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1.
Hypertension ; : HYPERTENSIONAHA11913735, 2019 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-31587574

RESUMO

The potential role of branched-chain amino acids (BCAAs) in the pathogenesis of cardiometabolic diseases is increasingly recognized, but the association of BCAAs with incident hypertension remains unknown. The aim of the present study was to explore the association of BCAAs with incident hypertension in a prospective population-based cohort study. We measured plasma concentrations of BCAAs by means of nuclear magnetic resonance spectroscopy in 4169 participants from the PREVEND (Prevention of Renal and Vascular End-stage Disease) study. We estimated the risk of incident hypertension using multivariable-adjusted Cox regression models. After a median follow-up of 8.6 years, incident hypertension was ascertained in 924 subjects. Cox regression analyses revealed a significant association between BCAAs and incident hypertension. The hazard ratio per one SD of BCAAs was 1.11 (95% CI, 1.02-1.20; P=0.01) after full adjustment for multiple clinical variables. Likewise, the fully adjusted association remained significant when evaluated as categorical variable (hazard ratio for upper quartile with lowest quartile as reference category, 1.36; 95% CI, 1.11-1.68; P=0.003). Furthermore, the net reclassification improvement assessment improved after addition of BCAAs to a traditional risk model (P<0.001). This prospective study revealed that high plasma concentrations of BCAAs are associated with an increased risk of newly developed hypertension. The association remained after adjusting for age, sex, body mass index, and lipid profile.

2.
Nat Genet ; 2019 Oct 02.
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.
Nutrients ; 11(9)2019 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-31540245

RESUMO

Taurine is a sulfur containing nutrient that has been shown to protect against oxidative stress, which has been implicated in the pathophysiology leading to late graft failure after renal transplantation. We prospectively investigated whether high urinary taurine excretion, reflecting high taurine intake, is associated with low risk for development of late graft failure in renal transplant recipients (RTR). Urinary taurine excretion was measured in a longitudinal cohort of 678 stable RTR. Prospective associations were assessed using Cox regression analyses. Graft failure was defined as the start of dialysis or re-transplantation. In RTR (58% male, 53 ± 13 years old, estimated glomerular filtration rate (eGFR) 45 ± 19 mL/min/1.73 m2), urinary taurine excretion (533 (210-946) µmol/24 h) was significantly associated with serum free sulfhydryl groups (ß = 0.126; P = 0.001). During median follow-up for 5.3 (4.5-6.0) years, 83 (12%) patients developed graft failure. In Cox regression analyses, urinary taurine excretion was inversely associated with graft failure (hazard ratio: 0.74 (0.67-0.82); P < 0.001). This association remained significant independent of potential confounders. High urinary taurine excretion is associated with low risk of late graft failure in RTR. Therefore, increasing taurine intake may potentially support graft survival in RTR. Further studies are warranted to determine the underlying mechanisms and the potential of taurine supplementation.

5.
Nutrients ; 11(9)2019 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-31547438

RESUMO

Sodium restriction may potentially reduce iodine intake. This study aimed to determine the effect of sodium restriction (dietary counseling) on 24-h urinary iodine excretion. Diuretics provide an alternative to sodium restriction and are frequently added to sodium restriction, so the effects of hydrochlorothiazide (50 mg daily) and combined therapy were also studied. We performed a post-hoc analysis of a Dutch multi-center, randomized cross-over trial in 45 patients with diabetic kidney disease with a mean age of 65 ± 9 years, mean eGFR of 65 ± 27 mL/min/1.73 m2, median albuminuria of 648 [230-2008] mg/24 h and 84% were male. During regular sodium intake with placebo, mean 24 h urinary sodium and iodine excretion were 224 ± 76 mmol/24 h and 252 ± 94 ug/24 h, respectively (r = 0.52, p < 0.001). Mean iodine excretion did not change significantly if sodium restriction and hydrochlorothiazide were applied separately; mean difference -8 ug/day (95% CI -38, 22; p = 0.6) and 14 ug/day (95% CI -24, 52; p = 0.5), respectively. Combined therapy induced a significant decrease in mean iodine excretion (-37 ug/day; 95% CI -67, -7; p = 0.02), yet this was not seen to a clinically meaningful level. The number of patients with an estimated intake below recommended daily allowances did not differ significantly between the four treatment periods (p = 0.3). These findings show that sodium restriction is not a risk factor for iodine deficiency.

