95% CI: 0.87-0.99), respectively.CONCLUSIONS: In vivo levels of omega-3 fatty acids including EPA, DPA, DHA, and EPA+DHA were not associated with increased risk of incident AF. Our data suggest the safety of habitual dietary intakes of omega-3 fatty acids with respect to AF risk. Coupled with the known benefits of these fatty acids in the prevention of adverse coronary events, our study suggests that current dietary guidelines recommending fish/omega-3 fatty acid consumption can be maintained.
  •  
43.
  • Quintana, Hedley Knewjen, et al. (author)
  • Comorbidities in relation to fatali of first myocardial infarction
  • 2018
  • In: Cardiovascular pathology. - : ELSEVIER SCIENCE INC. - 1054-8807 .- 1879-1336. ; 32, s. 32-37
  • Journal article (peer-reviewed)abstract
    • Introduction: Present knowledge concerning potential associations between comorbidities and the fatality of a first myocardial infarction (MI) is limited.Aim: To identify comorbidities in 45-70-year-old individuals who suffered a first MI and died within 7 days in Stockholm County from 1992-1994. In addition, to assess how each of the comorbidities identified, as well as the number of hospitalizations during the 10-year period prior to the MI, was associated with MI fatality.Methods: The data collected on our inception cohort of 1984 first Ml, of which 524 were fatal within 7 days, were primarily self-reported, proxy-reported by questionnaire and/or extracted from comprehensive national registers. Comorbidilies among fatal cases with a prevalence >2% were identified. Risk ratios (with 95% confidence intervals) for the association of Ml fatality with number of prior hospitalizations and specific comorbidities were calculated using binomial regression with log link. A structured review of autopsy reports on fatal cases was performed in order to identify additional indicators of comorbidities.Results: After adjusting for sex, age and disposable income, the number of previous hospitalizations was associated with 7-day Ml fatality. Of the comorbidities identified as prevalent in fatal cases, the following were associated with 7-day fatality in crude analysis: epilepsy, heart failure, stroke, alcoholism, cancer, renal diseases, asthma, psychiatric diseases, diabetes, and rheumatoid arthritis. Indicators of comorbidities identified from autopsy data included a silent MI, severe atherosclerosis of the abdominal aorta, and hepatic steatosis. Adjustments for sex and age (although not possible for epilepsy and alcoholism), did not substantially alter results.Conclusions: Our current findings indicate that in connection with a first MI, particular attention should be paid to those with repeated prior hospitalizations and/or epilepsy, heart failure, stroke, alcoholism, cancer, renal diseases, asthma, psychiatric diseases, diabetes and rheumatoid arthritis.
  •  
44.
  • Schillemans, Tessa, et al. (author)
  • Associations of Polymorphisms in the Peroxisome Proliferator-Activated Receptor Gamma Coactivator-1 Alpha Gene With Subsequent Coronary Heart Disease : An Individual-Level Meta-Analysis
  • 2022
  • In: Frontiers in Physiology. - : Frontiers Media S.A.. - 1664-042X. ; 13
  • Journal article (peer-reviewed)abstract
    • Background: The knowledge of factors influencing disease progression in patients with established coronary heart disease (CHD) is still relatively limited. One potential pathway is related to peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PPARGC1A), a transcription factor linked to energy metabolism which may play a role in the heart function. Thus, its associations with subsequent CHD events remain unclear. We aimed to investigate the effect of three different SNPs in the PPARGC1A gene on the risk of subsequent CHD in a population with established CHD.Methods: We employed an individual-level meta-analysis using 23 studies from the GENetIcs of sUbSequent Coronary Heart Disease (GENIUS-CHD) consortium, which included participants (n = 80,900) with either acute coronary syndrome, stable CHD, or a mixture of both at baseline. Three variants in the PPARGC1A gene (rs8192678, G482S; rs7672915, intron 2; and rs3755863, T528T) were tested for their associations with subsequent events during the follow-up using a Cox proportional hazards model adjusted for age and sex. The primary outcome was subsequent CHD death or myocardial infarction (CHD death/myocardial infarction). Stratified analyses of the participant or study characteristics as well as additional analyses for secondary outcomes of specific cardiovascular disease diagnoses and all-cause death were also performed.Results: Meta-analysis revealed no significant association between any of the three variants in the PPARGC1A gene and the primary outcome of CHD death/myocardial infarction among those with established CHD at baseline: rs8192678, hazard ratio (HR): 1.01, 95% confidence interval (CI) 0.98-1.05 and rs7672915, HR: 0.97, 95% CI 0.94-1.00; rs3755863, HR: 1.02, 95% CI 0.99-1.06. Similarly, no significant associations were observed for any of the secondary outcomes. The results from stratified analyses showed null results, except for significant inverse associations between rs7672915 (intron 2) and the primary outcome among 1) individuals aged >= 65, 2) individuals with renal impairment, and 3) antiplatelet users.Conclusion: We found no clear associations between polymorphisms in the PPARGC1A gene and subsequent CHD events in patients with established CHD at baseline.
