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1.
Artigo em Inglês | MEDLINE | ID: mdl-31599692

RESUMO

There exists a close relationship between cardiovascular diseases and chronic kidney disease. Apolipoprotein A1 and high-density lipoprotein (HDL) cholesterol are widely used as cardiovascular risk markers but they also have anti-inflammatory properties. The aim of this study was to investigate any associations between HDL levels and cytokine levels in urine. We randomly selected 90 urine samples from the Prospective Investigation of the Vasculature in Uppsala Seniors Study (41 males and 49 females). The samples were analyzed with 2 multiplex assays, Multiplex Inflammation I and Cardiovascular II kits (Olink Bioscience, Uppsala, Sweden). We analyzed the correlations between 158 cytokines in urine with apolipoprotein A1, HDL cholesterol, apolipoprotein B, and low-density lipoprotein cholesterol. There were strong correlations for apolipoprotein A1 and HDL cholesterol with individual cytokines. After adjustment for multiplicity testing, there were 33 significant correlations between apolipoprotein A1 and cytokine levels and 14 of these were also significantly correlated with HDL cholesterol. The strongest associations were observed for IL-1α, SPON2, RAGE, PAR-1, TRAIL-R2, IL-4RA, TNFRSF11A, and SCF. A total of 28 out of 33 correlations were negative, indicating a negative relationship between apolipoprotein A1 and urinary cytokines. The study shows a negative correlation between apolipoprotein A1 and HDL cholesterol and urinary cytokine levels. The finding is in agreement with the anti-inflammatory properties of HDL.

2.
Nat Genet ; 51(10): 1459-1474, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31578528

RESUMO

Elevated serum urate levels cause gout and correlate with cardiometabolic diseases via poorly understood mechanisms. We performed a trans-ancestry genome-wide association study of serum urate in 457,690 individuals, identifying 183 loci (147 previously unknown) that improve the prediction of gout in an independent cohort of 334,880 individuals. Serum urate showed significant genetic correlations with many cardiometabolic traits, with genetic causality analyses supporting a substantial role for pleiotropy. Enrichment analysis, fine-mapping of urate-associated loci and colocalization with gene expression in 47 tissues implicated the kidney and liver as the main target organs and prioritized potentially causal genes and variants, including the transcriptional master regulators in the liver and kidney, HNF1A and HNF4A. Experimental validation showed that HNF4A transactivated the promoter of ABCG2, encoding a major urate transporter, in kidney cells, and that HNF4A p.Thr139Ile is a functional variant. Transcriptional coregulation within and across organs may be a general mechanism underlying the observed pleiotropy between urate and cardiometabolic traits.

3.
Nat Commun ; 10(1): 4130, 2019 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31511532

RESUMO

Increased levels of the urinary albumin-to-creatinine ratio (UACR) are associated with higher risk of kidney disease progression and cardiovascular events, but underlying mechanisms are incompletely understood. Here, we conduct trans-ethnic (n = 564,257) and European-ancestry specific meta-analyses of genome-wide association studies of UACR, including ancestry- and diabetes-specific analyses, and identify 68 UACR-associated loci. Genetic correlation analyses and risk score associations in an independent electronic medical records database (n = 192,868) reveal connections with proteinuria, hyperlipidemia, gout, and hypertension. Fine-mapping and trans-Omics analyses with gene expression in 47 tissues and plasma protein levels implicate genes potentially operating through differential expression in kidney (including TGFB1, MUC1, PRKCI, and OAF), and allow coupling of UACR associations to altered plasma OAF concentrations. Knockdown of OAF and PRKCI orthologs in Drosophila nephrocytes reduces albumin endocytosis. Silencing fly PRKCI further impairs slit diaphragm formation. These results generate a priority list of genes and pathways for translational research to reduce albuminuria.

