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  • Feldreich, Tobias, et al. (författare)
  • The association between plasma proteomics and incident cardiovascular disease identifies MMP-12 as a promising cardiovascular risk marker in patients with chronic kidney disease
  • 2020
  • Ingår i: Atherosclerosis. - : ELSEVIER IRELAND LTD. - 0021-9150 .- 1879-1484. ; 307, s. 11-15
  • Tidskriftsartikel (refereegranskat)abstract
    • Background and aims: Previous proteomics efforts in patients with chronic kidney disease (CKD) have predominantly evaluated urinary protein levels. Therefore, our aim was to investigate the association between plasma levels of 80 cardiovascular disease-related proteins and the risk of major adverse cardiovascular events (MACE) in patients with CKD. Methods: Individuals with CKD stages 3-5 (eGFR below 60 ml min-1 [1.73 m]-2) from three community-based cohorts (PIVUS, ULSAM, SAVA), one diabetes cohort (CARDIPP) and one cohort with peripheral artery disease patients (PADVA) with information on 80 plasma protein biomarkers, assessed with a proximity extension assay, and follow-up data on incident MACE, were used as discovery sample. To validate findings and to asses generalizability to patients with CKD in clinical practice, an outpatient CKD-cohort (Malnutrition, Inflammation and Vascular Calcification (MIVC)) was used as replication sample. Results: In the discovery sample (total n = 1316), 249 individuals experienced MACE during 7.0 +/- 2.9 years (range 0.005-12.9) of follow-up, and in the replication sample, 71 MACE events in 283 individuals over a mean +/- SD change of 2.9 +/- 1.2 years (range 0.1-4.0) were documented. Applying Bonferroni correction, 18 proteins were significantly associated with risk of MACE in the discovery cohort, adjusting for age and sex in order of significance, GDF-15, FGF-23, REN, FABP4, IL6, TNF-R1, AGRP, MMP-12, AM, KIM-1, TRAILR2, TNFR2, CTSL1, CSF1, PlGF, CA-125, CCL20 and PAR-1 (p < 0.000625 for all). Only matrix metalloproteinase 12 (MMP-12) was significantly associated with an increased risk of MACE in the replication sample (hazard ratio (HR) per SD increase, 1.36, 95% CI (1.07-1.75), p = 0.013). Conclusions: Our proteomics analyses identified plasma MMP-12 as a promising cardiovascular risk marker in patients with CKD.
  • Sabale, Ugne, et al. (författare)
  • Healthcare utilization and costs following newly diagnosed type-2 diabetes in Sweden : A follow-up of 38,956 patients in a clinical practice setting
  • 2015
  • Ingår i: Primary Care Diabetes. - : ELSEVIER SCI LTD. - 1751-9918 .- 1878-0210. ; 9:5, s. 330-337
  • Tidskriftsartikel (refereegranskat)abstract
    • Aims: To describe healthcare resource use patterns and estimate healthcare costs of newly diagnosed Type 2 diabetes mellitus (T2DM) patients in Sweden. Methods: Patients with a newly diagnosed T2DM between 1999 and 2009 were identified from 84 Swedish primary care centres. Healthcare resource use data, excluding pharmaceuticals, were extracted from electronic patient records and a national patient register, and reported as per patient mean number of primary care contacts, laboratory tests and hospitalizations. Per patient mean healthcare costs are reported as annual and cumulative costs. Results: During a median (maximum) of 4.6 (9.0) years follow-up; 38,956 patients (183,513 patient years) on average made 81 primary care contacts, was hospitalized 2.14 times, and took 31 laboratory tests. Mean per patient annual healthcare costs were (sic)4128 (95% CI, 4054-4199) the first year after diagnosis, (sic)2708 (95% CI, 2641-2776) the second year, and (sic)3030 (95% CI, 2854-3204) in year 9 (2012 values). Mean per patient cumulative healthcare costs were (sic)26,503 (95% CI, 26,025-26,970) at 9 years of follow-up. Hospitalizations accounted for the majority of healthcare costs. Conclusions: Although newly diagnosed T2DM patients require a substantial amount of healthcare services in primary care, hospitalizations account for the majority of healthcare costs.
  • Locke, Adam E, et al. (författare)
  • Genetic studies of body mass index yield new insights for obesity biology.
