| 1. |
- Magnusson, Martin, et al.
(författare)
-
A diabetes-predictive amino acid score and future cardiovascular disease.
- 2013
-
Ingår i: European Heart Journal. - : Oxford University Press (OUP). - 1522-9645 .- 0195-668X. ; 34:26, s. 1982-1989
-
Tidskriftsartikel (refereegranskat)abstract
- AimsWe recently identified a metabolic signature of three amino acids (tyrosine, phenylalanine, and isoleucine) that strongly predicts diabetes development. As novel modifiable targets for intervention are needed to meet the expected increase of cardiovascular disease (CVD) caused by the diabetes epidemic, we investigated whether this diabetes-predictive amino acid score (DM-AA score) predicts development of CVD and its functional consequences.Methods and resultsWe performed a matched case-control study derived from the population-based Malmö Diet and Cancer Cardiovascular Cohort (MDC-CC), all free of CVD. During 12 years of follow-up, 253 individuals developed CVD and were matched for age, sex, and Framingham risk score with 253 controls. Amino acids were profiled in baseline plasma samples, using liquid chromatography-tandem mass spectrometry, and relationship to incident CVD was assessed using conditional logistic regression. We further examined whether the amino acid score also correlated with anatomical [intima-media thickness (IMT) and plaque formation] and functional (exercise-induced myocardial ischaemia) abnormalities. Compared with the lowest quartile of the DM-AA score, the odds ratio (95% confidence interval) for incident CVD in subjects belonging to quartiles 2, 3, and 4 was 1.27 (0.72-2.22), 1.96 (1.07-3.60), and 2.20 (1.12-4.31) (P(trend) = 0.010), respectively, after multivariate adjustment. Increasing quartile of the DM-AA score was cross-sectionally related to carotid IMT (P(trend) = 0.037) and with the presence of at least one plaque larger than 10 mm(2) (P(trend) = 0.001). Compared with the lowest quartile of the DM-AA score, the odds ratio (95% confidence interval) for inducible ischaemia in subjects belonging to quartiles 2, 3, and 4 was 3.31 (1.05-10.4), 4.24 (1.36-13.3), and 4.86 (1.47-16.1) (P(trend) = 0.011), respectively.ConclusionThis study identifies branched-chain and aromatic amino acids as novel markers of CVD development and as an early link between diabetes and CVD susceptibility.
|
|
| 2. |
- Cheng, Susan, et al.
(författare)
-
Distinct metabolomic signatures are associated with longevity in humans.
- 2015
-
Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 6
-
Tidskriftsartikel (refereegranskat)abstract
- Alterations in metabolism influence lifespan in experimental models, but data in humans are lacking. Here we use liquid chromatography/mass spectrometry to quantify 217 plasma metabolites and examine their relation to longevity in a large cohort of men and women followed for up to 20 years. We find that, higher concentrations of the citric acid cycle intermediate, isocitrate, and the bile acid, taurocholate, are associated with lower odds of longevity, defined as attaining 80 years of age. Higher concentrations of isocitrate, but not taurocholate, are also associated with worse cardiovascular health at baseline, as well as risk of future cardiovascular disease and death. None of the metabolites identified are associated with cancer risk. Our findings suggest that some, but not all, metabolic pathways related to human longevity are linked to the risk of common causes of death.
|
|
| 3. |
- Cheng, Susan, et al.
(författare)
-
Metabolite Profiling Identifies Pathways Associated With Metabolic Risk in Humans
- 2012
-
Ingår i: Circulation. - 1524-4539. ; 125:18, s. 132-2222
-
Tidskriftsartikel (refereegranskat)abstract
- Background-Although metabolic risk factors are known to cluster in individuals who are prone to developing diabetes mellitus and cardiovascular disease, the underlying biological mechanisms remain poorly understood. Methods and Results-To identify pathways associated with cardiometabolic risk, we used liquid chromatography/mass spectrometry to determine the plasma concentrations of 45 distinct metabolites and to examine their relation to cardiometabolic risk in the Framingham Heart Study (FHS; n=1015) and the Malmo Diet and Cancer Study (MDC; n=746). We then interrogated significant findings in experimental models of cardiovascular and metabolic disease. We observed that metabolic risk factors (obesity, insulin resistance, high blood pressure, and dyslipidemia) were associated with multiple metabolites, including branched-chain amino acids, other hydrophobic amino acids, tryptophan breakdown products, and nucleotide metabolites. We observed strong associations of insulin resistance traits with glutamine (standardized regression coefficients, -0.04 to -0.22 per 1-SD change in log-glutamine; P<0.001), glutamate (0.05 to 0.14; P<0.001), and the glutamine-toglutamate ratio (-0.05 to -0.20; P<0.001) in the discovery sample (FHS); similar associations were observed in the replication sample (MDC). High glutamine-to-glutamate ratio was associated with lower risk of incident diabetes mellitus in FHS (odds ratio, 0.79; adjusted P=0.03) but not in MDC. In experimental models, administration of glutamine in mice led to both increased glucose tolerance (P=0.01) and decreased blood pressure (P=0.05). Conclusions-Biochemical profiling identified circulating metabolites not previously associated with metabolic traits. Experimentally interrogating one of these pathways demonstrated that excess glutamine relative to glutamate, resulting from exogenous administration, is associated with reduced metabolic risk in mice. (Circulation. 2012;125:2222-2231.)