6.
Clin J Am Soc Nephrol ; 14(10): 1512-1520, 2019 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-31530552

RESUMO

BACKGROUND AND OBJECTIVES: In kidney transplant recipients, elevated circulating advanced glycation endproducts (AGEs) are the result of increased formation and decreased kidney clearance. AGEs trigger several intracellular mechanisms that ultimately yield excess cardiovascular disease. We hypothesized that, in stable kidney transplant recipients, circulating AGEs are associated with long-term risk of cardiovascular mortality, and that such a relationship is mediated by inflammatory, oxidative stress, and endothelial dysfunction biomarkers. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Prospective cohort study of stable kidney transplant recipients recruited between 2001 and 2003 in a university setting. We performed multivariable-adjusted Cox regression analyses to assess the association of AGEs (i.e., Nε -[Carboxymethyl]lysine (CML) and Nε -[Carboxyethyl]lysine (CEL), measured by tandem mass spectrometry) with cardiovascular mortality. Mediation analyses were performed according to Preacher and Hayes's procedure. RESULTS: We included 555 kidney transplant recipients (age 51±12 years, 56% men). During a median follow-up of 6.9 years, 122 kidney transplant recipients died (52% deaths were due to cardiovascular causes). CML and CEL concentrations were directly associated with cardiovascular mortality (respectively, hazard ratio, 1.55; 95% confidence interval, 1.24 to 1.95; P<0.001; and hazard ratio, 1.53; 95% confidence interval 1.18 to 1.98; P=0.002), independent of age, diabetes, smoking status, body mass index, eGFR and proteinuria. Further adjustments, including cardiovascular history, did not materially change these findings. In mediation analyses, free thiol groups and soluble vascular cell adhesion molecule-1 consistently explained approximately 35% of the association of CML and CEL with cardiovascular mortality. CONCLUSIONS: In stable kidney transplant recipients, circulating levels of AGEs are independently associated with long-term risk of cardiovascular mortality. PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2019_09_17_CJN00540119.mp3.

7.
Diabetes Care ; 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31488569

RESUMO

OBJECTIVE: To study whether fibroblast growth factor 23 (FGF23) is associated with adverse outcomes in patients with type 2 diabetes and normal or mildly impaired kidney function. RESEARCH DESIGN AND METHODS: We analyzed C-terminal FGF23 levels in 310 patients with type 2 diabetes and estimated glomerular filtration rate ≥60 mL/min/1.73 m2. Associations of FGF23 with all-cause mortality and major adverse cardiovascular events (MACE) were studied by Cox regression. RESULTS: During a follow-up of 5.8 years (3.3-6.5), 47 patients developed MACE and 28 patients died. FGF23 was associated with an increased risk of all-cause mortality (age- and sex-adjusted hazard ratio 2.78 [95% CI 1.76-4.40]) and MACE (1.67 [1.12-2.49]). Results were similar after additional adjustment for other potential confounders and were consistent upon replication in an independent cohort. CONCLUSIONS: In patients with type 2 diabetes and normal or mildly impaired kidney function, FGF23 is associated with an increased risk of cardiovascular events and mortality.

