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1.
Depress Anxiety ; 2019 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-31622521

RESUMO

BACKGROUND: Depression and anxiety may unfavorably impact on cardiac autonomic dysregulation. However, it is unclear whether this relationship results from a causal effect or may be attributable to confounding factors. We tested the relationship between depression and anxiety with heart rate (HR) and heart rate variability (HRV) across a 9-year follow-up (FU) period and investigated possible confounding by antidepressant use and genetic pleiotropy. METHODS: Data (no. of observations = 6,994, 65% female) were obtained from the longitudinal Netherlands Study of Depression and Anxiety, with repeated waves of data collection of HR, HRV, depression, anxiety, and antidepressant use. Summary statistics from meta-analyses of genome-wide association studies were used to derive polygenic risk scores of depression, HR, and HRV. RESULTS: Across the 9-year FU, generalized estimating equations analyses showed that the relationship between cardiac autonomic dysregulation and depression/anxiety rendered nonsignificant after adjusting for antidepressant use. A robust association was found between antidepressant use (especially tricyclic antidepressants, selective serotonin, and noradrenalin reuptake inhibitors) and unfavorable cardiac autonomic activity across all waves. However, no evidence was found for a genetic correlation of depression with HR and HRV, indicating that confounding by genetic pleiotropy is minimal. CONCLUSIONS: Our results indicate that the association between depression/anxiety and cardiac autonomic dysregulation does not result from a causal pathway or genetic pleiotropy, and these traits might therefore not be inevitably linked. Previously reported associations were likely confounded by the use of certain classes of antidepressants.

2.
JCI Insight ; 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31600170

RESUMO

BACKGROUND: The presence of an early repolarization pattern (ERP) on the surface electrocardiogram (ECG) is associated with risk of ventricular fibrillation and sudden cardiac death. Family studies have shown that ERP is a highly heritable trait but molecular genetic determinants are unknown. METHODS: To identify genetic susceptibility loci for ERP, we performed a GWAS and meta-analysis in 2,181 cases and 23,641 controls of European ancestry. RESULTS: We identified a genome-wide significant (p<5E-8) locus in the KCND3 (potassium voltage gated channel subfamily D member 3) gene that was successfully replicated in additional 1,124 cases and 12,510 controls. A subsequent joint meta-analysis of the discovery and replication cohorts identified rs1545300 as the lead SNP at the KCND3 locus (OR 0.82 per minor T allele, p=7.7E-12), but did not reveal additional loci. Co-localization analyses indicate causal effects of KCND3 gene expression levels on ERP in both cardiac left ventricle and tibial artery. CONCLUSIONS: In this study we identified for the first time a genome-wide significant association of a genetic variant with ERP. Our findings of a locus in the KCND3 gene not only provide insights into the genetic determinants but also into the pathophysiological mechanism of ERP, discovering a promising candidate for functional studies. FUNDING: For detailed information per study, see Acknowledgments.

3.
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.

4.
Eur J Hum Genet ; 2019 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-31363186

RESUMO

Dupuytren disease (DD), a fibroproliferative disorder of the palmar fascia that causes flexion contractures in the fingers, is prevalent in people of North-Western European descent and less so in other ethnicities. DD is a complex disorder, influenced by genetic risk variants. We aimed to study if the marked differences in prevalences in DD between ethnic (sub)groups could be explained by differences in allele frequencies of the 26 known genetic risk variants of DD. Therefore, genetic risk scores (GRS) composed of the 26 DD risk variants were calculated for the 26 populations from the 1000 Genomes database and correlated to observed DD prevalences from literature. For comparison, GRSs were generated for 10,000 sets of 26 random SNPs and also correlated to the observed DD prevalences to determine the significance of the observed correlation. To determine whether differences in allele frequencies between ethnicities were caused by natural selection, fixation indices (Fst) were calculated from the 26 SNPs and from the sets of 26 random SNPs for comparison. Observed prevalences could be determined from literature for 10 populations. Their correlation with the GRS composed of DD SNPs proved to be 0.60 (p = 0.0003). The Fsts between British and other populations were low for European, ad mixed American, and South-Asian populations, and moderate for East-Asians. African populations were significantly different from expected values determined from the random sets. In conclusion, the 26 known genetic risk variants associated with DD explain for a substantial part (R2 = 0.36) the differing DD prevalences observed between ethnicities.

