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1.
Sci Rep ; 9(1): 13954, 2019 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-31562371

RESUMO

Omics data facilitate the gain of novel insights into the pathophysiology of diseases and, consequently, their diagnosis, treatment, and prevention. To this end, omics data are integrated with other data types, e.g., clinical, phenotypic, and demographic parameters of categorical or continuous nature. We exemplify this data integration issue for a chronic kidney disease (CKD) study, comprising complex clinical, demographic, and one-dimensional 1H nuclear magnetic resonance metabolic variables. Routine analysis screens for associations of single metabolic features with clinical parameters while accounting for confounders typically chosen by expert knowledge. This knowledge can be incomplete or unavailable. We introduce a framework for data integration that intrinsically adjusts for confounding variables. We give its mathematical and algorithmic foundation, provide a state-of-the-art implementation, and evaluate its performance by sanity checks and predictive performance assessment on independent test data. Particularly, we show that discovered associations remain significant after variable adjustment based on expert knowledge. In contrast, we illustrate that associations discovered in routine univariate screening approaches can be biased by incorrect or incomplete expert knowledge. Our data integration approach reveals important associations between CKD comorbidities and metabolites, including novel associations of the plasma metabolite trimethylamine-N-oxide with cardiac arrhythmia and infarction in CKD stage 3 patients.

2.
Sci Rep ; 9(1): 13156, 2019 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31511587

RESUMO

Prevalence estimates and evidence informing treatment targets for thyroid dysfunction largely come from studies of middle-aged adults. We conducted a cross-sectional analysis to determine the prevalence of thyroid dysfunction and risk factors for abnormal thyroid tests in participants aged ≥65 in the Atherosclerosis Risk in Communities (ARIC) study (N = 5,392). We measured serum concentrations of triiodothyronine (T3), free thyroxine (FT4), thyroid peroxidase antibody (Anti-TPO), and thyroid stimulating hormone (TSH). In this population (58% women, 22% black), 17% reported medication use for thyroid dysfunction. Among those not on treatment, the prevalence of overt and subclinical hypothyroidism was 0.82% and 6.06%, respectively. Overt and subclinical hyperthyroidism affected 0.26% and 0.78%, respectively. Multivariable adjusted TSH, FT4 and T3 levels were 25%, 1.3% and 3.9% lower in blacks compared to whites, respectively. Men were less likely to be anti-TPO positive compared to women (p < 0.001). Former and never smoking were associated with lower T3 and FT4 levels compared to current smoking. The prevalence of thyroid dysfunction in older adults is nearly 25%. Multiple illnesses can interact to contribute to declines in health. Additional attention to thyroid dysfunction and screening in this age group is recommended.

3.
Nat Commun ; 10(1): 3842, 2019 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-31451708

RESUMO

Chronic kidney disease (CKD), defined by low estimated glomerular filtration rate (eGFR), contributes to global morbidity and mortality. Here we conduct a transethnic Genome-Wide Association Study of eGFR in 280,722 participants of the Million Veteran Program (MVP), with replication in 765,289 participants from the Chronic Kidney Disease Genetics (CKDGen) Consortium. We identify 82 previously unreported variants, confirm 54 loci, and report interesting findings including association of the sickle cell allele of betaglobin among non-Hispanic blacks. Our transcriptome-wide association study of kidney function in healthy kidney tissue identifies 36 previously unreported and nine known genes, and maps gene expression to renal cell types. In a Phenome-Wide Association Study in 192,868 MVP participants using a weighted genetic score we detect associations with CKD stages and complications and kidney stones. This investigation reinterprets the genetic architecture of kidney function to identify the gene, tissue, and anatomical context of renal homeostasis and the clinical consequences of dysregulation.

4.
Cancer Epidemiol Biomarkers Prev ; 28(7): 1259-1261, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31263056

RESUMO

BACKGROUND: Evidence is mounting that intraprostatic inflammation influences prostate cancer development. Uric acid crystals depositing in the prostate could result in injury and inflammation, increasing prostate cancer risk. METHODS: Included were 6,574 men ages 45-64 years who enrolled in the Atherosclerosis Risk in Communities study in 1987 to 1989. We used Cox proportional hazards regression to estimate the association of serum urate concentration alone and to improve accuracy, jointly with a genetic risk score (GRS, N = 4,983) derived from variants predictive of urate concentration, with prostate cancer (N = 813) risk. RESULTS: Serum urate concentration or joint categories of urate concentration and GRS were not associated with prostate cancer risk (P trend for quartiles = 0.3). Results were generally similar by race and after excluding users of medications that influence uric acid. CONCLUSIONS: Serum urate alone and with a urate-associated GRS were not associated with prostate cancer risk. IMPACT: It is unlikely that circulating urate concentration influences prostate cancer development.