9.
Amino Acids ; 2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31535220

RESUMO

L-Arginine:glycine amidinotransferase (AGAT) is the main producer of the creatine precursor, guanidinoacetate (GAA), and L-homoarginine (hArg). We and others previously reported lower levels of circulating and urinary hArg in renal transplant recipients (RTR) compared to healthy subjects. In adults, hArg emerged as a novel risk factor for renal and cardiovascular adverse outcome. Urinary GAA was found to be lower in children and adolescents with kidney transplants compared to healthy controls. Whether GAA is also a risk factor in the renal and cardiovascular systems of adults, is not yet known. In the present study, we aimed to investigate the significance of circulating GAA and the GAA-to-hArg molar ratio (GAA/hArg) in adult RTR. We hypothesized that GAA/hArg represents a measure of the balanced state of the AGAT activity in the kidneys, and would prospectively allow assessing a potential association between GAA/hArg and long-term outcome in RTR. The median follow-up period was 5.4 years. Confounders and potential mediators of GAA/hArg associations were evaluated with multivariate linear regression analyses, and the association with all-cause and cardiovascular mortality or death-censored graft loss was studied with Cox regression analyses. The study cohort consisted of 686 stable RTR and 140 healthy kidney donors. Median plasma GAA concentration was significantly lower in the RTR compared to the kidney donors before kidney donation: 2.19 [1.77-2.70] µM vs. 2.78 [2.89-3.35] µM (P < 0.001). In cross-sectional multivariable analyses in RTR, HDL cholesterol showed the strongest association with GAA/hArg. In prospective analyses in RTR, GAA/hArg was associated with a higher risk for all-cause mortality (hazard ratio (HR): 1.35 [95% CI 1.19-1.53]) and cardiovascular mortality (HR: 1.46 [95% CI 1.24-1.73]), independent of potential confounders. GAA but not GAA/hArg was associated with death-censored graft loss in crude survival and Cox regression analyses. The association of GAA and death-censored graft loss was lost after adjustment for eGFR. Our study suggests that in the kidneys of RTR, the AGAT-catalyzed biosynthesis of GAA is decreased. That high GAA/hArg is associated with a higher risk for all-cause and cardiovascular mortality may suggest that low plasma hArg is a stronger contributor to these adverse outcomes in RTR than GAA.

10.
Clin Chem Lab Med ; 2019 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-31373896

RESUMO

Background The dried blood spot (DBS) method allows patients and researchers to collect blood on a sampling card using a skin-prick. An important issue in the application of DBSs is that samples for therapeutic drug monitoring are frequently rejected because of poor spot quality, leading to delayed monitoring or missing data. We describe the development and performance of a web-based application (app), accessible on smartphones, tablets or desktops, capable of assessing DBS quality at the time of sampling by means of analyzing a picture of the DBS. Methods The performance of the app was compared to the judgment of experienced laboratory technicians for samples obtained in a trained and untrained setting. A robustness- and user test were performed. Results In a trained setting the app yielded an adequate decision in 90.0% of the cases with 4.1% false negatives (insufficient quality DBSs incorrectly not rejected) and 5.9% false positives (sufficient quality DBSs incorrectly rejected). In an untrained setting this was 87.4% with 5.5% false negatives and 7.1% false positives. A patient user test resulted in a system usability score of 74 out of 100 with a median time of 1 min and 45 s to use the app. Robustness testing showed a repeatability of 84%. Using the app in a trained and untrained setting improves the amount of sufficient quality samples from 80% to 95.9% and 42.2% to 87.9%, respectively. Conclusions The app can be used in trained and untrained setting to decrease the amount of insufficient quality DBS samples.

11.
PLoS One ; 14(8): e0220659, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31386691

RESUMO

Non-alcoholic fatty liver disease (NAFLD) is featured by increased plasma very low density lipoproteins (VLDL). The extent to which plasma apolipoprotein E (ApoE) levels are elevated in NAFLD is unclear. We determined whether plasma ApoE is elevated in subjects with suspected NAFLD. Plasma ApoE and genotypes were determined in 6,762 participants of the Prevention of Renal and Vascular End-Stage Disease (PREVEND) cohort. A Fatty Liver Index (FLI) ≥ 60 was used as a proxy of NAFLD. A total of 1,834 participants had a FLI ≥ 60, which coincided with increased triglycerides, non-HDL cholesterol, ApoB and ApoE (all P<0.001). In multivariable linear regression analysis, plasma ApoE levels were positively associated with an elevated FLI when taking account of ApoE genotypes and other clinical and laboratory covariates (fully adjusted model: ß = 0.201, P<0.001). Stratified analysis for ApoE genotypes (ApoE ε3ε3 homozygotes, ApoE ε2 carriers, and ApoE ε3ε4 and ε4ε4 carriers combined), also showed positive associations of plasma ApoE levels with an elevated FLI in each group (all P<0.001). In conclusion, it is suggested that NAFLD is characterized by increased plasma ApoE levels, even when taking account of the various ApoE genotypes. Increased plasma ApoE may contribute to altered VLDL metabolism and to increased atherosclerosis susceptibility in NAFLD.