5.
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.

6.
Nat Hum Behav ; 3(9): 950-961, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31358974

RESUMO

Excessive alcohol consumption is one of the main causes of death and disability worldwide. Alcohol consumption is a heritable complex trait. Here we conducted a meta-analysis of genome-wide association studies of alcohol consumption (g d-1) from the UK Biobank, the Alcohol Genome-Wide Consortium and the Cohorts for Heart and Aging Research in Genomic Epidemiology Plus consortia, collecting data from 480,842 people of European descent to decipher the genetic architecture of alcohol intake. We identified 46 new common loci and investigated their potential functional importance using magnetic resonance imaging data and gene expression studies. We identify genetic pathways associated with alcohol consumption and suggest genetic mechanisms that are shared with neuropsychiatric disorders such as schizophrenia.

7.
PLoS Med ; 16(6): e1002818, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31170159

RESUMO

BACKGROUND: Emerging data in chronic kidney disease (CKD) patients suggest that iron deficiency and higher circulating levels of erythropoietin (EPO) stimulate the expression and concomitant cleavage of the osteocyte-derived, phosphate-regulating hormone fibroblast growth factor 23 (FGF23), a risk factor for premature mortality. To date, clinical implications of iron deficiency and high EPO levels in the general population, and the potential downstream role of FGF23, are unclear. Therefore, we aimed to determine the associations between iron deficiency and higher EPO levels with mortality, and the potential mediating role of FGF23, in a cohort of community-dwelling subjects. METHODS AND FINDINGS: We analyzed 6,544 community-dwelling subjects (age 53 ± 12 years; 50% males) who participated in the Prevention of Renal and Vascular End-Stage Disease (PREVEND) study-a prospective population-based cohort study, of which we used the second survey (2001-2003)-and follow-up was performed for a median of 8 years. We measured circulating parameters of iron status, EPO levels, and plasma total FGF23 levels. Our primary outcome was all-cause mortality. In multivariable linear regression analyses, ferritin (ß = -0.43), transferrin saturation (TSAT) (ß = -0.17), hepcidin (ß = -0.36), soluble transferrin receptor (sTfR; ß = 0.33), and EPO (ß = 0.28) were associated with FGF23 level, independent of potential confounders. During median (interquartile range [IQR]) follow-up of 8.2 (7.7-8.8) years, 379 (6%) subjects died. In multivariable Cox regression analyses, lower levels of TSAT (hazard ratio [HR] per 1 standard deviation [SD], 0.84; 95% confidence interval [CI], 0.75-0.95; P = 0.004) and higher levels of sTfR (HR, 1.15; 95% CI 1.03-1.28; P = 0.01), EPO (HR, 1.17; 95% CI 1.05-1.29; P = 0.004), and FGF23 (HR, 1.20; 95% CI 1.10-1.32; P < 0.001) were each significantly associated with an increased risk of death, independent of potential confounders. Adjustment for FGF23 levels markedly attenuated the associations of TSAT (HR, 0.89; 95% CI 0.78-1.01; P = 0.06), sTfR (HR, 1.08; 95% CI 0.96-1.20; P = 0.19), and EPO (HR, 1.10; 95% CI 0.99-1.22; P = 0.08) with mortality. FGF23 remained associated with mortality (HR, 1.15; 95% CI 1.04-1.27; P = 0.008) after adjustment for TSAT, sTfR, and EPO levels. Mediation analysis indicated that FGF23 explained 31% of the association between TSAT and mortality; similarly, FGF23 explained 32% of the association between sTfR and mortality and 48% of the association between EPO and mortality (indirect effect P < 0.05 for all analyses). The main limitations of this study were the observational study design and the absence of data on intact FGF23 (iFGF23), precluding us from discerning whether the current results are attributable to an increase in iFGF23 or in C-terminal FGF23 fragments. CONCLUSIONS AND RELEVANCE: In this study, we found that functional iron deficiency and higher EPO levels were each associated with an increased risk of death in the general population. Our findings suggest that FGF23 could be involved in the association between functional iron deficiency and increased EPO levels and death. Investigation of strategies aimed at correcting iron deficiency and reducing FGF23 levels is warranted.

