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| 2. |
- Nelson, C. P., et al.
(författare)
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Genetically Determined Height and Coronary Artery Disease
- 2015
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Ingår i: New England Journal of Medicine. - 0028-4793 .- 1533-4406. ; 372:17, s. 1608-1618
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND The nature and underlying mechanisms of an inverse association between adult height and the risk of coronary artery disease (CAD) are unclear.METHODS We used a genetic approach to investigate the association between height and CAD, using 180 height-associated genetic variants. We tested the association between a change in genetically determined height of 1 SD (6.5 cm) with the risk of CAD in 65,066 cases and 128,383 controls. Using individual-level genotype data from 18,249 persons, we also examined the risk of CAD associated with the presence of various numbers of height-associated alleles. To identify putative mechanisms, we analyzed whether genetically determined height was associated with known cardiovascular risk factors and performed a pathway analysis of the height-associated genes.RESULTS We observed a relative increase of 13.5% (95% confidence interval [CI], 5.4 to 22.1; P<0.001) in the risk of CAD per 1-SD decrease in genetically determined height. There was a graded relationship between the presence of an increased number of height-raising variants and a reduced risk of CAD (odds ratio for height quar-tile 4 versus quartile 1, 0.74; 95% CI, 0.68 to 0.84; P<0.001). Of the 12 risk factors that we studied, we observed significant associations only with levels of low-density lipoprotein cholesterol and triglycerides (accounting for approximately 30% of the association). We identified several overlapping pathways involving genes associated with both development and atherosclerosis.CONCLUSIONS There is a primary association between a genetically determined shorter height and an increased risk of CAD, a link that is partly explained by the association between shorter height and an adverse lipid profile. Shared biologic processes that determine achieved height and the development of atherosclerosis may explain some of the association.
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| 3. |
- 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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| 4. |
- Folkersen, Lasse, et al.
(författare)
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Genomic and drug target evaluation of 90 cardiovascular proteins in 30,931 individuals.
- 2020
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Ingår i: Nature metabolism. - : Springer Science and Business Media LLC. - 2522-5812. ; 2:10, s. 1135-1148
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Tidskriftsartikel (refereegranskat)abstract
- Circulating proteins are vital in human health and disease and are frequently used as biomarkers for clinical decision-making or as targets for pharmacological intervention. Here, we map and replicate protein quantitative trait loci (pQTL) for 90 cardiovascular proteins in over 30,000 individuals, resulting in 451 pQTLs for 85 proteins. For each protein, we further perform pathway mapping to obtain trans-pQTL gene and regulatory designations. We substantiate these regulatory findings with orthogonal evidence for trans-pQTLs using mouse knockdown experiments (ABCA1 and TRIB1) and clinical trial results (chemokine receptors CCR2 and CCR5), with consistent regulation. Finally, we evaluate known drug targets, and suggest new target candidates or repositioning opportunities using Mendelian randomization. This identifies 11 proteins with causal evidence of involvement in human disease that have not previously been targeted, including EGF, IL-16, PAPPA, SPON1, F3, ADM, CASP-8, CHI3L1, CXCL16, GDF15 and MMP-12. Taken together, these findings demonstrate the utility of large-scale mapping of the genetics of the proteome and provide a resource for future precision studies of circulating proteins in human health.
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| 5. |
- Ganna, Andrea, et al.
(författare)
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Large-scale Metabolomic Profiling Identifies Novel Biomarkers for Incident Coronary Heart Disease
- 2014
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Ingår i: PLOS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 10:12, s. e1004801-
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Tidskriftsartikel (refereegranskat)abstract
- Analyses of circulating metabolites in large prospective epidemiological studies could lead to improved prediction and better biological understanding of coronary heart disease (CHD). We performed a mass spectrometry-based non-targeted metabolomics study for association with incident CHD events in 1,028 individuals (131 events; 10 y. median follow-up) with validation in 1,670 individuals (282 events; 3.9 y. median follow-up). Four metabolites were replicated and independent of main cardiovascular risk factors [lysophosphatidylcholine 18∶1 (hazard ratio [HR] per standard deviation [SD] increment = 0.77, P-value<0.001), lysophosphatidylcholine 18∶2 (HR = 0.81, P-value<0.001), monoglyceride 18∶2 (MG 18∶2; HR = 1.18, P-value = 0.011) and sphingomyelin 28∶1 (HR = 0.85, P-value = 0.015)]. Together they contributed to moderate improvements in discrimination and re-classification in addition to traditional risk factors (C-statistic: 0.76 vs. 0.75; NRI: 9.2%). MG 18∶2 was associated with CHD independently of triglycerides. Lysophosphatidylcholines were negatively associated with body mass index, C-reactive protein and with less evidence of subclinical cardiovascular disease in additional 970 participants; a reverse pattern was observed for MG 18∶2. MG 18∶2 showed an enrichment (P-value = 0.002) of significant associations with CHD-associated SNPs (P-value = 1.2×10-7 for association with rs964184 in the ZNF259/APOA5 region) and a weak, but positive causal effect (odds ratio = 1.05 per SD increment in MG 18∶2, P-value = 0.05) on CHD, as suggested by Mendelian randomization analysis. In conclusion, we identified four lipid-related metabolites with evidence for clinical utility, as well as a causal role in CHD development.