|
|
| 4. |
- Ganda, Anjali, et al.
(författare)
-
Mild Renal Dysfunction and Metabolites Tied to Low HDL Cholesterol Are Associated With Monocytosis and Atherosclerosis
- 2013
-
Ingår i: Circulation. - 1524-4539. ; 127:9, s. 988-996
-
Tidskriftsartikel (refereegranskat)abstract
- Background-The number of circulating blood monocytes impacts atherosclerotic lesion size, and in mouse models, elevated levels of high-density lipoprotein cholesterol suppress blood monocyte counts and atherosclerosis. We hypothesized that individuals with mild renal dysfunction at increased cardiovascular risk would have reduced high-density lipoprotein levels, high blood monocyte counts, and accelerated atherosclerosis. Methods and Results-To test whether mild renal dysfunction is associated with an increase in a leukocyte subpopulation rich in monocytes that has a known association with future coronary events, we divided individuals from the Malmo Diet and Cancer study (MDC) into baseline cystatin C quintiles (n=4757). Lower levels of renal function were accompanied by higher monocyte counts, and monocytes were independently associated with carotid bulb intima-media thickness cross-sectionally (P=0.02). Cystatin C levels were positively and plasma high-density lipoprotein cholesterol levels negatively associated with monocyte counts at baseline, after adjustment for traditional risk factors. Several amino acid metabolites tied to low levels of high-density lipoprotein cholesterol and insulin resistance measured in a subset of individuals (n=752) by use of liquid chromatography-mass spectrometry were independently associated with a 22% to 34% increased risk of being in the top quartile of monocytes (P<0.05). Conclusions-A low high-density lipoprotein cholesterol, insulin resistance phenotype occurs in subjects with mild renal dysfunction and is associated with elevated monocytes and atherosclerosis. High blood monocyte counts may represent a previously unrecognized mechanism underlying the strong relationship between cystatin C and cardiovascular risk. (Circulation. 2013; 127: 988-996.)
|
|
| 5. |
- Ganda, Anjali, et al.
(författare)
-
Plasma metabolite profiles, cellular cholesterol efflux, and non-traditional cardiovascular risk in patients with CKD
- 2017
-
Ingår i: Journal of Molecular and Cellular Cardiology. - : Elsevier BV. - 1095-8584 .- 0022-2828. ; 112, s. 114-122
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Patients with chronic kidney disease (CKD) experience high rates of atherosclerotic cardiovascular disease and death that are not fully explained by traditional risk factors. In animal studies, defective cellular cholesterol efflux pathways which are mediated by the ATP binding cassette transporters ABCA1 and ABCG1 are associated with accelerated atherosclerosis. We hypothesized that cholesterol efflux in humans would vary in terms of cellular components, with potential implications for cardiovascular disease.METHODS: We recruited 120 CKD patients (eGFR<30mL/min/1.73m(2)) and 120 control subjects (eGFR ≥60mL/min/1.73m(2)) in order to measure cholesterol efflux using either patients' HDL and THP-1 macrophages or patients' monocytes and a flow cytometry based cholesterol efflux assay. We also measured cell-surface levels of the common β subunit of the IL-3/GM-CSF receptor (IL-3Rβ) which has been linked to defective cholesterol homeostasis and may promote monocytosis. In addition, we measured plasma inflammatory cytokines and plasma metabolite profiles.RESULTS: There was a strong positive correlation between cell-surface IL-3Rβ levels and monocyte counts in CKD (P<0.001). ABCA1 mRNA was reduced in CKD vs. control monocytes (P<0.05), across various etiologies of CKD. Cholesterol efflux to apolipoprotein A1 was impaired in monocytes from CKD patients with diabetic nephropathy (P<0.05), but we found no evidence for a circulating HDL-mediated defect in cholesterol efflux in CKD. Profiling of plasma metabolites showed that medium-chain acylcarnitines were both independently associated with lower levels of cholesterol transporter mRNA in CKD monocytes at baseline (P<0.05), and with cardiovascular events in CKD patients after median 2.6years of follow-up.CONCLUSIONS: Cholesterol efflux in humans varies in terms of cellular components. We report a cellular defect in ABCA1-mediated cholesterol efflux in monocytes from CKD patients with diabetic nephropathy. Unlike several traditional risk factors for atherosclerotic cardiovascular disease, plasma metabolites inversely associated with endogenous cholesterol transporters predicted cardiovascular events in CKD patients. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others.).