12.
PLoS One ; 14(8): e0220368, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31393962

RESUMO

BACKGROUND: Multimorbidity is considered a major challenge for current health care. Lifestyle interventions, as a broad and generic approach, may have the potential to improve the management of care among patients with multimorbidity. The objective of this study was to evaluate the association of multimorbidity defined within the cardiometabolic disease domains with dietary patterns, representing habitual dietary intake. DESIGN: We studied 129 369 participants from the Lifelines Cohort study (42% male, 45±13 years (range 18-93)) in which diet was assessed using a 110-item food frequency questionnaire. A composite morbidity score was applied in multivariable ordered logistic regression to test the association with dietary patterns derived by principal components analysis, based on sex-specific dietary pattern scores. RESULTS: Four dietary patterns were retained, accounting for 26.6% of the variation in overall diet. After control for potential confounders, men and women in the highest quintile of "meat, alcohol and potato pattern" and "snack pattern" had a higher likelihood of having higher morbidity scores than those in the lowest quintile (e.g. men: OR = 1.83(95% CI:1.71-1.97), OR = 1.18(95% CI 1.11-1.27 respectively). The opposite was observed with respect to the "bread and sweets pattern" and "vegetable, fish and fruit pattern" (e.g. women: OR = 0.88(95% CI: 0.81-0.96), OR = 0.86(95% CI 0.81-0.92 respectively). The association partially attenuated after adjusting for BMI, but the associations remained significant among men. CONCLUSIONS: Robust associations between dietary patterns and multimorbidity within the cardiometabolic domain, in particular a "meat, alcohol and potato pattern", suggest an important opportunity of dietary interventions in multimobidity prevention. Generic prevention strategies based on population derived dietary patterns may have the potential to enhance lifestyle management among people with multimorbidity.

13.
Clin Nutr ; 2019 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-31378513

RESUMO

BACKGROUND & AIMS: Urinary creatinine excretion reflecting endogenous creatinine synthesis rate (CSR) is an established measure of muscle mass in the general populations and in patients with chronic kidney disease. There is increasing data to suggest that CSR not only reflects muscle mass, but also muscle function. In dialysis patients, CSR has rarely been studied since it requires dialysate collection. We aimed to study whether CSR is associated with muscle strength, and self-reported physical health in dialysis patients. METHODS: Total daily CSR (dialytic removal plus, if applicable, urinary excretion), handgrip strength, and self-reported physical health according subscales of the Checklist Individual Strength and the Short Form-36 were assessed in 50 dialysis patients. Associations of CSR, indexed to body surface area, with handgrip strength and self-reported physical health were studied using multivariable linear regression models. RESULTS: Median age was 69 [interquartile range 60-78] years. Mean CSR was higher in men than in women (9.5 ± 3.3 mmol/24 h versus 6.8 ± 1.9 mmol/24 h respectively, P = 0.007). Age, BMI, and plasma albumin were positively associated with CSR. CSR was positively associated with handgrip strength (adjusted (a-) ß: 0.44 [95% CI: 0.18 to 0.71), physical functioning (a-ß: 0.54 [95% CI: 0.19 to 0.88]), social functioning (a-ß: 0.43 [95%CI 0.08 to 0.76]), and inversely with physical inactivity (adjusted ß: -0.69 [95% CI: -1.00 to -0.38), fatigue (adjusted ß: -0.61 [95% CI: -0.93 to -0.27]), and role limitation due to physical health (a-ß: 0.39 [95% CI: 0.04 to 0.74]). CONCLUSIONS: In dialysis patients, a greater CSR is associated with higher muscle strength, better physical and social functioning, and physical activity, and with less fatigue, and role limitation due to physical health. Thus, CSR reflects muscle function, self-reported physical health and social functioning in dialysis patients.