  • 2015
  • Ingår i: Nature. - : Nature Publishing Group. - 0028-0836 .- 1476-4687. ; 518:7538, s. 197-401
  • Tidskriftsartikel (refereegranskat)abstract
    • Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.
  • Nowak, Christoph, et al. (författare)
  • Multiplex proteomics for prediction of major cardiovascular events in type 2 diabetes
  • 2018
  • Ingår i: Diabetologia. - : SPRINGER. - 0012-186X .- 1432-0428. ; 61:8, s. 1748-1757
  • Tidskriftsartikel (refereegranskat)abstract
    • Aims/hypothesis Multiplex proteomics could improve understanding and risk prediction of major adverse cardiovascular events (MACE) in type 2 diabetes. This study assessed 80 cardiovascular and inflammatory proteins for biomarker discovery and prediction of MACE in type 2 diabetes. Methods We combined data from six prospective epidemiological studies of 30-77-year-old individuals with type 2 diabetes in whom 80 circulating proteins were measured by proximity extension assay. Multivariable-adjusted Cox regression was used in a discovery/replication design to identify biomarkers for incident MACE. We used gradient-boosted machine learning and lasso regularised Cox regression in a random 75% training subsample to assess whether adding proteins to risk factors included in the Swedish National Diabetes Register risk model would improve the prediction of MACE in the separate 25% test subsample. Results Of 1211 adults with type 2 diabetes (32% women), 211 experienced a MACE over a mean (+/- SD) of 6.4 +/- 2.3 years. We replicated associations (< 5% false discovery rate) between risk of MACE and eight proteins: matrix metalloproteinase (MMP)-12, IL-27 subunit alpha (IL-27a), kidney injury molecule (KIM)-1, fibroblast growth factor (FGF)-23, protein S100-A12, TNF receptor (TNFR)-1, TNFR-2 and TNF-related apoptosis-inducing ligand receptor (TRAIL-R)2. Addition of the 80-protein assay to established risk factors improved discrimination in the separate test sample from 0.686 (95% CI 0.682, 0.689) to 0.748 (95% CI 0.746, 0.751). A sparse model of 20 added proteins achieved a C statistic of 0.747 (95% CI 0.653, 0.842) in the test sample. Conclusions/interpretation We identified eight protein biomarkers, four of which are novel, for risk of MACE in community residents with type 2 diabetes, and found improved risk prediction by combining multiplex proteomics with an established risk model. Multiprotein arrays could be useful in identifying individuals with type 2 diabetes who are at highest risk of a cardiovascular event.
  • Shungin, Dmitry, et al. (författare)
  • New genetic loci link adipose and insulin biology to body fat distribution.
  • 2015
  • Ingår i: Nature. - : Nature Publishing Group. - 0028-0836 .- 1476-4687. ; 518:7538, s. 187-378
  • Tidskriftsartikel (refereegranskat)abstract
    • Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.
  • Bergström, Göran, et al. (författare)
  • Prevalence of Subclinical Coronary Artery Atherosclerosis in the General Population.