8.
Am J Clin Nutr ; 109(6): 1555-1568, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30997492

RESUMO

BACKGROUND: Dairy products contain many nutritious components that may benefit metabolic health. There are indications that glucose metabolism and insulin sensitivity, which are generally disturbed in overweight and obese individuals, may improve by increased dairy intake. This may also affect one's metabolic flexibility. OBJECTIVE: The aim of this study was to investigate the effects of high compared with low dairy intake on glucose metabolism, insulin sensitivity, and metabolic flexibility in overweight adults (aged 45-65 y). METHODS: In this randomized intervention study, subjects consumed a high- and a low-dairy diet [HDD (5-6 dairy portions) and LDD (≤1 dairy portion), respectively] for 6 wk in a crossover design, with a washout period of 4 wk. Dairy portions were 200 g semi-skimmed yoghurt, 30 g reduced-fat (30+) cheese, and 250 mL semiskimmed milk and buttermilk. After 6 wk, a 75-g oral-glucose-tolerance test (13C-labeled) and a subsequent fasting challenge were performed. Metabolic flexibility was studied by determining the respiratory quotient (RQ) using indirect calorimetry. Fasting and postprandial plasma concentrations of glucose and insulin were analyzed. The dual isotope technique enabled calculation of glucose kinetics. RESULTS: The study was completed by 45 overweight men and postmenopausal women [age 58.9 ± 4.3 y, BMI 27.9 ± 1.9 kg/m2 (mean ± SD)]. Fasting RQ and ΔRQ, reflecting metabolic flexibility, did not differ after both diets. Fasting glucose concentrations were similar, whereas fasting insulin concentrations were lower after the LDD (LDD: 8.1 ± 2.8 mU/L; HDD: 8.9 ± 3.3 mU/L; P = 0.024). This resulted in a higher HOMA-IR after the HDD (P = 0.027). Postprandial glucose and insulin responses as well as glucose kinetics were similar after both diets. CONCLUSIONS: The amount of dairy intake during a 6-wk period had a neutral effect on metabolic flexibility or postprandial glucose metabolism in middle-aged overweight subjects. More trials are needed to study the effects of specific dairy types and to differentiate between metabolic subgroups. This trial was registered at trialregister.nl as NTR4899.

9.
Am J Nephrol ; 49(3): 193-202, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30808845

RESUMO

BACKGROUND: Serum urea level is a heritable trait, commonly used as a diagnostic marker for kidney function. Genome-wide association studies (GWAS) in East-Asian populations identified a number of genetic loci related to serum urea, however there is a paucity of data for European populations. METHODS: We performed a two-stage meta-analysis of GWASs on serum urea in 13,312 participants, with independent replication in 7,379 participants of European ancestry. RESULTS: We identified 6 genome-wide significant single nucleotide polymorphisms (SNPs) in or near 6 loci, of which 2 were novel (POU2AF1 and ADAMTS9-AS2). Replication of East-Asian and Scottish data provided evidence for an additional 8 loci. SNPs tag regions previously associated with anthropometric traits, serum magnesium, and urinary albumin-to-creatinine ratio, as well as expression quantitative trait loci for genes preferentially expressed in kidney and gastro-intestinal tissues. CONCLUSIONS: Our findings provide insights into the genetic underpinnings of urea metabolism, with potential relevance to kidney function.