  •  
45.
  • Schunkert, Heribert, et al. (author)
  • Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease
  • 2011
  • In: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 43:4, s. 153-333
  • Journal article (peer-reviewed)abstract
    • We performed a meta-analysis of 14 genome-wide association studies of coronary artery disease (CAD) comprising 22,233 individuals with CAD (cases) and 64,762 controls of European descent followed by genotyping of top association signals in 56,682 additional individuals. This analysis identified 13 loci newly associated with CAD at P < 5 x 10(-8) and confirmed the association of 10 of 12 previously reported CAD loci. The 13 new loci showed risk allele frequencies ranging from 0.13 to 0.91 and were associated with a 6% to 17% increase in the risk of CAD per allele. Notably, only three of the new loci showed significant association with traditional CAD risk factors and the majority lie in gene regions not previously implicated in the pathogenesis of CAD. Finally, five of the new CAD risk loci appear to have pleiotropic effects, showing strong association with various other human diseases or traits.
  •  
46.
  • Scott, Robert A., et al. (author)
  • An Expanded Genome-Wide Association Study of Type 2 Diabetes in Europeans
  • 2017
  • In: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 66:11, s. 2888-2902
  • Journal article (peer-reviewed)abstract
    • To characterize type 2 diabetes (T2D)-associated variation across the allele frequency spectrum, we conducted a meta-analysis of genome-wide association data from 26,676 T2D case and 132,532 control subjects of European ancestry after imputation using the 1000 Genomes multiethnic reference panel. Promising association signals were followed up in additional data sets (of 14,545 or 7,397 T2D case and 38,994 or 71,604 control subjects). We identified 13 novel T2D-associated loci (P < 5 x 10(-8)), including variants near the GLP2R, GIP, and HLA-DQA1 genes. Our analysis brought the total number of independent T2D associations to 128 distinct signals at 113 loci. Despite substantially increased sample size and more complete coverage of low-frequency variation, all novel associations were driven by common single nucleotide variants. Credible sets of potentially causal variants were generally larger than those based on imputation with earlier reference panels, consistent with resolution of causal signals to common risk haplotypes. Stratification of T2D-associated loci based on T2D-related quantitative trait associations revealed tissue-specific enrichment of regulatory annotations in pancreatic islet enhancers for loci influencing insulin secretion and in adipocytes, monocytes, and hepatocytes for insulin action-associated loci. These findings highlight the predominant role played by common variants of modest effect and the diversity of biological mechanisms influencing T2D pathophysiology.
  •  
47.
  • Scott, Robert A., et al. (author)
  • Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways
  • 2012
  • In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 44:9, s. 991-1005
  • Journal article (peer-reviewed)abstract
    • Through genome-wide association meta-analyses of up to 133,010 individuals of European ancestry without diabetes, including individuals newly genotyped using the Metabochip, we have increased the number of confirmed loci influencing glycemic traits to 53, of which 33 also increase type 2 diabetes risk (q < 0.05). Loci influencing fasting insulin concentration showed association with lipid levels and fat distribution, suggesting impact on insulin resistance. Gene-based analyses identified further biologically plausible loci, suggesting that additional loci beyond those reaching genome-wide significance are likely to represent real associations. This conclusion is supported by an excess of directionally consistent and nominally significant signals between discovery and follow-up studies. Functional analysis of these newly discovered loci will further improve our understanding of glycemic control.