4.
Diabetologia ; 62(11): 1998-2006, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31446444

RESUMO

AIMS/HYPOTHESIS: The pathogenesis of type 2 diabetes is not fully understood. We investigated whether circulating levels of preselected proteins were associated with the outcome 'diabetes' and whether these associations were causal. METHODS: In 2467 individuals of the population-based, cross-sectional EpiHealth study (45-75 years, 50% women), 249 plasma proteins were analysed by the proximity extension assay technique. DNA was genotyped using the Illumina HumanCoreExome-12 v1.0 BeadChip. Diabetes was defined as taking glucose-lowering treatment or having a fasting plasma glucose of ≥7.0 mmol/l. The associations between proteins and diabetes were assessed using logistic regression. To investigate causal relationships between proteins and diabetes, a bidirectional two-sample Mendelian randomisation was performed based on large, genome-wide association studies belonging to the DIAGRAM and MAGIC consortia, and a genome-wide association study in the EpiHealth study. RESULTS: Twenty-six proteins were positively associated with diabetes, including cathepsin D, retinal dehydrogenase 1, α-L-iduronidase, hydroxyacid oxidase 1 and galectin-4 (top five findings). Three proteins, lipoprotein lipase, IGF-binding protein 2 and paraoxonase 3 (PON-3), were inversely associated with diabetes. Fourteen of the proteins are novel discoveries. The Mendelian randomisation study did not disclose any significant causal effects between the proteins and diabetes in either direction that were consistent with the relationships found between the protein levels and diabetes. CONCLUSIONS/INTERPRETATION: The 29 proteins associated with diabetes are involved in several physiological pathways, but given the power of the study no causal link was identified for those proteins tested in Mendelian randomisation. Therefore, the identified proteins are likely to be biomarkers for type 2 diabetes, rather than representing causal pathways.

5.
Ups J Med Sci ; 124(3): 187-192, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31429631

RESUMO

Background: Newer therapeutic agents for type 2 diabetes mellitus can improve cardiovascular outcomes, but diabetes remains underdiagnosed in patients with myocardial infarction (MI). We sought to identify proteomic markers of undetected dysglycaemia (impaired fasting glucose, impaired glucose tolerance, or diabetes mellitus) to improve the identification of patients at highest risk for diabetes. Materials and methods: In this prospective cohort, 626 patients without known diabetes underwent oral glucose tolerance testing (OGTT) during admission for MI. Proximity extension assay was used to measure 81 biomarkers. Multivariable logistic regression, adjusting for risk factors, was used to evaluate the association of biomarkers with dysglycaemia. Subsequently, lasso regression was performed in a 2/3 training set to identify proteomic biomarkers with prognostic value for dysglycaemia, when added to risk factors, fasting plasma glucose, and glycated haemoglobin A1c. Determination of discriminatory ability was performed in a 1/3 test set. Results: In total, 401/626 patients (64.1%) met the criteria for dysglycaemia. Using multivariable logistic regression, cathepsin D had the strongest association with dysglycaemia. Lasso regression selected seven markers, including cathepsin D, that improved prediction of dysglycaemia (area under the receiver operator curve [AUC] 0.848 increased to 0.863). In patients with normal fasting plasma glucose, only cathepsin D was selected (AUC 0.699 increased to 0.704). Conclusions: Newly detected dysglycaemia, including manifest diabetes, is common in patients with acute MI. Cathepsin D improved the prediction of dysglycaemia, which may be helpful in the a priori risk determination of diabetes as a motivation for confirmatory OGTT.

6.
ESC Heart Fail ; 6(4): 764-773, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31148414

RESUMO

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 (ß = -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.

7.
Nat Genet ; 51(6): 957-972, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31152163

RESUMO

Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through trans-ancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these, 147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.