10.
Sci Rep ; 9(1): 1664, 2019 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-30733514

RESUMO

This family study from Oman (n = 1231) explored the heritability and genetic and environmental correlations of heart rate variability (HRV) and baroreceptor reflex sensitivity (BRS) with ambulatory and beat-to-beat blood pressure (BP). Ambulatory BP was measured for 24 hours to calculate mean values for daytime and sleep separately. Time and frequency domain HRV indices, BRS, office beat-to-beat BP, and heart rate (HR) were measured for 10 minutes at rest. SOLAR software was used to perform univariate and bivariate quantitative genetic analyses adjusting for age, age2, sex, their interactions and BMI. Heritability of SBP and DBP ranged from 16.8% to 40.4% for daytime, sleeping, 24-hour and office beat-to-beat measurements. HR and BRS showed a heritability of 31.9% and 20.6%, respectively, and for HRV indices heritability ranged from 11.1% to 20.5%. All HRV measurements and BRS were found to be negatively correlated with BP, but phenotypic correlation coefficients were relatively weak; HR was positively correlated with BP. None of the genetic correlations were statistically significant while environmental factors explained most of the correlations for all HRV indices with BP. Our study found consistent but weak correlations among HRV, HR, BRS and ambulatory/office beat-to-beat BP. However, environmental rather than genetic factors contributed most to those correlations.

11.
Plast Reconstr Surg ; 143(2): 512-518, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30688894

RESUMO

BACKGROUND: Dupuytren's disease is a very common, highly heritable palmar fibromatosis. In a recent genome-wide association study, 26 single-nucleotide polymorphisms were found to be associated with development of Dupuytren's disease. The authors generated a weighted genetic risk score based on the genotype at these single-nucleotide polymorphisms. In two independent cohorts, they tested the association among high weighted genetic risk score, clinical features that predict a high risk of recurrence, and recurrence after surgery. METHODS: Clinical data were obtained from patient questionnaires and clinical records, with missing data accounted for by imputation. Genotyping was performed as part of the recent genome-wide association study. Logistic regression was performed to study the association among weighted genetic risk score, high-risk clinical features, and recurrence, with a weighted genetic risk score analyzed as a continuous variable, and also grouped into four categories. RESULTS: Using univariable logistic regression, a high weighted genetic risk score was associated with the presence of all high-risk clinical features: early age of onset, bilateral disease, ectopic disease, and a positive family history (p ≤ 0.004). After multivariable logistic regression accounting for these factors, an increased weighted genetic risk score was still associated with the need for repeated Dupuytren's disease surgery (p = 0.004). CONCLUSIONS: The authors' results suggest that a weighted genetic risk score is useful in predicting the risk of disease recurrence, and may be used by surgeons to personalize prognostication. In the future, a weighted genetic risk score may be useful for determining the most appropriate initial surgical procedure in patients with Dupuytren's disease. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III.


Assuntos
Contratura de Dupuytren/cirurgia , Recidiva Local de Neoplasia/genética , Idade de Início , Idoso , Estudos de Coortes , Contratura de Dupuytren/genética , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Recidiva Local de Neoplasia/diagnóstico , Países Baixos , Projetos Piloto , Polimorfismo de Nucleotídeo Único , Prognóstico , Fatores de Risco , Inquéritos e Questionários/estatística & dados numéricos , Reino Unido
12.
Nat Commun ; 9(1): 5141, 2018 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-30510157