  •  
48.
  • Shang, Ming-Mei, et al. (author)
  • Lim domain binding 2 : a key driver of transendothelial migration of leukocytes and atherosclerosis
  • 2014
  • In: Arteriosclerosis, Thrombosis and Vascular Biology. - 1079-5642 .- 1524-4636. ; 34:9, s. 2068-2077
  • Journal article (peer-reviewed)abstract
    • OBJECTIVE: Using a multi-tissue, genome-wide gene expression approach, we recently identified a gene module linked to the extent of human atherosclerosis. This atherosclerosis module was enriched with inherited risk for coronary and carotid artery disease (CAD) and overlapped with genes in the transendothelial migration of leukocyte (TEML) pathway. Among the atherosclerosis module genes, the transcription cofactor Lim domain binding 2 (LDB2) was the most connected in a CAD vascular wall regulatory gene network. Here, we used human genomics and atherosclerosis-prone mice to evaluate the possible role of LDB2 in TEML and atherosclerosis.APPROACH AND RESULTS: mRNA profiles generated from blood macrophages in patients with CAD were used to infer transcription factor regulatory gene networks; Ldlr(-/-)Apob(100/100) mice were used to study the effects of Ldb2 deficiency on TEML activity and atherogenesis. LDB2 was the most connected gene in a transcription factor regulatory network inferred from TEML and atherosclerosis module genes in CAD macrophages. In Ldlr(-/-)Apob(100/100) mice, loss of Ldb2 increased atherosclerotic lesion size ≈2-fold and decreased plaque stability. The exacerbated atherosclerosis was caused by increased TEML activity, as demonstrated in air-pouch and retinal vasculature models in vivo, by ex vivo perfusion of primary leukocytes, and by leukocyte migration in vitro. In THP1 cells, migration was increased by overexpression and decreased by small interfering RNA inhibition of LDB2. A functional LDB2 variant (rs10939673) was associated with the risk and extent of CAD across several cohorts.CONCLUSIONS: As a key driver of the TEML pathway in CAD macrophages, LDB2 is a novel candidate to target CAD by inhibiting the overall activity of TEML.
  •  
49.
  • Shungin, Dmitry, et al. (author)
  • New genetic loci link adipose and insulin biology to body fat distribution.
  • 2015
  • In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 518:7538, s. 187-378
  • Journal article (peer-reviewed)abstract
    • Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.
  •  
50.
  • Silveira, Angela, et al. (author)
  • Plasma IL-5 concentration and subclinical carotid atherosclerosis
  • 2015
  • In: Atherosclerosis. - : Elsevier BV. - 0021-9150 .- 1879-1484. ; 239:1, s. 125-130
  • Journal article (peer-reviewed)abstract
    • Objective: Genetic variants robustly associated with coronary artery disease were reported in the vicinity of the interleukin (IL)-5 locus, and animal studies suggested a protective role for IL-5 in atherosclerosis. Therefore, we set this work to explore IL-5 as a plasma biomarker for early subclinical atherosclerosis, as determined by measures of baseline severity and change over time of carotid intima-media thickness (cIMT).Methods: We used biobank and databases of IMPROVE, a large European prospective cohort study of high-risk individuals (n = 3534) free of clinically overt cardiovascular disease at enrollment, in whom composite and segment-specific measures of cIMT were recorded at baseline and after 15 and 30 months. IL-5 was measured with an immunoassay in plasma samples taken at baseline.Results: IL-5 levels were lower in women than in men, lower in the South than in North of Europe, and showed positive correlations with most established risk factors. IL-5 showed significant inverse relationships with cIMT change over time in the common carotid segment in women, but no significant relationships to baseline cIMT in either men or women.Conclusions: Our results suggest that IL-5 may be part of protective mechanisms operating in early atherosclerosis, at least in women. However, the relationships are weak and whereas IL-5 has been proposed as a potential molecular target to treat allergies, it is difficult to envisage such a scenario in coronary artery disease.
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