| 1. |
- Mubanga, Mwenya
(författare)
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Dog Ownership and Cardiovascular Disease
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The relationship between pet ownership and human health has been studied extensively; however, the effect of dog ownership on human health has had conflicting results. The overall aim of this research project was to investigate the impact of dog ownership, and the death of the dog, on human cardiovascular health and all-cause mortality.Study I was a population-based study investigating the association between dog ownership with the risk of cardiovascular disease (CVD) and death. Of 3,432,153 individuals included, dog ownership (13.1%) was associated with a lower risk of CVD- and all-cause death by 23% and 20%, respectively. In single-person households, there was an inverse association between dog ownership and incident CVD, as well as a stronger inverse association with CVD-death and all-cause death.Study II was a population-based study investigating the association between dog ownership and initiation of treatment for cardiovascular risk factors in 2,026,865 adults. Dog ownership (14.6%) was associated with a slightly elevated risk of initiating treatment (2%) for hypertension and dyslipidaemia, but not for diabetes mellitus. However, some evidence for residual confounding was found.Study III investigated the risk of death after hospitalization for a first-ever acute myocardial infarction (n=181,696) or first-ever ischemic stroke (n=157,617) in two population-based cohorts. Dog ownership was associated with a 20% to 24% lower risk of all-cause mortality and CVD-death, respectively.In Study I-III, ownership of hunting breed dogs was associated with the lowest risk of the outcomes, while owning dogs of mixed pedigree was associated with worse cardiovascular health.Study IV found evidence of an increased risk of CVD after the loss of a life-insured pet (dog or cat; n=147,251) during the first week, 3-6 months after and 6-12 months after pet-loss.This thesis has used the Swedish population and health registers to investigate the relationship between various aspects of dog ownership and cardiovascular risk. By using defined, quantifiable end-points and robust statistical methods, this project has made an important contribution to the body of research underlying the positive relationship between dog ownership and cardiovascular health, paving the way for further research into causal mechanisms.
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| 2. |
- Nowak, Christoph, 1986-
(författare)
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Insulin Resistance : Causes, biomarkers and consequences
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The worldwide increasing number of persons affected by largely preventable diseases like diabetes demands better prevention and treatment. Insulin is required for effective utilisation of circulating nutrients. Impaired responsiveness to insulin (insulin resistance, IR) is a hallmark of type 2 diabetes and independently raises the risk of heart attack and stroke. The pathophysiology of IR is incompletely understood. High-throughput measurement of large numbers of circulating biomarkers may provide new insights beyond established risk factors.The aims of this thesis were to (i) use proteomics, metabolomics and genomics methods in large community samples to identify biomarkers of IR; (ii) assess biomarkers for risk prediction and insights into aetiology and consequences of IR; and (iii) use Mendelian randomisation analysis to assess causality.In Study I, analysis of 80 circulating proteins in 70-to-77-year-old Swedes identified cathepsin D as a biomarker for IR and highlighted a tentative causal effect of IR on raised plasma tissue plasminogen activator levels. In Study II, nontargeted fasting plasma metabolomics was used to discover 52 metabolites associated with glycaemic traits in non-diabetic 70-year-old men. Replication in independent samples of several thousand persons provided evidence for a causal effect of IR on reduced plasma oleic acid and palmitoleic acid levels. In Study III, nontargeted metabolomics in plasma samples obtained at three time points during an oral glucose challenge in 70-year-old men identified associations between a physiologic measure of IR and concentration changes in medium-chain acylcarnitines, monounsaturated fatty acids, bile acids and lysophosphatidylethanolamines. Study IV provided evidence in two large longitudinal cohorts for causal effects of type 2 diabetes and impaired insulin secretion on raised coronary artery disease risk.In conclusion, the Studies in this thesis provide new insights into the pathophysiology and adverse health consequences of IR and illustrate the value of combining traditional epidemiologic designs with recent molecular techniques and bioinformatics methods. The results provide limited evidence for the role of circulating proteins and small molecules in IR and require replication in separate studies and validation in experimental designs.
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| 3. |
- Lind, Lars, et al.
(författare)
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Longitudinal effects of aging on plasma proteins levels in older adults : associations with kidney function and hemoglobin levels
- 2019
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 14:2
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: A targeted proteomics chip has been shown to be useful to discover novel associations of proteins with cardiovascular disease. We investigated how these proteins change with aging, and whether this change is related to a decline in kidney function, or to a change in hemoglobin levels.MATERIAL AND METHODS: In the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study, including 1,016 participants from the general population aged 70 at baseline, 84 proteins were measured at ages 70, 75, 80. At these occasions, glomerular filtration rate (eGFR) was estimated and the hemoglobin levels were measured.RESULTS: Sixty-one of the 84 evaluated proteins changed significantly during the 10-year follow-up (multiple testing-adjusted alpha = 0.00059), most showing an increase. The change in eGFR was inversely related to changes of protein levels for the vast majority of proteins (74%). The change in hemoglobin was significantly related to the change in 40% of the evaluated proteins, with no obvious preference of the direction of these relationships.CONCLUSION: The majority of evaluated proteins increased with aging in adults. Therefore, normal ranges for proteins might be given in age-strata. The increase in protein levels was associated with the degree of reduction in eGFR for the majority of proteins, while no clear pattern was seen for the relationships between the proteins and the change in hemoglobin levels. Studies on changes in urinary proteins are warranted to understand the association between the reduction in eGFR and increase in plasma protein levels.