RESUMO

Carotid artery intima media thickness (cIMT) and carotid plaque are measures of subclinical atherosclerosis associated with ischemic stroke and coronary heart disease (CHD). Here, we undertake meta-analyses of genome-wide association studies (GWAS) in 71,128 individuals for cIMT, and 48,434 individuals for carotid plaque traits. We identify eight novel susceptibility loci for cIMT, one independent association at the previously-identified PINX1 locus, and one novel locus for carotid plaque. Colocalization analysis with nearby vascular expression quantitative loci (cis-eQTLs) derived from arterial wall and metabolic tissues obtained from patients with CHD identifies candidate genes at two potentially additional loci, ADAMTS9 and LOXL4. LD score regression reveals significant genetic correlations between cIMT and plaque traits, and both cIMT and plaque with CHD, any stroke subtype and ischemic stroke. Our study provides insights into genes and tissue-specific regulatory mechanisms linking atherosclerosis both to its functional genomic origins and its clinical consequences in humans.

13.
Int J Cardiol ; 2018 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-30297186

RESUMO

BACKGROUND: Early repolarization (ER) is a risk marker for sudden cardiac death. Higher risk is associated with horizontal/descending ST-segment ER in the inferior or inferolateral ECG leads. Studies in family cohorts have demonstrated substantial heritability for the ER pattern, but genome-wide association studies (GWAS) have failed to identify statistically significant and replicable genetic signals. METHODS AND RESULTS: We assessed the narrow-sense and common single nucleotide polymorphism (SNP) heritability of ER and ER subtypes using ECG data from 5829 individuals (TwinsUK, BRIGHT and GRAPHIC cohorts). ER prevalence was 8.3%. In 455 monozygous vs 808 dizygous twin pairs, concordances and twin correlations for ER subtypes (except horizontal/descending ST-segment ER) were higher and familial resemblance (except notched ER) was significant. Narrow-sense heritability estimates derived from 1263 female twin pairs using the structural equation program Mx ranged from 0.00-0.47 and common SNP heritability estimates derived from 4009 unrelated individuals of both sexes using Genome-wide Restricted Maximum Likelihood (GREML) ranged from 0.00-0.36, but none were statistically significant. CONCLUSION: From our data, ER shows limited genetic predisposition. There appears to be significant environmental influence and these modest narrow-sense and common SNP heritability estimates may explain why previous GWAS have been unsuccessful.

14.
Cell Physiol Biochem ; 49(1): 144-159, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30184526

RESUMO

BACKGROUND/AIMS: Classical Hodgkin lymphoma (cHL) is among the most frequent lymphoma subtypes. The tumor cells originate from crippled germinal center (GC)-B cells that escaped from apoptosis. MicroRNAs (miRNAs) play important roles in B-cell maturation and aberrant expression of miRNAs contributes to the pathogenesis of cHL. Our aim was to identify oncogenic miRNAs relevant for growth of cHL using a high-throughput screening approach. METHODS: A lentiviral pool of 63 miRNA inhibition constructs was used to identify miRNAs essential to cell growth in three cHL cell lines in duplicate. As a negative control we also infected cHL cell lines with a lentiviral barcoded empty vector pool consisting of 222 constructs. The abundance of individual constructs was followed over time by a next generation sequencing approach. The effect on growth was confirmed using individual GFP competition assays and on apoptosis using Annexin-V staining. Our previously published Argonaute 2 (Ago2) immunoprecipitation (IP) data were used to identify target genes relevant for cell growth / apoptosis. Luciferase assays and western blotting were performed to confirm targeting by miRNAs. RESULTS: Four miRNA inhibition constructs, i.e. miR-449a-5p, miR-625-5p, let-7f-2-3p and miR-21-5p, showed a significant decrease in abundance in at least 4 of 6 infections. In contrast, none of the empty vector constructs showed a significant decrease in abundance in 3 or more of the 6 infections. The most abundantly expressed miRNA, i.e. miR-21-5p, showed significantly higher expression levels in cHL compared to GC-B cells. GFP competition assays confirmed the negative effect of miR-21-5p inhibition on HL cell growth. Annexin-V staining of cells infected with miR-21-5p inhibitor indicated a significant increase in apoptosis at day 7 and 9 after viral infection, consistent with the decrease in growth. Four miR-21-5p cell growth- and apoptosis-associated targets were AGO2-IP enriched in cHL cell lines and showed a significant decrease in expression in cHL cell lines in comparison to normal GC-B cells. For the two most abundantly expressed, i.e. BTG2 and PELI1, we confirmed targeting by miR-21-5p using luciferase assays and for PELI1 we also confirmed this at the protein level by western blotting. CONCLUSION: Using a miRNA loss-of-function high-throughput screen we identified four miRNAs with oncogenic effects in cHL and validated the results for the in cHL abundantly expressed miR-21-5p. MiR-21-5p is upregulated in cHL compared to GC-B cells and protects cHL cells from apoptosis possibly via targeting BTG2 and PELI1.