|
|
| 6. |
- Geidenstam, Nina, et al.
(författare)
-
Amino Acid Signatures to Evaluate the Beneficial Effects of Weight Loss
- 2017
-
Ingår i: International Journal of Endocrinology. - : Hindawi Limited. - 1687-8337 .- 1687-8345. ; 2017
-
Tidskriftsartikel (refereegranskat)abstract
- Aims. We investigated the relationship between circulating amino acid levels and obesity; to what extent weight loss followed by weight maintenance can correct amino acid abnormalities; and whether amino acids are related to weight loss. Methods. Amino acids associated with waist circumference (WC) and BMI were studied in 804 participants from the Malmö Diet and Cancer Cardiovascular Cohort (MDC-CC). Changes in amino acid levels were analyzed after weight loss and weight maintenance in 12 obese subjects and evaluated in a replication cohort (n = 83). Results. Out of the eight identified BMI-associated amino acids from the MDC-CC, alanine, isoleucine, tyrosine, phenylalanine, and glutamate decreased after weight loss, while asparagine increased after weight maintenance. These changes were validated in the replication cohort. Scores that were constructed based on obesity-associated amino acids and known risk factors decreased in the ≥10% weight loss group with an associated change in BMI (R(2) = 0.16-0.22, p < 0.002), whereas the scores increased in the <10% weight loss group (p < 0.0004). Conclusions. Weight loss followed by weight maintenance leads to differential changes in amino acid levels associated with obesity. Treatment modifiable scores based on epidemiological and interventional data may be used to evaluate the potential metabolic benefit of weight loss.
|
|
| 7. |
- Holm, Hannes, et al.
(författare)
-
Longitudinal and postural changes of blood pressure predict dementia : the Malmö Preventive Project
- 2017
-
Ingår i: European Journal of Epidemiology. - : Springer Science and Business Media LLC. - 0393-2990 .- 1573-7284. ; 32:4, s. 327-336
-
Tidskriftsartikel (refereegranskat)abstract
- The role of blood pressure (BP) changes in dementia is debatable. We aimed to analyse how resting and postural BP changes relate to incident dementia over a long-term follow-up. In the prospective population-based Malmö Preventive Project, 18,240 study participants (mean age: 45 ± 7 years, 63% male) were examined between 1974 and 1992 with resting and standing BP measurement, and re-examined between 2002 and 2006 at mean age of 68 ± 6 years with resting BP. A total of 428 participants (2.3%) were diagnosed with dementia through Dec 31, 2009. The association of resting and postural BP changes with risk of dementia was studied using multivariable-adjusted Cox regression models controlling for traditional risk factors. Diastolic BP (DBP) decrease on standing indicated higher risk of dementia [Hazard ratio (HR) per 10 mmHg: 1.22; 95% confidence interval (CI) 1.01–1.44, p = 0.036], which was mainly driven by increased risk in normotensive individuals. Higher systolic (SBP) and diastolic BP at re-examination was associated with lower risk of dementia (HR per 10 mmHg: 0.94; 95% CI 0.89–0.99, p = 0.011; and 0.87; 0.78–0.96, p = 0.006, respectively). Extreme decrease in SBP/DBP between baseline and re-examination (4th quartile; −7 ± 12/−15 ± 7 mmHg, respectively) indicated higher risk of dementia (HR 1.46; 95% CI 1.11–1.93, p = 0.008, and 1.54; 95% CI 1.14–2.08, p = 0.005; respectively) compared with reference group characterised by pronounced BP increase over the same period (1st quartile; +44 ± 13/+15 ± 7 mmHg). Diastolic BP decrease on standing in the middle age, decline in BP between middle-and advanced age, and lower BP in advanced age are independent risk factors of developing dementia.
|
|
| 8. |
- Holm, Hannes, et al.