  • 2021
  • Ingår i: Circulation. - : Wolters Kluwer. - 0009-7322 .- 1524-4539. ; 144:12, s. 916-929
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Early detection of coronary atherosclerosis using coronary computed tomography angiography (CCTA), in addition to coronary artery calcification (CAC) scoring, may help inform prevention strategies. We used CCTA to determine the prevalence, severity, and characteristics of coronary atherosclerosis and its association with CAC scores in a general population.METHODS: We recruited 30 154 randomly invited individuals age 50 to 64 years to SCAPIS (the Swedish Cardiopulmonary Bioimage Study). The study includes individuals without known coronary heart disease (ie, no previous myocardial infarctions or cardiac procedures) and with high-quality results from CCTA and CAC imaging performed using dedicated dual-source CT scanners. Noncontrast images were scored for CAC. CCTA images were visually read and scored for coronary atherosclerosis per segment (defined as no atherosclerosis, 1% to 49% stenosis, or ≥50% stenosis). External validity of prevalence estimates was evaluated using inverse probability for participation weighting and Swedish register data.RESULTS: In total, 25 182 individuals without known coronary heart disease were included (50.6% women). Any CCTA-detected atherosclerosis was found in 42.1%; any significant stenosis (≥50%) in 5.2%; left main, proximal left anterior descending artery, or 3-vessel disease in 1.9%; and any noncalcified plaques in 8.3% of this population. Onset of atherosclerosis was delayed on average by 10 years in women. Atherosclerosis was more prevalent in older individuals and predominantly found in the proximal left anterior descending artery. Prevalence of CCTA-detected atherosclerosis increased with increasing CAC scores. Among those with a CAC score >400, all had atherosclerosis and 45.7% had significant stenosis. In those with 0 CAC, 5.5% had atherosclerosis and 0.4% had significant stenosis. In participants with 0 CAC and intermediate 10-year risk of atherosclerotic cardiovascular disease according to the pooled cohort equation, 9.2% had CCTA-verified atherosclerosis. Prevalence estimates had excellent external validity and changed marginally when adjusted to the age-matched Swedish background population.CONCLUSIONS: Using CCTA in a large, random sample of the general population without established disease, we showed that silent coronary atherosclerosis is common in this population. High CAC scores convey a significant probability of substantial stenosis, and 0 CAC does not exclude atherosclerosis, particularly in those at higher baseline risk.
  • Carlsson, Axel C., et al. (författare)
  • Growth differentiation factor 15 (GDF-15) is a potential biomarker of both diabetic kidney disease and future cardiovascular events in cohorts of individuals with type 2 diabetes : a proteomics approach
  • 2020
  • Ingår i: Upsala Journal of Medical Sciences. - : Uppsala Medical Society. - 0300-9734 .- 2000-1967. ; 125:1, s. 37-43
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Diabetic kidney disease (DKD) is a leading risk factor for end-stage renal disease and is one of the most important risk factors for cardiovascular disease in patients with diabetes. It is possible that novel markers portraying the pathophysiological underpinning processes may be useful. Aim: To investigate the associations between 80 circulating proteins, measured by a proximity extension assay, and prevalent DKD and major adverse cardiovascular events (MACE) in type 2 diabetes. Methods: We randomly divided individuals with type 2 diabetes from three cohorts into a two-thirds discovery and one-third replication set (total n = 813, of whom 231 had DKD defined by estimated glomerular filtration rate <60 mg/mL/1.73 m(2) and/or urinary albumin-creatinine ratio >= 3 g/mol). Proteins associated with DKD were also assessed as predictors for incident major adverse cardiovascular events (MACE) in persons with DKD at baseline. Results: Four proteins were positively associated with DKD in models adjusted for age, sex, cardiovascular risk factors, glucose control, and diabetes medication: kidney injury molecule-1 (KIM-1, odds ratio [OR] per standard deviation increment, 1.65, 95% confidence interval [CI] 1.27-2.14); growth differentiation factor 15 (GDF-15, OR 1.40, 95% CI 1.16-1.69); myoglobin (OR 1.57, 95% CI 1.30-1.91), and matrix metalloproteinase 10 (MMP-10, OR 1.43, 95% CI 1.17-1.74). In patients with DKD, GDF-15 was significantly associated with increased risk of MACE after adjustments for baseline age, sex, microalbuminuria, and kidney function and (59 MACE events during 7 years follow-up, hazard ratio per standard deviation increase 1.43 [95% CI 1.03-1.98]) but not after further adjustments for cardiovascular risk factors. Conclusion: Our proteomics approach confirms and extends previous associations of higher circulating levels of GDF-15 with both micro- and macrovascular disease in patients with type 2 diabetes. Our data encourage additional studies evaluating the clinical utility of our findings.