Assuntos
MicroRNAs/metabolismo , Regiões 3' não Traduzidas , Antagomirs/metabolismo , Apoptose , Linhagem Celular Tumoral , Proliferação de Células/genética , Células HEK293 , Sequenciamento de Nucleotídeos em Larga Escala , Doença de Hodgkin/metabolismo , Doença de Hodgkin/patologia , Humanos , Proteínas Imediatamente Precoces/genética , Proteínas Imediatamente Precoces/metabolismo , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Oncogenes/genética , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo
15.
BMC Nephrol ; 19(1): 225, 2018 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-30208847

RESUMO

BACKGROUND: Iron deficiency is highly prevalent in chronic kidney disease (CKD) patients. In clinical practice, iron deficiency is defined based on a combination of two commonly used markers, ferritin and transferrin saturation (TSAT). However, no consensus has been reached which cutoffs of these parameters should be applied to define iron deficiency. Hence, we aimed to assess prospectively which cutoffs of ferritin and TSAT performed optimally for outcomes in CKD patients. METHODS: We meticulously analyzed 975 CKD community dwelling patients of the Prevention of Renal and Vascular Endstage Disease prospective study based on an estimated glomerular filtration rate < 60 ml/min/1.73m2, albuminuria > 30 mg/24 h, or albumin-to-creatinine ratio ≥ 30 mg/g. Cox proportional hazard regression analyses using different sets and combinations of cutoffs of ferritin and TSAT were performed to assess prospective associations with all-cause mortality, cardiovascular mortality, and development of anemia. RESULTS: Of the included 975 CKD patients (62 ± 12 years, 64% male with an estimated glomerular filtration rate of 77 ± 23 ml/min/1.73m2), 173 CKD patients died during a median follow-up of 8.0 (interquartile range 7.5-8.7) years of which 70 from a cardiovascular cause. Furthermore, 164 CKD patients developed anemia. The highest risk for all-cause mortality (hazard ratio, 2.83; 95% confidence interval, 1.53-5.24), cardiovascular mortality (4.15; 1.78-9.66), and developing anemia (3.07; 1.69-5.57) was uniformly observed for a TSAT< 10%, independent of serum ferritin level. CONCLUSION: In this study, we have shown that of the traditionally used markers of iron status, reduced TSAT, especially TSAT< 10%, is most strongly associated with the risk of adverse outcomes in CKD patients irrespective of serum ferritin level, suggesting that clinicians should focus more on TSAT rather than ferritin in this patient setting. Specific attention to iron levels below this cutoff seems warranted in CKD patients.