Assuntos
Estudos de Associação Genética/métodos , Predisposição Genética para Doença , Locos de Características Quantitativas , Característica Quantitativa Herdável , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/fisiopatologia , Mapeamento Cromossômico , Grupo com Ancestrais do Continente Europeu , Estudo de Associação Genômica Ampla , Taxa de Filtração Glomerular , Humanos , Padrões de Herança , Testes de Função Renal , Fenótipo , Polimorfismo de Nucleotídeo Único , Insuficiência Renal Crônica/urina , Uromodulina/urina
8.
Atherosclerosis ; 284: 202-208, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30959314

RESUMO

BACKGROUND AND AIMS: Raised levels of serum endostatin, a biologically active fragment of collagen XVIII, have been observed in patients with ischemic heart disease but association with incident cardiovascular events in patients with stable coronary heart disease is uncertain. METHODS: The CLARICOR-trial is a randomized, placebo-controlled trial of stable coronary heart disease patients evaluating 14-day treatment with clarithromycin. The primary outcome was a composite of acute myocardial infarction, unstable angina pectoris, cerebrovascular disease or all-cause mortality. In the present sub-study using 10-year follow-up data, we investigated associations between serum endostatin at entry (randomization) and the composite outcome and its components during follow-up. The placebo group was used as discovery sample (1204 events, n = 1998) and the clarithromycin-treated group as replication sample (1220 events, n = 1979). RESULTS: In Cox regression models adjusting for cardiovascular risk factors, glomerular filtration rate, and current pharmacological treatment, higher serum endostatin was associated with an increased risk of the composite outcome in the discovery sample (hazard ratio per standard deviation increase 1.11, 95% CI 1.03-1.19, p = 0.004), but slightly weaker and not statistically significant in the replication sample (hazard ratio 1.06, 95% CI 1.00-1.14, p = 0.06). In contrast, strong and consistent associations were found between endostatin and cardiovascular and all-cause mortality in all multivariable models and sub-samples. Addition of endostatin to a model with established cardiovascular risk factors provided no substantial improvement of risk prediction (<1%). CONCLUSIONS: Raised levels of serum endostatin might be associated with cardiovascular events in patients with stable coronary heart disease. The clinical utility of endostatin measurements remains to be established.

9.
J Am Heart Assoc ; 8(8): e010546, 2019 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-30947615

RESUMO

Background In patients with myocardial infarction ( MI ), reduced kidney function is recognized as an important predictor of poor prognosis, but the impact of albuminuria, a representative measure of kidney damage, has not been extensively evaluated. Methods and Results In the SCREAM (Stockholm Creatinine Measurements) project (2006-2012), we identified 2469 patients with incident MI with dipstick proteinuria measured within a year before MI (427 patients also had urine albumin to creatinine ratio [ ACR ] measured concurrently) and obtained estimates for ACR with multiple imputation in participants with data solely on dipstick proteinuria. We quantified the association of ACR with the post- MI composite and individual outcomes of all-cause mortality, cardiovascular mortality, recurrent MI , ischemic stroke, or heart failure using Cox models and then evaluated the improvement in C statistic. During a median follow-up of 1.0 year after MI , 1607 participants (65.1%) developed the post- MI composite outcome. Higher ACR levels were independently associated with all outcomes except for ischemic stroke. Per 8-fold higher ACR (eg, 40 versus 5 mg/g), the hazard ratio of composite outcome was 1.21 (95% CI , 1.08-1.35). The addition of the ACR improved the C statistic of the post- MI composite by 0.040 (95% CI, 0.030-0.051). Largely similar results were obtained regardless of diabetic status and when ACR or dipstick was separately analyzed without imputation. Conclusions In patients with MI , albuminuria was a potent predictor of subsequent outcomes, suggesting the importance of paying attention to the information on albuminuria, in addition to kidney function, in this high-risk population.