  • Grundvold, Irene, et al. (författare)
  • Body weight and risk of atrial fibrillation in 7,169 patients with newly diagnosed type 2 diabetes; an observational study
  • 2015
  • Ingår i: Cardiovascular Diabetology. - : BioMed Central / Springer Verlag (Germany). - 1475-2840 .- 1475-2840. ; 14, s. 5-
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Obesity, type 2 diabetes and atrial fibrillation (AF) are closely associated, but the underlying mechanisms are not fully understood. We aimed to explore associations between body mass index (BMI) or weight change with risk of AF in patients with type 2 diabetes. Methods: A total of 7,169 participations with newly diagnosed type 2 diabetes were stratified according to baseline BMI, and after a second BMI measurement within 18 months, further grouped according to relative weight change as "weight gain" (> 1 BMI unit), " stable weight" (+/- 1 BMI unit) and " weight loss" (< 1 BMI unit). The mean follow-up period was 4.6 years, and the risk of AF was estimated using adjusted Cox regression models. Results: Average age at diabetes diagnosis was 60 years and the patients were slightly obese (mean BMI 30.2 kg/m(2)). During follow-up, 287 patients developed incident AF, and those with overweight or obesity at baseline had 1.9 fold and 2.9-fold higher risk of AF, respectively, than those with normal BMI. The 14% of the patients with subsequent weight gain had 1.5-fold risk of AF compared with those with stable weight or weight loss. Conclusions: In patients with newly diagnosed type 2 diabetes, baseline overweight and obesity, as well as modest weight increase during the first 18 months after diagnosis, were associated with a substantially increased risk of incident AF. Patients with type 2 diabetes may benefit from efforts to prevent weight gain in order to reduce the risk of incident AF.
  • Kalkan, Almina, et al. (författare)
  • Increased healthcare utilization costs following initiation of insulin treatment in type 2 diabetes : A long-term follow-up in clinical practice
  • 2017
  • Ingår i: Primary Care Diabetes. - : Elsevier. - 1751-9918 .- 1878-0210. ; 11:2, s. 184-192
  • Tidskriftsartikel (refereegranskat)abstract
    • Aims: To compare long-term changes in healthcare utilization and costs for type 2 diabetes patients before and after insulin initiation, as well as healthcare costs after insulin versus non-insulin anti-diabetic (NIAD) initiation. Methods: Patients newly initiated on insulin (n. =2823) were identified in primary health care records from 84 Swedish primary care centers, between 1999 to 2009. First, healthcare costs per patient were evaluated for primary care, hospitalizations and secondary outpatient care, before and up to seven years after insulin initiation. Second, patients prescribed insulin in second line were matched to patients prescribed NIAD in second line, and the healthcare costs of the matched groups were compared. Results: The total mean annual healthcare cost increased from €1656 per patient 2 years before insulin initiation to €3814 seven years after insulin initiation. The total cumulative mean healthcare cost per patient at year 5 after second-line treatment was €13,823 in the insulin group compared to €9989 in the NIAD group. Conclusions: Initiation of insulin in type 2 diabetes patients was followed by increased healthcare costs. The increases in costs were larger than those seen in a matched patient population initiated on NIAD treatment in second-line.
  • Sundström, Johan, et al. (författare)
  • Blood pressure levels and risk of cardiovascular events and mortality in type-2 diabetes : cohort study of 34 009 primary care patients
  • 2013
  • Ingår i: Journal of Hypertension. - : Lippincott Williams & Wilkins. - 0263-6352 .- 1473-5598. ; 31:8, s. 1603-1610
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective:The optimal blood pressure (BP) in persons with type-2 diabetes is debated. We investigated shapes of the associations of SBP and DBP levels with risk of cardiovascular events and mortality in a large primary care-based sample of diabetic patients.Methods:We investigated all 34009 consecutive cardiovascular disease-free type-2 diabetes patients aged 35 years or older (mean age 64 years) at 84 primary care centers in central Sweden between 1999 and 2008. We followed this cohort until the end of 2009 in national registries for the incidence of major cardiovascular events (a composite endpoint of myocardial infarction, stroke, heart failure, or cardiovascular mortality) or total mortality.Results:During up to 11 years of follow-up, 6344 patients (18.7%) had a first cardiovascular event, and 6235 died (18.3%). The associations of annually updated SBP and DBP with risk of major cardiovascular events were U-shaped. The lowest risk of cardiovascular events was observed at a SBP of 135-139mmHg and a DBP of 74-76mmHg, and the lowest mortality risk at a SBP of 142-150mmHg and a DBP of 78-79mmHg, in both antihypertensive drug-untreated and drug-treated persons.Conclusion:In a large primary care-based sample of patients with type-2 diabetes, associations of SBP and DBP with risk of major cardiovascular events and mortality were U-shaped. This may have implications for risk stratification of persons with diabetes.
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