14.
Diabetes ; 68(10): 1915-1923, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31375510

RESUMO

In renal transplant recipients (RTRs), new-onset diabetes after transplantation (NODAT) is a frequent and serious complication limiting survival of graft and patient. However, the underlying pathophysiology remains incompletely understood. In vitro and in preclinical models, HDL can preserve ß-cell function, largely by mediating cholesterol efflux, but this concept has not been evaluated in humans. This study investigated whether baseline cholesterol efflux capacity (CEC) in RTRs is associated with incident NODAT during follow-up. This prospective longitudinal study included 405 diabetes-free RTRs with a functioning graft for >1 year. During a median (interquartile range) follow-up of 9.6 (6.6-10.2) years, 57 patients (14.1%) developed NODAT. HDL CEC was quantified using incubation of human macrophage foam cells with apolipoprotein B-depleted plasma. Baseline CEC was significantly lower in patients developing NODAT during follow-up (median 6.84% [interquartile range 5.84-7.50%]) compared with the NODAT-free group (7.44% [6.46-8.60%]; P = 0.001). Kaplan-Meier analysis showed a lower risk for incident NODAT with increasing sex-stratified tertiles of HDL efflux capacity (P = 0.004). Linear regression analysis indicated that CEC is independently associated with incident NODAT (P = 0.04). In Cox regression analyses, CEC was significantly associated with NODAT (hazard ratio 0.53 [95% CI 0.38-0.76]; P < 0.001), independent of HDL cholesterol levels (P = 0.015), adiposity (P = 0.018), immunosuppressive medication (P = 0.001), and kidney function (P = 0.01). Addition of CEC significantly improved the predictive power of the Framingham Diabetes Risk Score (P = 0.004). This study establishes HDL CEC as a strong predictor of NODAT in RTRs, independent of several other recognized risk factors.

15.
J Am Heart Assoc ; 8(16): e011130, 2019 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-31423921

RESUMO

Background In patients with chronic heart failure and chronic kidney disease, correction of anemia with erythropoietin-stimulating agents targeting normal hemoglobin levels is associated with an increased risk of cardiovascular morbidity and mortality. Emerging data suggest a direct effect of erythropoietin on fibroblast growth factor 23 (FGF23), elevated levels of which have been associated with adverse outcomes. We investigate effects of erythropoietin-stimulating agents in patients with both chronic heart failure and chronic kidney disease focusing on FGF23. Methods and Results In the EPOCARES (Erythropoietin in CardioRenal Syndrome) study, we randomized 56 anemic patients (median age 74 [interquartile range 69-80] years, 66% male) with both chronic heart failure and chronic kidney disease into 3 groups, of which 2 received epoetin beta 50 IU/kg per week for 50 weeks, and the third group served as control. Measurements were performed at baseline and after 2, 26, and 50 weeks. Data were analyzed using linear mixed-model analysis. After 50 weeks of erythropoietin-stimulating agent treatment, hematocrit and hemoglobin levels increased. Similarly, C-terminal FGF23 levels, in contrast to intact FGF23 levels, rose significantly due to erythropoietin-stimulating agents as compared with the controls. During median follow-up for 5.7 (2.0-5.7) years, baseline C-terminal FGF23 levels were independently associated with increased risk of mortality (hazard ratio 2.20; 95% CI, 1.35-3.59; P=0.002). Conclusions Exogenous erythropoietin increases C-terminal FGF23 levels markedly over a period of 50 weeks, elevated levels of which, even at baseline, are significantly associated with an increased risk of mortality. The current results, in a randomized trial setting, underline the strong relationship between erythropoietin and FGF23 physiology in patients with chronic heart failure and chronic kidney disease. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT00356733.

