| 11. |
- de las Fuentes, Lisa, et al.
(författare)
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Gene-educational attainment interactions in a multi-ancestry genome-wide meta-analysis identify novel blood pressure loci
- 2021
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Ingår i: Molecular Psychiatry. - : Springer Nature. - 1359-4184 .- 1476-5578. ; 26:6, s. 2111-2125
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Tidskriftsartikel (refereegranskat)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.
(författare)
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Common variants associated with plasma triglycerides and risk for coronary artery disease
- 2013
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:11, s. 1345-
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Tidskriftsartikel (refereegranskat)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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| 13. |
- Ekblom Bak, Elin, 1981-, et al.
(författare)
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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
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Ingår i: European Journal of Preventive Cardiology. - : Sage Publications. - 2047-4873 .- 2047-4881. ; 8:12, s. 1376-1385
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Tidskriftsartikel (refereegranskat)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.
(författare)
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Pulmonary function and atherosclerosis in the general population : causal associations and clinical implications
- 2024
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Ingår i: European Journal of Epidemiology. - : Springer Nature. - 0393-2990 .- 1573-7284.
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Tidskriftsartikel (refereegranskat)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.
(författare)
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Novel genetic associations for blood pressure identified via gene-alcohol interaction in up to 570K individuals across multiple ancestries
- 2018
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Ingår i: PLOS ONE. - : Public library science. - 1932-6203. ; 13:6
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Tidskriftsartikel (refereegranskat)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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| 16. |
- Gaulton, Kyle J, et al.
(författare)
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Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci.
- 2015
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 47:12, s. 1415-1415
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Tidskriftsartikel (refereegranskat)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.
(författare)
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Identification of the BCAR1-CFDP1-TMEM170A Locus as a Determinant of Carotid Intima-Media Thickness and Coronary Artery Disease Risk
- 2012
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Ingår i: Circulation: Cardiovascular Genetics. - 1942-325X .- 1942-3268. ; 5:6, s. 656-665
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Tidskriftsartikel (refereegranskat)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.
(författare)
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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
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Ingår i: European Heart Journal. - : Oxford University Press. - 0195-668X .- 1522-9645. ; 44:32, s. 3040-3058
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Tidskriftsartikel (refereegranskat)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.
(författare)
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A gene-centric study of common carotid artery remodelling
- 2013
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Ingår i: Atherosclerosis. - : Elsevier BV. - 0021-9150 .- 1879-1484. ; 226:2, s. 440-446
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Tidskriftsartikel (refereegranskat)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.
(författare)
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Multi-Organ Expression Profiling Uncovers a Gene Module in Coronary Artery Disease Involving Transendothelial Migration of Leukocytes and LIM Domain Binding 2 : The Stockholm Atherosclerosis Gene Expression (STAGE) Study
- 2009
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Ingår i: PLoS Genetics. - : PLoS Genetics. - 1553-7390 .- 1553-7404. ; 5:12, s. e1000754-
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Tidskriftsartikel (refereegranskat)abstract
- Environmental exposures filtered through the genetic make-up of each individual alter the transcriptional repertoire in organs central to metabolic homeostasis, thereby affecting arterial lipid accumulation, inflammation, and the development of coronary artery disease (CAD). The primary aim of the Stockholm Atherosclerosis Gene Expression (STAGE) study was to determine whether there are functionally associated genes (rather than individual genes) important for CAD development. To this end, two-way clustering was used on 278 transcriptional profiles of liver, skeletal muscle, and visceral fat (n=66/tissue) and atherosclerotic and unaffected arterial wall (n=40/tissue) isolated from CAD patients during coronary artery bypass surgery. The first step, across all mRNA signals (n=15,042/12,621 RefSeqs/genes) in each tissue, resulted in a total of 60 tissue clusters (n=3958 genes). In the second step (performed within tissue clusters), one atherosclerotic lesion (n=49/48) and one visceral fat (n=59) cluster segregated the patients into two groups that differed in the extent of coronary stenosis (P=0.008 and P=0.00015). The associations of these clusters with coronary atherosclerosis were validated by analyzing carotid atherosclerosis expression profiles. Remarkably, in one cluster (n=55/54) relating to carotid stenosis (P=0.04), 27 genes in the two clusters relating to coronary stenosis were confirmed (n=16/17, P<10-27and-30). Genes in the transendothelial migration of leukocytes (TEML) pathway were overrepresented in all three clusters, referred to as the atherosclerosis module (A-module). In a second validation step, using three independent cohorts, the A-module was found to be genetically enriched with CAD risk by 1.8-fold (P<0.004). The transcription co-factor LIM domain binding 2 (LDB2) was identified as a potential high-hierarchy regulator of the A-module, a notion supported by subnetwork analysis, cellular and lesion expression of LDB2, and the expression of 13 TEML genes in Ldb2-deficient arterial wall. Thus, the A-module appears to be important for atherosclerosis development and together with LDB2 merits further attention in CAD research.
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