(författare)
-
N-Terminal Prosomatostatin and Risk of Vascular Dementia
- 2017
-
Ingår i: Cerebrovascular Diseases. - : S. Karger. - 1015-9770 .- 1421-9786. ; 44:5-6, s. 259-265
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Increased somatostatin plasma concentration has been found in patients with vascular dementia. However, it is unknown whether or not somatostatin levels may predict dementia development in the general population. To this end, we sought to assess the association of circulating N-terminal prosomatostatin (NT-proSST) with incident dementia among community-dwelling older adults.METHODS: In the prospective population-based Malmö Preventive Project, 5,347 study participants (mean age: 69 ± 6years; 70% men) provided plasma for the determination of NT-proSST concentration. Of these, 373 participants (7%) were diagnosed with dementia (120 Alzheimer's disease, 83 vascular, 102 mixed, and 68 other aetiology) during a follow-up period of 4.6 ± 1.3 years. The association of NT-proSST with the risk of dementia and its subtypes was studied using multivariable-adjusted Cox regression models controlling for age, gender, body mass index, systolic blood pressure, antihypertensive treatment, smoking, diabetes, lipid levels and prevalent stroke.RESULTS: Higher levels of NT-proSST were significantly associated with an increased risk of vascular dementia (hazard ratio [HR] per 1 SD: 1.29; 95% CI 1.05-1.59; p = 0.016), whereas no association was observed with Alzheimer's disease (HR per 1 SD: 0.99; 95% CI 0.81-1.20; p = 0.91), all-cause dementia (HR per 1 SD: 1.04; 95% CI 0.94-1.16; p = 0.44), and mixed dementia (HR per 1 SD: 0.98; 95% CI 0.79-1.21; p = 0.84). Levels of NT-proSST above 563 pmol/L (highest quartile) conferred distinctly increased risk of vascular dementia (HR 1.66; 95% CI 1.05-2.63; p = 0.029) compared with lower values.CONCLUSIONS: Higher levels of circulating N-terminal-prosomatostatin are associated with increased incidence of vascular dementia. Our findings might be of importance for the understanding of dementia development in older adults.
|
|
| 9. |
- Jujic, Amra, et al.
(författare)
-
A genetic variant of the atrial natriuretic peptide gene is associated with left ventricular hypertrophy in a non-diabetic population - the Malmo preventive project study.
- 2013
-
Ingår i: BMC Medical Genetics. - : BioMed Central. - 1471-2350. ; 14:64
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Epidemiological studies have shown considerable heritability of blood pressure, thus suggesting a role for genetic factors. Previous studies have shown an association of a single nucleotide polymorphism rs5068 on the NPPA locus gene with higher levels of circulating atrial natriuretic peptide as well as with lower intra individual blood pressure, but up to date, no association between rs5068 and cardiac organ damage, i.e. left ventricular hypertrophy, has been accounted for in humans. Our sought explore if rs5068 is associated with left ventricular hypertrophy as measured by echocardiographic examination in a non-diabetic population. METHODS: 968 non-diabetic individuals from the Malmo Preventive Project (mean age 67 years; 31% women) were genotyped and examined with echocardiography. Logistic regression was used to adjust for covariates. RESULTS: The minor allele of rs5068 was associated with decreased prevalence of left ventricular hypertrophy (p = 0.021) after adjustment for sex and age. In the multivariate logistic analysis including; age, sex, systolic blood pressure, antihypertensive and/or cardioprotective treatment, body mass index and fasting plasma glucose, the association of rs5068 with left ventricular hypertrophy was, as expected, attenuated (p = 0.061). CONCLUSION: In a non-diabetic population, the minor allele of rs5068 was associated with lower left ventricular mass. These findings suggest that rs5068, or genetic variants in linkage disequilibrium, might affect susceptibility to left ventricular hypertrophy and support the possible protective role of natriuretic peptides.
|
|
| 10. |
- Jujic, Amra, et al.
(författare)
-
Atrial natriuretic Peptide and type 2 diabetes development - biomarker and genotype association study.
- 2014
-
Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:2
-
Tidskriftsartikel (refereegranskat)abstract
- We have recently shown that low plasma levels of mid-regional atrial natriuretic peptide (MR-ANP) predict development of diabetes and glucose progression over time, independently of known risk factors for diabetes development. However, since MR-ANP levels might be influenced by unknown factors causing diabetes, we cannot rule out that such relationship might be confounded. Previous studies have shown an association of a single nucleotide polymorphism rs5068 on the natriuretic peptide precursor A (NPPA) locus gene with higher levels of circulating ANP. Since gene variants are inherited randomly and not subject to confounding, we aimed to investigate whether the variant rs5068 within the NPPA locus is associated with incident type 2 diabetes.
|
|