16.
J Nutr ; 2019 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-31268139

RESUMO

BACKGROUND: Alcohol consumption is a frequently studied risk factor for chronic diseases, but many studies are hampered by self-report of alcohol consumption. The urinary metabolite ethyl glucuronide (EtG), reflecting alcohol consumption during the past 72 h, is a promising objective marker, but population data are lacking. OBJECTIVE: The objective of this study was to assess the reliability of EtG as a marker for habitual alcohol consumption compared with self-report and other biomarkers in the general population. METHODS: Among 6211 participants in the Prevention of Renal and Vascular End-Stage Disease (PREVEND) cohort, EtG concentrations were measured in 24-h urine samples. EtG was considered positive when concentrations were ≥100 ng/mL. Habitual alcohol consumption was self-reported by questionnaire (categories: no/almost never, 1-4 units per month, 2-7 units per week, 1-3 units per day or ≥4 units per day). Plasma HDL cholesterol concentration, erythrocyte mean corpuscular volume (MCV), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and γ-glutamyltransferase (GGT) were determined as indirect biomarkers of alcohol consumption. Sensitivity, specificity, positive and negative predictive value, and proportions of agreement between reported consumption and EtG were calculated. To test the agreement of EtG concentration and alcohol consumption in categories, linear regression analysis was performed. In addition, the association between EtG concentrations and indirect biomarkers was analyzed. RESULTS: Mean age was 53.7 y, and 52.9% of participants men. Of the self-reported abstainers, 92.3% had an EtG concentration <100 ng/mL. Sensitivity was 66.3%, positive predictive value was 96.3%, and negative predictive value was 47.4%. The proportion of positive agreement was 78.5%, and the proportion of negative agreement was 62.7%. EtG concentrations were linearly associated with higher categories of alcohol consumption (P-trend < 0.001), adjusted for age, sex, and renal function. EtG was positively related to MCV, HDL cholesterol, and GGT but not to AST and ALT concentrations. CONCLUSIONS: This study shows that urinary EtG is in reasonable agreement with self-reported alcohol consumption and therefore can be used as an objective marker of habitual alcohol consumption in the general population.

17.
Sci Rep ; 9(1): 9439, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31263163

RESUMO

Type 2 diabetes (T2D) affects the health of millions of people worldwide. The identification of genetic determinants associated with changes in glycemia over time might illuminate biological features that precede the development of T2D. Here we conducted a genome-wide association study of longitudinal fasting glucose changes in up to 13,807 non-diabetic individuals of European descent from nine cohorts. Fasting glucose change over time was defined as the slope of the line defined by multiple fasting glucose measurements obtained over up to 14 years of observation. We tested for associations of genetic variants with inverse-normal transformed fasting glucose change over time adjusting for age at baseline, sex, and principal components of genetic variation. We found no genome-wide significant association (P < 5 × 10-8) with fasting glucose change over time. Seven loci previously associated with T2D, fasting glucose or HbA1c were nominally (P < 0.05) associated with fasting glucose change over time. Limited power influences unambiguous interpretation, but these data suggest that genetic effects on fasting glucose change over time are likely to be small. A public version of the data provides a genomic resource to combine with future studies to evaluate shared genetic links with T2D and other metabolic risk traits.

18.
Arterioscler Thromb Vasc Biol ; 39(9): 1874-1883, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31315436

RESUMO

OBJECTIVE: Focus is shifting from HDL-C (high-density lipoprotein cholesterol) as predictive biomarker for cardiovascular disease (CVD) towards antiatherogenic HDL functionalities. Still, limited data exist on the prospective association of HDL function metrics with CVD events. The current work aimed to determine, if baseline HDL-C efflux capacity (CEC) is associated with future CVD events in the general population. Approach and Results: We performed a prospective study among participants of the PREVEND (Prevention of Renal and Vascular End-stage Disease) cohort (follow-up, 12 years). From the overall n=8592 subjects 325 with previous CVD events were excluded; of the remaining 8267 eligible participants all subjects with new CVD events during follow-up were selected and individually matched to controls for age, sex, smoking status, and HDL-C levels. CEC at baseline was quantified using human THP-1-derived macrophage foam cells and apolipoprotein B-depleted plasma. Despite identical HDL-C and apoA (apolipoprotein)-I levels between cases (n=351) and controls (n=354) CEC was significantly lower in cases (0.93±0.29 versus 1.01±0.24 arbitrary units; P<0.001). In all subjects combined, CEC correlated positively with HDL-C and apoA-I and negatively with body mass index, hsCRP (high-sensitivity C-reactive protein), and urinary albumin excretion. CEC was inversely associated with incident CVD events, both expressed per quartile and per 1 SD change (odds ratio, 0.73; 95% CI, 0.62-0.86; P<0.001); this association remained significant after adjustments for HDL-C, hsCRP, kidney function, and several other clinical covariates. CONCLUSIONS: Combined these data demonstrate that in the general population baseline CEC is significantly associated with the future development of CVD events independent of HDL-C and apoA-I plasma levels.