16.
BMC Nephrol ; 19(1): 242, 2018 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-30236065

RESUMO

BACKGROUND: Although the efficacy of iron sucrose (IS) and ferric carboxymaltose (FCM) in treating anemia in hemodialysis (HD) patients has been studied individually, a comparison of these two intravenous iron formulations has not yet been performed in HD patients. METHODS: We performed a retrospective audit on records of 221 stable HD patients from different HD centers in the Netherlands, who were switched from IS to FCM on a 1:1 ratio. To assess the effect of the switch on iron status parameters, data from 3 time points before and 3 time points after the switch were analyzed using linear mixed effects models. Subanalyses were done in 2 subgroups of patients anemic or iron deficient at baseline. RESULTS: Hemoglobin increased in all groups (anemic [1.4 g/dL, P < 0.001] iron deficient [0.6 g/dL, P < 0.001]), while the weekly iron dose was significantly lower when patients received FCM compared to IS (48 vs 55 mg/week, P = 0.04). Furthermore, serum ferritin and transferrin saturation increased in all groups (anemic [64 µg/L, 5.0%, P < 0.001] iron deficient [76 µg/L, 3.6%, P < 0.001]). Finally, the darbepoetin α dose decreased significantly in all groups (anemic [- 16 µg/wk., P = 0.01] iron deficient [- 11 µg/wk., P < 0.001]). CONCLUSIONS: In this real-life study in HD patients, a switch from IS to FCM resulted in an improvement of iron status parameters despite a lower weekly dose of FCM. Furthermore, the ESA dose was reduced during FCM, while hemoglobin levels increased.

17.
Artigo em Inglês | MEDLINE | ID: mdl-30165500

RESUMO

Background: It currently remains understudied whether low consumption of fruits and vegetables after kidney transplantation may be a modifiable cardiovascular risk factor. We aimed to investigate the associations between consumption of fruits and vegetables and cardiovascular mortality in renal transplant recipients (RTRs). Methods: Consumption of fruits and vegetables was assessed in an extensively phenotyping cohort of RTRs. Multivariable-adjusted Cox proportional hazards regression analyses were performed to assess the risk of cardiovascular mortality. Results: We included 400 RTRs (age 52 ± 12 years, 54% males). At a median follow-up of 7.2 years, 23% of RTRs died (53% were due to cardiovascular causes). Overall, fruit consumption was not associated with cardiovascular mortality {hazard ratio [HR] 0.82 [95% confidence interval (CI) 0.60-1.14]; P = 0.24}, whereas vegetable consumption was inversely associated with cardiovascular mortality [HR 0.49 (95% CI 0.34-0.71); P < 0.001]. This association remained independent of adjustment for several potential confounders. The association of fruit consumption with cardiovascular mortality was significantly modified by estimated glomerular filtration rate (eGFR; Pinteraction = 0.01) and proteinuria (Pinteraction = 0.01), with significant inverse associations in patients with eGFR > 45 mL/min/1.73 m2 [HR 0.56 (95% CI 0.35-0.92); P = 0.02] or the absence of proteinuria [HR 0.62 (95% CI 0.41-0.92); P = 0.02]. Conclusions: In RTRs, a relatively higher vegetable consumption is independently and strongly associated with lower cardiovascular mortality. A relatively higher fruit consumption is also associated with lower cardiovascular mortality, although particularly in RTRs with eGFR > 45 mL/min/1.73 m2 or an absence of proteinuria. Further studies seem warranted to investigate whether increasing consumption of fruits and vegetables may open opportunities for potential interventional pathways to decrease the burden of cardiovascular mortality in RTRs.

18.
Nat Commun ; 9(1): 2904, 2018 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-30046033

RESUMO

Electrocardiographic PR interval measures atrio-ventricular depolarization and conduction, and abnormal PR interval is a risk factor for atrial fibrillation and heart block. Our genome-wide association study of over 92,000 European-descent individuals identifies 44 PR interval loci (34 novel). Examination of these loci reveals known and previously not-yet-reported biological processes involved in cardiac atrial electrical activity. Genes in these loci are over-represented in cardiac disease processes including heart block and atrial fibrillation. Variants in over half of the 44 loci were associated with atrial or blood transcript expression levels, or were in high linkage disequilibrium with missense variants. Six additional loci were identified either by meta-analysis of ~105,000 African and European-descent individuals and/or by pleiotropic analyses combining PR interval with heart rate, QRS interval, and atrial fibrillation. These findings implicate developmental pathways, and identify transcription factors, ion-channel genes, and cell-junction/cell-signaling proteins in atrio-ventricular conduction, identifying potential targets for drug development.