10.
Clin J Am Soc Nephrol ; 14(4): 530-539, 2019 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-30872279

RESUMO

BACKGROUND AND OBJECTIVES: Community-based reports regarding eGFR and the risk of cancer are conflicting. We here explore plausible links between kidney function and cancer incidence in a large Scandinavian population-based cohort. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In the Stockholm Creatinine Measurements project, we quantified the associations of baseline eGFR with the incidence of cancer among 719,033 Swedes ages ≥40 years old with no prior history of cancer. Study outcomes were any type and site-specific cancer incidence rates on the basis of International Classification of Diseases-10 codes over a median follow-up of 5 years. To explore the possibility of detection bias and reverse causation, we divided the follow-up time into different time periods (≤12 and >12 months) and estimated risks for each of these intervals. RESULTS: In total, 64,319 cases of cancer (affecting 9% of participants) were detected throughout 3,338,226 person-years. The relationship between eGFR and cancer incidence was U shaped. Compared with eGFR of 90-104 ml/min, lower eGFR strata associated with higher cancer risk (adjusted hazard ratio, 1.08; 95% confidence interval, 1.05 to 1.11 for eGFR=30-59 ml/min and adjusted hazard ratio, 1.24; 95% confidence interval, 1.15 to 1.35 for eGFR<30 ml/min). Lower eGFR strata were significantly associated with higher risk of skin, urogenital, prostate, and hematologic cancers. Any cancer risk as well as skin (nonmelanoma) and urogenital cancer risks were significantly elevated throughout follow-up time, but they were higher in the first 12 months postregistration. Associations with hematologic and prostate cancers abrogated after the first 12 months of observation, suggesting the presence of detection bias and/or reverse causation. CONCLUSIONS: There is a modestly higher cancer risk in individuals with mild to severe CKD driven primarily by skin and urogenital cancers, and this is only partially explained by bias.

11.
Am J Nephrol ; 49(3): 186-192, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30712037

RESUMO

BACKGROUND: Our aim was to study the association between the country of birth and incident end-stage kidney disease (ESKD) in several immigrant groups in Sweden, using individuals born in Sweden or with Swedish-born parents as referents. METHODS: A cohort study of first- and second-generation immigrants residing in Sweden between January 1, 1998 and December 31, 2012 was performed. Outcomes were defined as having at least one registered diagnosis of ESKD in the National Patient Register. The incidence of ESKD in different immigrant groups was used in the Cox regression models to estimate hazard ratios (HRs) and 95% CIs. All models were stratified by sex and adjusted for age, geographical residence, educational level, marital status, and neighbourhood socioeconomic status. RESULTS: Compared to their referents, higher incidence rates and HRs of ESKD (HR; 95% CI) were observed in general among foreign-born men (1.10; 1.04-1.16) and women (1.12; 1.04-1.21) but not among second-generation immigrants (persons born in Sweden with foreign-born parents). A particularly high -incidence was noted among men and women from -East-European countries, as well as from non-European regions. A lower incidence of ESKD was noted among men from Finland. CONCLUSIONS: We observed substantial differences in incidence of ESKD between immigrant groups and the Swedish-born population, which may be clinically relevant when monitoring preventive measures in patient subgroups with a higher risk of deteriorating kidney disease, and suggest higher attention to hypertension and diabetes control in immigrants. Mechanisms attributable to the migration process or ethnic differences may lead to an increased risk of ESKD.

12.
PLoS One ; 14(2): e0212060, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30802263

RESUMO

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.


Assuntos
Envelhecimento , Proteínas Sanguíneas/análise , Hemoglobinas/análise , Rim/fisiologia , Idoso , Feminino , Taxa de Filtração Glomerular , Humanos , Estudos Longitudinais , Masculino
13.
Lancet Diabetes Endocrinol ; 7(2): 115-127, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30635225