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| 4. |
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| 5. |
- Evangelou, Evangelos, et al.
(författare)
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Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits.
- 2018
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 50:10, s. 1412-1425
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Tidskriftsartikel (refereegranskat)abstract
- High blood pressure is a highly heritable and modifiable risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits (systolic, diastolic and pulse pressure) to date in over 1 million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also highlight shared genetic architecture between blood pressure and lifestyle exposures. Our findings identify new biological pathways for blood pressure regulation with potential for improved cardiovascular disease prevention in the future.
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| 6. |
- Lind, Lars, et al.
(författare)
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Can the Plasma Concentration Ratio of Triglyceride/High-Density Lipoprotein Cholesterol Identify Individuals at High Risk of Cardiovascular Disease During 40-Year Follow-Up?
- 2018
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Ingår i: Metabolic Syndrome and Related Disorders. - : Mary Ann Liebert Inc. - 1540-4196 .- 1557-8518. ; 16:8, s. 433-439
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The plasma concentration ratio of triglyceride (TG)/high-density lipoprotein cholesterol (HDL-C) is a simple way to estimate insulin resistance. We aimed to evaluate the TG/HDL-C ratio as a simple clinical way to identify apparently healthy individuals with insulin resistance and enhanced risk of future cardiovascular disease (CVD).METHODS: One thousand seven hundred twenty men, aged 50 years, free from diabetes and CVD when evaluated at baseline in 1970-1974 were followed for 40 years regarding incident CVD (myocardial infarction and/or ischemic stroke, n = 576).RESULTS: Participants with a high TG/HDL-C ratio (highest quartile >1.8) at baseline were more insulin resistant, with a significantly more adverse cardiometabolic risk profile (P < 0.001) at baseline, compared with those with a lower ratio. This group also showed an increased risk of CVD [hazard ratio, HR 1.47 (95% confidence interval 1.26-1.93) P < 0.001]. Fourteen percent of subjects with metabolic syndrome, in whom insulin resistance is increased, were also at enhanced CVD risk [HR 1.75 (1.42-2.16) P < 0.001].CONCLUSIONS: Twenty-five percent of apparently healthy 50-year-old men with the highest TG/HDL-C plasma concentration ratio had a significantly more adverse cardiometabolic profile at baseline, and developed more CVD over the next 40 years, compared with those not meeting this cut point. Determining the TG/HDL-C ratio in middle-aged men provided a simple and potentially clinically useful way to identify increased risk of developing CVD in persons free of diabetes or manifest CVD.
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| 7. |
- Lind, Lars, et al.
(författare)
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Proteomic profiling of endothelium-dependent vasodilation
- 2019
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Ingår i: Journal of Hypertension. - 0263-6352 .- 1473-5598. ; 37:1, s. 216-222
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Tidskriftsartikel (refereegranskat)abstract
- Objective: As endothelial dysfunction is an early event in atherosclerosis formation, we investigated if proteins previously related to cardiovascular disease also were related to endothelial function using a novel targeted proteomics approach.Methods: In the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study (n = 850970, all aged 70 years), endothelium-dependent vasodilation (EDV) in the forearm was assessed by intraarterial infusion of acetylcholine. Flow-mediated vasodilation (FMD) was investigated in the brachial artery by ultrasound. The same investigations were carried out in the Prospective investigation of Obesity, Energy and Metabolism (POEM) study (n = 375-461, all aged 50 years). After strict quality control, 84 cardiovascular-related proteins measured by the proximity extension assay were studied in relation to EDV and FMD in PIVUS (discovery sample) and POEM (validation sample).Results: Of the 15 proteins being significantly related to EDV in PIVUS (false discovery rate < 0.025), seven could be replicated in POEM at nominal significance and same effect direction when adjusted for sex and storage time. Of those, only cathepsin D remained significant following further adjustment for traditional cardiovascular risk factors (beta, -0.08; 95% confidence interval, -0.16, -0.01; P = 0.033; change in ln-transformed EDV per 1-SD increase in protein level). No protein was significantly related to FMD.Conclusion: Using a discovery/validation approach in two samples, our results indicate an inverse association between plasma cathepsin D levels and endothelial-dependent vasodilation.
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| 8. |
- Morris, Andrew P, et al.
(författare)
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Trans-ethnic kidney function association study reveals putative causal genes and effects on kidney-specific disease aetiologies
- 2019
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- Chronic kidney disease (CKD) affects ~10% of the global population, with considerable ethnic differences in prevalence and aetiology. We assemble genome-wide association studies of estimated glomerular filtration rate (eGFR), a measure of kidney function that defines CKD, in 312,468 individuals of diverse ancestry. We identify 127 distinct association signals with homogeneous effects on eGFR across ancestries and enrichment in genomic annotations including kidney-specific histone modifications. Fine-mapping reveals 40 high-confidence variants driving eGFR associations and highlights putative causal genes with cell-type specific expression in glomerulus, and in proximal and distal nephron. Mendelian randomisation supports causal effects of eGFR on overall and cause-specific CKD, kidney stone formation, diastolic blood pressure and hypertension. These results define novel molecular mechanisms and putative causal genes for eGFR, offering insight into clinical outcomes and routes to CKD treatment development.