19.
Addiction ; 113(11): 2073-2086, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30003630

RESUMO

BACKGROUND AND AIMS: Cannabis is one of the most commonly used substances among adolescents and young adults. Earlier age at cannabis initiation is linked to adverse life outcomes, including multi-substance use and dependence. This study estimated the heritability of age at first cannabis use and identified associations with genetic variants. METHODS: A twin-based heritability analysis using 8055 twins from three cohorts was performed. We then carried out a genome-wide association meta-analysis of age at first cannabis use in a discovery sample of 24 953 individuals from nine European, North American and Australian cohorts, and a replication sample of 3735 individuals. RESULTS: The twin-based heritability for age at first cannabis use was 38% [95% confidence interval (CI) = 19-60%]. Shared and unique environmental factors explained 39% (95% CI = 20-56%) and 22% (95% CI = 16-29%). The genome-wide association meta-analysis identified five single nucleotide polymorphisms (SNPs) on chromosome 16 within the calcium-transporting ATPase gene (ATP2C2) at P < 5E-08. All five SNPs are in high linkage disequilibrium (LD) (r2  > 0.8), with the strongest association at the intronic variant rs1574587 (P = 4.09E-09). Gene-based tests of association identified the ATP2C2 gene on 16q24.1 (P = 1.33e-06). Although the five SNPs and ATP2C2 did not replicate, ATP2C2 has been associated with cocaine dependence in a previous study. ATP2B2, which is a member of the same calcium signalling pathway, has been associated previously with opioid dependence. SNP-based heritability for age at first cannabis use was non-significant. CONCLUSION: Age at cannabis initiation appears to be moderately heritable in western countries, and individual differences in onset can be explained by separate but correlated genetic liabilities. The significant association between age of initiation and ATP2C2 is consistent with the role of calcium signalling mechanisms in substance use disorders.

20.
Mayo Clin Proc ; 93(3): 337-343, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29502563

RESUMO

Cigarette smoking continues to be one of the major risk factors for increased morbidity and mortality worldwide. Among many adverse health effects, smoking can induce erythrocytosis, which is commonly believed to result from elevated serum erythropoietin (EPO) levels. Currently, however, this notion is only alleged, without data available to substantiate it. Hence, we analyzed data from the Prevention of Renal and Vascular End-Stage Disease study, a prospective population-based cohort study. Smoking behavior was quantified as number of cigarettes smoked per day and as 24-hour urinary cotinine excretion levels, an objective and quantitative measure of nicotine exposure. In 6808 community-dwelling participants, the prevalence of nonsmokers, former smokers, and current smokers were 29%, 43%, and 28%, respectively. Hematocrit levels were higher in current smokers (41.4%±3.6%) than in nonsmokers (40.3%±3.6%) (P<.001). In contrast, median EPO levels were lower in current smokers (7.5 IU/L; interquartile range [IQR], 5.7-9.6 IU/L) than in nonsmokers (7.9 IU/L; IQR, 6.0-10.7 IU/L) (P<.001). In multivariate linear regression analysis, current smoking, compared with nonsmoking, was independently positively associated with hematocrit levels (ß=.12; P<.001) and hemoglobin levels (ß=.11; P<.001), but inversely associated with EPO levels (ß=-.09; P<.001). In sensitivity analyses, we observed a dose-dependent inverse association of smoking exposure reflected by 24-hour urinary cotinine excretion levels with EPO levels. Contrary to common belief, we identified that in the general population, smoking is inversely associated with EPO levels. Future mechanistic insight is needed to unravel the currently identified association, and if reproduced in other studies, guidelines for diagnosis of secondary erythrocytosis may need to be revisited.

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