19.
Diabetes Care ; 42(9): 1645-1652, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31296643

RESUMO

OBJECTIVE: Posttransplantation diabetes mellitus (PTDM) contributes to risk for cardiovascular morbidity and mortality in renal transplant recipients (RTRs). In the general population, consumption of a diet containing few fruits and vegetables predisposes to type 2 diabetes. The role of diet as a potential modifiable risk factor for PTDM has not been explored. Our focus was to investigate the prospective associations of fruit and vegetable intake with risk of PTDM in stable RTRs. RESEARCH DESIGN AND METHODS: We included 472 adult RTRs who had a functioning graft ≥1 year. Fruit and vegetable intake was assessed by using a 177-item food frequency questionnaire. PTDM was defined according the American Diabetes Association's diagnostic criteria for diabetes. RESULTS: During 5.2 years of follow-up, 52 RTRs (11%) developed PTDM. Fruit intake was not associated with PTDM (hazard ratio [HR] 0.90 [95% CI 0.79-1.03] per 2log g/day; P = 0.13), whereas vegetable intake was inversely associated with PTDM (HR 0.77 [95% CI 0.63-0.94] per 2log g/day; P = 0.009). Mediation analyses revealed that ±50% of the association between vegetable intake and PTDM was mediated by variations in key components of the metabolic syndrome (i.e., HDL cholesterol, triglycerides, and waist circumference) as determined by the National Cholesterol Education Program's Adult Treatment Panel III Expert Panel. CONCLUSIONS: In this study vegetable intake, but not fruit intake, was associated with lower risk of PTDM in RTRs, likely largely through beneficial effects on key components of the metabolic syndrome. These findings further support accumulating evidence that supports a recommendation of higher vegetable intake by RTRs.

20.
BMJ Open ; 9(7): e029716, 2019 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-31350252

RESUMO

INTRODUCTION: Prospective cohort studies on the association between subclinical thyroid dysfunction and depressive symptoms have yielded conflicting findings, possibly because of differences in age, sex, thyroid-stimulating hormone cut-off levels or degree of baseline depressive symptoms. Analysis of individual participant data (IPD) may help clarify this association. METHODS AND ANALYSIS: We will conduct a systematic review and IPD meta-analysis of prospective studies on the association between subclinical thyroid dysfunction and depressive symptoms. We will identify studies through a systematic search of the literature in the Ovid Medline, Ovid Embase, Cochrane Central Register of Controlled Trials (CENTRAL) and Cumulative Index to Nursing and Allied Health Literature (CINAHL) databases from inception to April 2019 and from the Thyroid Studies Collaboration. We will ask corresponding authors of studies that meet our inclusion criteria to collaborate by providing IPD. Our primary outcome will be depressive symptoms at the first available individual follow-up, measured on a validated scale. We will convert all the scores to the Beck Depression Inventory scale. For each cohort, we will estimate the mean difference of depressive symptoms between participants with subclinical hypothyroidism or hyperthyroidism and control adjusted for depressive symptoms at baseline. Furthermore, we will adjust our multivariable linear regression analyses for age, sex, education and income. We will pool the effect estimates of all studies in a random-effects meta-analysis. Heterogeneity will be assessed by I2. Our secondary outcomes will be depressive symptoms at a specific follow-up time, at the last available individual follow-up and incidence of depression at the first, last and at a specific follow-up time. For the binary outcome of incident depression, we will use a logistic regression model. ETHICS AND DISSEMINATION: Formal ethical approval is not required as primary data will not be collected. Our findings will have considerable implications for patient care. We will seek to publish this systematic review and IPD meta-analysis in a high-impact clinical journal. PROSPERO REGISTRATION NUMBER: CRD42018091627.

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