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| 9. |
- Mubanga, Mwenya, et al.
(författare)
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Dog ownership and Cardiovascular Risk Factors : a nationwide prospective register-based cohort study
- 2019
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Ingår i: BMJ Open. - : BMJ. - 2044-6055. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Objective To study the association between dog ownership and cardiovascular risk factors.Design A nationwide register–based cohort study and a cross-sectional study in a subset.Setting A cohort of 2 026 865 participants was identified from the Register of the Total Population and linked to national registers for information on dog ownership, prescribed medication, hospital admissions, education level, income and country of birth. Participants were followed from 1 October, 2006, to the end of the study on 31 December, 2012, assessing medication for a cardiovascular risk factor, emigration and death. Cross-sectional associations were further assessed in 10 110 individuals from the TwinGene study with additional adjustment for professional level, employment status, Charlson comorbidity index, disability and tobacco use.Participants All Swedish residents aged 45–80 years on 1 October, 2006.Main outcome measures Initiation of medication for hypertension, dyslipidaemia and diabetes mellitus.Results After adjustment for confounders, the results indicated slightly higher likelihood of initiating antihypertensive (HR, 1.02; 95% CI, 1.01 to 1.03) and lipid-lowering treatment (HR, 1.02; 95% CI, 1.01 to 1.04) in dog owners than in non-owners, particularly among those aged 45–60 years and in those owning mixed breed or companion/toy breed dogs. No association of dog ownership with initiation of treatment for diabetes was found in the overall analysis (HR, 0.98; 95% CI, 0.95 to 1.01). Sensitivity analyses in the TwinGene cohort indicated confounding of the association between dog ownership and prevalent treatment for hypertension, dyslipidaemia and diabetes mellitus, respectively, from factors not available in the national cohort, such as employment status and non cardiovascularchronic disease status.Conclusions In this large cohort study, dog ownership was associated with a minimally higher risk of initiation of treatment for hypertension and dyslipidaemia implying that the previously reported lower risk of cardiovascular mortality among dog owners in this cohort is not explained by reduced hypertension and dyslipidaemia. These observations may suffer from residual confounding despite access to multiple important covariates, and future studies may add valuable information.
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| 10. |
- Stenemo, Markus, et al.
(författare)
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The metabolites urobilin and sphingomyelin (30:1) are associated with incident heart failure in the general population
- 2019
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Ingår i: ESC Heart Failure. - : Wiley. - 2055-5822. ; 6:4, s. 764-773
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: We aimed to investigate whether metabolomic profiling of blood can lead to novel insights into heart failure pathogenesis or improved risk prediction.METHODS AND RESULTS: Mass spectrometry-based metabolomic profiling was performed in plasma or serum samples from three community-based cohorts without heart failure at baseline (total n = 3924; 341 incident heart failure events; median follow-up ranging from 4.6 to 13.9 years). Cox proportional hazard models were applied to assess the association of each of the 206 identified metabolites with incident heart failure in the discovery cohorts Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) (n = 920) and Uppsala Longitudinal Study of Adult Men (ULSAM) (n = 1121). Replication was undertaken in the independent cohort TwinGene (n = 1797). We also assessed whether metabolites could improve the prediction of heart failure beyond established risk factors (age, sex, body mass index, low-density and high-density lipoprotein cholesterol, triglycerides, lipid medication, diabetes, systolic and diastolic blood pressure, blood pressure medication, glomerular filtration rate, smoking status, and myocardial infarction prior to or during follow-up). Higher circulating urobilin and lower sphingomyelin (30:1) were associated with incident heart failure in age-adjusted and sex-adjusted models in the discovery and replication sample. The hazard ratio for urobilin in the replication cohort was estimated to 1.29 per standard deviation unit, 95% confidence interval (CI 1.03-1.63), and for sphingomyelin (30:1) to 0.72 (95% CI 0.58-0.89). Results remained similar after further adjustment for established heart failure risk factors in meta-analyses of all three cohorts. Urobilin concentrations were inversely associated with left ventricular ejection fraction at baseline in the PIVUS cohort (β = -0.70, 95% CI -1.03 to -0.38). No major improvement in risk prediction was observed when adding the top 2 metabolites (C-index 0.787, 95% CI 0.752-0.823) or nine Lasso-selected metabolites (0.790, 95% CI 0.754-0.826) to a modified Atherosclerosis Risk in Communities heart failure risk score model (0.780, 95% CI 0.745-0.816).CONCLUSIONS: Our metabolomic profiling of three community-based cohorts study identified associations of circulating levels of the haem breakdown product urobilin, and sphingomyelin (30:1), a cell membrane component involved in signal transduction and apoptosis, with incident heart failure.
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