RESUMO

BACKGROUND: Change in albuminuria as a surrogate endpoint for progression of chronic kidney disease is strongly supported by biological plausibility, but empirical evidence to support its validity in epidemiological studies is lacking. We aimed to assess the consistency of the association between change in albuminuria and risk of end-stage kidney disease in a large individual participant-level meta-analysis of observational studies. METHODS: In this meta-analysis, we collected individual-level data from eligible cohorts in the Chronic Kidney Disease Prognosis Consortium (CKD-PC) with data on serum creatinine and change in albuminuria and more than 50 events on outcomes of interest. Cohort data were eligible if participants were aged 18 years or older, they had a repeated measure of albuminuria during an elapsed period of 8 months to 4 years, subsequent end-stage kidney disease or mortality follow-up data, and the cohort was active during this consortium phase. We extracted participant-level data and quantified percentage change in albuminuria, measured as change in urine albumin-to-creatinine ratio (ACR) or urine protein-to-creatinine ratio (PCR), during baseline periods of 1, 2, and 3 years. Our primary outcome of interest was development of end-stage kidney disease after a baseline period of 2 years. We defined an end-stage kidney disease event as initiation of kidney replacement therapy. We quantified associations of percentage change in albuminuria with subsequent end-stage kidney disease using Cox regression in each cohort, followed by random-effects meta-analysis. We further adjusted for regression dilution to account for imprecision in the estimation of albuminuria at the participant level. We did multiple subgroup analyses, and also repeated our analyses using participant-level data from 14 clinical trials, including nine clinical trials not in CKD-PC. FINDINGS: Between July, 2015, and June, 2018, we transferred and analysed data from 28 cohorts in the CKD-PC, which included 693 816 individuals (557 583 [80%] with diabetes). Data for 675 904 individuals and 7461 end-stage kidney disease events were available for our primary outcome analysis. Change in ACR was consistently associated with subsequent risk of end-stage kidney disease. The adjusted hazard ratio (HR) for end-stage kidney disease after a 30% decrease in ACR during a baseline period of 2 years was 0·83 (95% CI 0·74-0·94), decreasing to 0·78 (0·66-0·92) after further adjustment for regression dilution. Adjusted HRs were fairly consistent across cohorts and subgroups (ie, estimated glomerular filtration rate, diabetes, and sex), but the association was somewhat stronger among participants with higher baseline ACR than among those with lower baseline ACR (pinteraction<0·0001). In individuals with baseline ACR of 300 mg/g or higher, a 30% decrease in ACR over 2 years was estimated to confer a more than 1% absolute reduction in 10-year risk of end-stage kidney disease, even at early stages of chronic kidney disease. Results were generally similar when we used change in PCR and when study populations from clinical trials were assessed. INTERPRETATION: Change in albuminuria was consistently associated with subsequent risk of end-stage kidney disease across a range of cohorts, lending support to the use of change in albuminuria as a surrogate endpoint for end-stage kidney disease in clinical trials of progression of chronic kidney disease in the setting of increased albuminuria. FUNDING: US National Kidney Foundation and US National Institute of Diabetes and Digestive and Kidney Diseases.

14.
Nat Commun ; 10(1): 29, 2019 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-30604766

RESUMO

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.


Assuntos
Taxa de Filtração Glomerular/genética , Hipertensão/genética , Cálculos Renais/genética , Rim/fisiopatologia , Insuficiência Renal Crônica/genética , Adulto , Idoso , Pressão Sanguínea/genética , Grupos Étnicos/genética , Feminino , Loci Gênicos/genética , Estudo de Associação Genômica Ampla , Código das Histonas/genética , Histonas/metabolismo , Humanos , Hipertensão/etnologia , Hipertensão/fisiopatologia , Cálculos Renais/etnologia , Cálculos Renais/fisiopatologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Insuficiência Renal Crônica/etnologia , Insuficiência Renal Crônica/fisiopatologia
15.
J Hypertens ; 37(1): 216-222, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30339551

RESUMO

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 = 850-970, all aged 70 years), endothelium-dependent vasodilation (EDV) in the forearm was assessed by intra-arterial 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.