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| 6. |
- Lind, Lars, et al.
(författare)
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A detailed cardiovascular characterization of obesity without the metabolic syndrome
- 2011
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Ingår i: Arteriosclerosis, Thrombosis and Vascular Biology. - : American Heart Association. - 1079-5642 .- 1524-4636. ; 31:8, s. e27-e34
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Although obesity without metabolic disturbances has been regarded as harmless, we have recently shown that obese subjects without the metabolic syndrome (MetS) has an increased risk of cardiovascular (CV) disorders and mortality during long-term follow-up. To investigate the basis for that increased risk, we studied the impact of obesity without MetS on multiple markers of subclinical CV disease.Methods and results: At age 70, 1016 subjects were investigated in the Prospective Investigation of the Vasculature in Uppsala Seniors study. According to body mass index (BMI)/MetS status, they were categorized as normal weight (BMI <25 kg/m2) without MetS (National Cholesterol Education Program criteria, n=319), normal weight with MetS (n=19), overweight (BMI 25 to 29.9 kg/m2) without MetS (n=333), overweight with MetS (n=94), obese (BMI =30 kg/m2) without MetS (n=102), and obese with MetS (n=118). Several different measurements of endothelial reactivity, arterial compliance (plethysmography and ultrasound), carotid artery atherosclerosis, and echocardiography were performed, and 7 markers of coagulation/fibrinolysis were measured. Subjects with obesity without MetS showed impaired vasoreactivity, a more echolucent carotid artery wall, increased left ventricular mass and function together with impaired coagulation/fibrinolysis compared with normal-weight subjects without the MetS (P<0.05 to 0.001). The majority of these disturbances were also seen in overweight subjects without the MetS.Conclusion: In contrast to some previous studies, our data do not support that obesity without MetS is a benign condition, because obesity without MetS was associated with impairments in multiple markers of subclinical CV disease. This was also the case for overweight subjects without the MetS.
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| 7. |
- Lind, Lars, et al.
(författare)
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A Multi-Cohort Metabolomics Analysis Discloses Sphingomyelin (32:1) Levels to be Inversely Related to Incident Ischemic Stroke
- 2020
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Ingår i: Journal of Stroke & Cerebrovascular Diseases. - : Elsevier BV. - 1052-3057 .- 1532-8511. ; 29:2
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Tidskriftsartikel (refereegranskat)abstract
- Background and Purpose:To search for novel pathophysiological pathways related to ischemic stroke using a metabolomics approach.Methods: We identified 204 metabolites in plasma by liquid chromatography mass spectrometry in 3 independent population-based samples (TwinGene, Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) and Uppsala Longitudinal Study of Adult Men). TwinGene was used for discovery and the other 2 samples were meta-analyzed as replication. In PIVUS, traditional cardiovascular (CV) risk factors, multiple markers of subclinical CV disease, markers of coagulation/fibrinolysis were measured and analyzed in relation to top metabolites.Results:In TwinGene (177 incident cases, median follow-up 4.3 years), levels of 28 metabolites were associated with incident ischemic stroke at a false discover rate (FDR) of 5%. In the replication (together 194 incident cases, follow-up 10 and 12 years, respectively), only sphingomyelin (32:1) was significantly associated (HR.69 per SD change, 95% CI.57-0.83, P value = .00014; FDR <5%) when adjusted for systolic blood pressure, diabetes, smoking, low density lipoportein (LDL)- and high density lipoprotein (HDL), body mass index (BMI) and atrial fibrillation. In PIVUS, sphingomyelin (32:1) levels were significantly related to both LDL- and HDL-cholesterol in a positive fashion, and to serum triglycerides, BMI and diabetes in a negative fashion. Furthermore, sphingomyelin (32:1) levels were related to vasodilation in the forearm resistance vessels, and inversely to leukocyte count (P < .0069 and .0026, respectively).Conclusions:An inverse relationship between sphingomyelin (32:1) and incident ischemic stroke was identified, replicated, and characterized. A possible protective role for sphingomyelins in stroke development has to be further investigated in additional experimental and clinical studies.