16.
J Nephrol ; 2018 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-30499038

RESUMO

INTRODUCTION: Proteomic profiling of end-stage renal disease (ESRD) patients could lead to improved risk prediction and novel insights into cardiovascular disease mechanisms. Plasma levels of 92 cardiovascular disease-associated proteins were assessed by proximity extension assay (Proseek Multiplex CVD-1, Olink Bioscience, Uppsala, Sweden) in a discovery cohort of dialysis patients, the Mapping of Inflammatory Markers in Chronic Kidney disease cohort [MIMICK; n = 183, 55% women, mean age 63 years, 46 cardiovascular deaths during follow-up (mean 43 months)]. Significant results were replicated in the incident and prevalent hemodialysis arm of the Salford Kidney Study [SKS dialysis study, n = 186, 73% women, mean age 62 years, 45 cardiovascular deaths during follow-up (mean 12 months)], and in the CKD5-LD-RTxcohort with assessments of coronary artery calcium (CAC)-score by cardiac computed tomography (n = 89, 37% women, mean age 46 years). RESULTS: In age and sex-adjusted Cox regression in MIMICK, 11 plasma proteins were nominally associated with cardiovascular mortality (in order of significance: Kidney injury molecule-1 (KIM-1), Matrix metalloproteinase-7, Tumour necrosis factor receptor 2, Interleukin-6, Matrix metalloproteinase-1, Brain-natriuretic peptide, ST2 protein, Hepatocyte growth factor, TNF-related apoptosis inducing ligand receptor-2, Spondin-1, and Fibroblast growth factor 25). Only plasma KIM-1 was associated with cardiovascular mortality after correction for multiple testing, but also after adjustment for dialysis vintage, cardiovascular risk factors and inflammation (hazard ratio) per standard deviation (SD) increase 1.84, 95% CI 1.26-2.69, p = 0.002. Addition of KIM-1, or nine of the most informative proteins to an established risk-score (modified AROii CVM-score) improved discrimination of cardiovascular mortality risk from C = 0.777 to C = 0.799 and C = 0.823, respectively. In the SKS dialysis study, KIM-1 predicted cardiovascular mortality in age and sex adjusted models (hazard ratio per SD increase 1.45, 95% CI 1.03-2.05, p = 0.034) and higher KIM-1 was associated with higher CACscores in the CKD5-LD-RTx-cohort. CONCLUSIONS: Our proteomics approach identified plasma KIM-1 as a risk marker for cardiovascular mortality and coronary artery calcification in three independent ESRD-cohorts. The improved risk prediction for cardiovascular mortality by plasma proteomics merit further studies.

17.
Scand Cardiovasc J ; : 1-9, 2018 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-30445882

RESUMO

OBJECTIVE: An increased risk of being diagnosed with coronary heart disease or atrial fibrillation has been shown among different immigrant groups. However, less is known on the risk of being diagnosed with congestive heart failure (CHF). DESIGN: We studied CHF in immigrants including all adults ≥45 years in Sweden (n = 3,274,119) from 1998 to 2012. CHF was defined as at the first event registered in the National Patient Register. Risk of incident CHF in immigrant groups compared to the Swedish-born population was assessed by Cox regression, stratified by sex, adjusting for age, socio-demographic status, and co-morbidities. RESULTS: During a mean follow-up of 14 years in total, a total of 302,340 (9.2%) events of CHF were registered. We found the following: higher incidence in men from Bosnia, Iraq, Lebanon, Russia and Africa; among women from Bosnia, Iraq, Lebanon, Turkey, Central Europe and Finland; lower incidence in men from Iceland, Latin America, Southern Europe, Norway and Western Europe; and among women from Iceland, Southern Europe, Norway, Denmark and Western Europe. CONCLUSION: It is important to be aware of the increased incidence of CHF in some immigrant groups, especially from countries and areas where the immigrants have been refugees, in order to enable for a timely diagnosis, treatment of and prevention of CHF and its debilitating complications.

18.
Scand Cardiovasc J ; : 1-15, 2018 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-30474426

RESUMO

OBJECTIVE: Increased levels of circulating endostatin have been observed in patients with prevalent ischemic heart disease. However, the association between circulating endostatin, and incident myocardial infarction (MI) is less studied. Our main aim was to study the association between circulating endostatin and incident MI in the community adjusted for established cardiovascular risk factors in men and women. DESIGN: Circulating endostatin was measured in a nested case control study based on three large community-based Swedish cohorts, including 533 MI cases, and 1003 age-, sex- and cohort-matched controls. Odds ratios (OR) with 95% confidence intervals (CI) were calculated with adjustments for established cardiovascular risk factors. RESULTS: Higher endostatin was associated with a higher incidence of MI independently of established cardiovascular risk factors (OR 1.19, 95 % CI 1.03-1.37, p = 0.02), but this association was abolished after additional adjustment for C-reactive protein. Sex-stratified analyses suggest that the association was substantially stronger in women as compared to men Conclusions: In our community based sample, higher endostatin predicted incident myocardial infarction predominantly in women but not independently of CRP. Thus, our findings do not support a broad utility of endostatin measurements for the prediction of incident myocardial infarction in clinical practice.