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| 8. |
- Lind, Lars, et al.
(författare)
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Methylation-based estimated biological age and cardiovascular disease
- 2018
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Ingår i: European Journal of Clinical Investigation. - : John Wiley & Sons. - 0014-2972 .- 1365-2362. ; 48:2
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: DNA methylation changes over life at specific sites in the genome, which can be used to estimate "biological age." The aim of this population-based longitudinal cohort study was to investigate the association between estimated biological age and incident cardiovascular disease (CVD).MATERIALS AND METHODS: Based on formulas published by Hannum et al and Horvath et al, "biological age" was calculated using data from the Illumina 450k Bead Methylation chip in 832 participants free from cardiovascular disease in the Prospective Study of the Vasculature in Uppsala Seniors (PIVUS) study (50% women, all aged 70 years at the examination). The difference between estimated biological and chronological age was calculated (DiffAge).RESULTS: During 10 years of follow-up, 153 incident cases of cardiovascular disease occurred. In the sex-adjusted analyses, the Horvath estimation of DiffAge was significantly related to incident cardiovascular disease (HR 1.040, 95% CI 1.010-1.071, P = .0079). Thus, for each year of increased biological age, a 4% increased risk of future cardiovascular disease was observed. This relationship was still significant following adjustment for the traditional risk factors sex, BMI, diabetes, HDL and LDL-cholesterol, systolic blood pressure and smoking (HR 1.033, 95% CI 1.004-1.063, P = .024). No such significant association was found using the Hannum formula.CONCLUSIONS: DNA methylation-based estimation of "biological age" per Horvath was associated with incident cardiovascular disease.
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| 9. |
- Lind, Lars, et al.
(författare)
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Use of a proximity extension assay proteomics chip to discover new biomarkers for human atherosclerosis
- 2015
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Ingår i: Atherosclerosis. - : Elsevier BV. - 0021-9150 .- 1879-1484. ; 242:1, s. 205-210
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Tidskriftsartikel (refereegranskat)abstract
- Background and aims: We used a proteomics array to simultaneously measure multiple proteins that have been suggested to be associated with atherosclerosis and related them to plaque prevalence in carotid arteries in a human population-based study. Methods: In the Prospective Study of the Vasculature in Uppsala Seniors (PIVUS; n = 931, 50% women, all aged 70 years), the number of carotid arteries with plaques was recorded by ultrasound. Levels of 82 proteins were assessed in plasma by a proximity extension assay (Proseek Multiplex CVD, Olink Bioscience, Uppsala, Sweden) and related to carotid measures in a regression framework. Results: Following adjustment for multiple testing with Bonferroni correction, seven of the proteins were significantly related to the number of carotid arteries affected by plaques in sex-adjusted models (osteoprotegrin, T-cell immunoglobulin and mucin domain (TIM)-1, growth/differentiation factor 15 (GDF-15), matrix metalloprotease-12 (MMP-12), renin, tumor necrosis factor ligand superfamily member 14 (TNFSF14) and growth hormone). Of these, renin (odds ratio [OR], 1.30; 95% confidence interval [CI], 1.13-1.49 per standard deviation increase), growth hormone (OR, 1.24; 95% CI, 1.08-1.43), osteoprotegerin (OR, 1.22; 95% CI, 1.05-1.43) and TNFSF14 (OR, 1.17; 95% CI, 1.01-1.35) were related to plaque prevalence independently of each other and traditional cardiovascular risk factors. Conclusion: A novel targeted proteomics approach using the proximity extension technique discovered several new associations of candidate proteins with carotid artery plaque prevalence in a large human sample.
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| 10. |
- Willer, Cristen J., et al.
(författare)
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Discovery and refinement of loci associated with lipid levels
- 2013
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:11, s. 1274-1283
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Tidskriftsartikel (refereegranskat)abstract
- Levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides and total cholesterol are heritable, modifiable risk factors for coronary artery disease. To identify new loci and refine known loci influencing these lipids, we examined 188,577 individuals using genome-wide and custom genotyping arrays. We identify and annotate 157 loci associated with lipid levels at P < 5 x 10(-8), including 62 loci not previously associated with lipid levels in humans. Using dense genotyping in individuals of European, East Asian, South Asian and African ancestry, we narrow association signals in 12 loci. We find that loci associated with blood lipid levels are often associated with cardiovascular and metabolic traits, including coronary artery disease, type 2 diabetes, blood pressure, waist-hip ratio and body mass index. Our results demonstrate the value of using genetic data from individuals of diverse ancestry and provide insights into the biological mechanisms regulating blood lipids to guide future genetic, biological and therapeutic research.
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