19.
Int Health ; 2018 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-30364949

RESUMO

Aim: To study association between country of birth and risk of first-onset atrial fibrillation (AF) in first- and second-generation immigrants to Sweden under 45 y of age. Methods: The study population included all individuals (n = 3 248 457) under the age of 45 y in Sweden, including immigrants (n = 722 249). AF was defined as first registered diagnosis in the National Patient Register. Association between country of birth and risk of AF was assessed by Cox regression, calculating HRs and 95% CIs, using Swedish-born individuals as referents. All models were stratified by sex, and in different models were adjusted for age, area of residence in Sweden, educational level, marital status, neighbourhood socioeconomic status and co-morbidity(ies). Results: A higher fully adjusted HR of incident AF was found in the total sample of first-generation immigrants, 1.44 (95% CI 1.35 to 1.54), in males born in Denmark, Lebanon and Iraq, and in females born in Turkey and Iraq. Lower HRs were found in male and female immigrants from Latin America and Iran, and female immigrants from Finland. Among second-generation immigrants, the fully adjusted HR was significantly lower, 0.70 (95% CI 0.58 to 0.83). Conclusions: Clinicians may show a greater awareness of AF in some groups of younger immigrants to enable early diagnosis.

20.
Arterioscler Thromb Vasc Biol ; 38(10): 2505-2518, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30354202

RESUMO

Objective- Revealing patterns of associations between circulating protein and lipid levels could improve biological understanding of cardiovascular disease (CVD). In this study, we investigated the associations between proteins related to CVD and triglyceride (TG), total cholesterol, LDL (low-density lipoprotein), and HDL (high-density lipoprotein) cholesterol levels in individuals from the general population. Approach and Results- We measured plasma protein levels using the Olink ProSeek CVD I or II+III arrays and analyzed 57 proteins available in 3 population-based cohorts: EpiHealth (n=2029; 52% women; median age, 61 years), PIVUS (Prospective Study of the Vasculature in Uppsala Seniors; n=790; 51% women; all aged 70 years), and ULSAM (Uppsala Longitudinal Study of Adult Men; n=551; all men aged 77 years). A discovery analysis was performed in EpiHealth in a regression framework (adjusted for sex, age, body mass index, smoking, glucose levels, systolic blood pressure, blood pressure medication, diabetes mellitus medication, and CVD history), and associations with false discovery rate <0.05 were further tested in PIVUS and ULSAM, where a P value of 0.05 was considered a successful replication (validation false discovery rate of 0.1%). We used summary statistics from a genome-wide association study on each protein biomarker (meta-analysis of EpiHealth, PIVUS, ULSAM, and IMPROVE [Carotid Intima-Media Thickness and IMT-Progression as Predictors of Vascular Events in a High-Risk European Population]) and publicly available data from Global Lipids Genetics Consortium to perform Mendelian randomization analyses to address possible causality of protein levels. Of 57 tested proteins, 42 demonstrated an association with at least 1 lipid fraction; 35 were associated with TG, 15 with total cholesterol, 9 with LDL cholesterol, and 24 with HDL cholesterol. Among these associations, we found KIM-1 (kidney injury molecule-1), TNFR (TNF [tumor necrosis factor] receptor) 1 and 2, TRAIL-R2 (TRAIL [TNF-related apoptosis-inducing ligand] receptor 2), and RETN (resistin) to be associated with all 4 lipid fractions. Further, 15 proteins were related to both TG and HDL cholesterol in a consistent and biologically expected manner, that is, higher TG and lower HDL cholesterol or vice versa. Another common pattern of associations was concomitantly higher TG, total cholesterol, and LDL cholesterol, which is associated with higher CVD risk. We did not find evidence of causal links for protein levels. Conclusions- Our comprehensive analysis of plasma proteins and lipid fractions of 3370 individuals from the general population provides new information about lipid metabolism.

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