5.
Kidney Int ; 96(2): 480-488, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31248648

RESUMO

Damage of mitochondrial DNA (mtDNA) with reduction in copy number has been proposed as a biomarker for mitochondrial dysfunction and oxidative stress. Chronic kidney disease (CKD) is associated with increased mortality and risk of cardiovascular disease, but the underlying mechanisms remain incompletely understood. Here we investigated the prognostic role of mtDNA copy number for cause-specific mortality in 4812 patients from the German Chronic Kidney Disease study, an ongoing prospective observational national cohort study of patients with CKD stage G3 and A1-3 or G1-2 with overt proteinuria (A3) at enrollment. MtDNA was quantified in whole blood using a plasmid-normalized PCR-based assay. At baseline, 1235 patients had prevalent cardiovascular disease. These patients had a significantly lower mtDNA copy number than patients without cardiovascular disease (fully-adjusted model: odds ratio 1.03, 95% confidence interval [CI] 1.01-1.05 per 10 mtDNA copies decrease). After four years of follow-up, we observed a significant inverse association between mtDNA copy number and all-cause mortality, adjusted for kidney function and cardiovascular disease risk factors (hazard ratio 1.37, 95% CI 1.09-1.73 for quartile 1 compared to quartiles 2-4). When grouped by causes of death, estimates pointed in the same direction for all causes but in a fully-adjusted model decreased copy numbers were significantly lower only in infection-related death (hazard ratio 1.82, 95% CI 1.08-3.08). A similar association was observed for hospitalizations due to infections in 644 patients (hazard ratio 1.19, 95% CI 1.00-1.42 in the fully-adjusted model). Thus, our data support a role of mitochondrial dysfunction in increased cardiovascular disease and mortality risks as well as susceptibility to infections in patients with CKD.

6.
Genet Epidemiol ; 43(7): 776-785, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31218750

RESUMO

Nontraditional glycemic biomarkers, including fructosamine, glycated albumin, and 1,5-anhydroglucitol (1,5-AG) are potential alternatives or complement to traditional measures of hyperglycemia. Genetic variants are associated with these biomarkers, but the heritability, or extent to which genetics control their variation, is not known. We estimated pedigree-based, SNP-based, and bivariate heritabilities for traditional glycemic biomarkers (fasting glucose, HbA1c), and nontraditional biomarkers (fructosamine, glycated albumin, 1,5-AG) among white participants in the Atherosclerosis Risk in Communities (ARIC) Study (N = 400 first-degree relatives from sibships, N = 5,575 unrelated individuals). Pedigree-based heritabilities (representing heritability from the entire genome) for nontraditional biomarkers were substantial (0.44-0.55) and comparable to HbA1c (0.34); the fasting glucose estimate was nonsignificant. SNP-based heritabilities (representing heritability from common variants) were lower than pedigree-based heritabilities for all biomarkers. Bivariate heritabilities showed shared genetics between fructosamine and glycated albumin (0.46 pedigree-based, 1.00 SNP-based) and glycated albumin and 1,5-AG (0.50 pedigree-based, 0.47 SNP-based). Genetic factors contribute to a considerable proportion of the variance of fructosamine, glycated albumin, and 1,5-AG and a portion of this heritability likely comes from common variants.

7.
Sci Rep ; 9(1): 5941, 2019 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-30976018

RESUMO

Serum 1,5-anhydroglucitol (1,5-AG) is an emerging biomarker used to monitor glycemic control in persons with diabetes. We performed whole-exome sequencing, examining the association between rare, coding genetic variants and 1,5-AG among European ancestry (N = 6,589) and African ancestry (N = 2,309) participants without diagnosed diabetes in the Atherosclerosis Risk in Communities (ARIC) Study. Five variants representing 3 independent signals on chromosome 17 in SLC5A10, a glucose transporter not previously known to transport 1,5-AG, were associated with 1,5-AG levels up to 10.38 µg/mL lower per allele (1,5-AG range 3.4-32.8 µg/mL) in the European ancestry sample and validated in the African ancestry sample. Together these variants explained 6% of the variance in 1,5-AG. Two of these variants (rs61741107, p = 8.85E-56; rs148178887, p = 1.13E-36) were rare, nonsynonymous, and predicted to be damaging or deleterious by multiple algorithms. Gene-based SKAT-O analysis supported these results (SLC5A10 p = 5.13E-64 in European ancestry, validated in African ancestry, p = 0.006). Interestingly, these novel variants are not associated with other biomarkers of hyperglycemia or diabetes (p > 0.2). The large effect sizes and protein-altering, multiple independent signals suggest SLC5A10 may code for an important transporter of 1,5-AG in the kidney, with a potential nonglucose-related effect on 1,5-AG, impacting its clinical utility as a diabetes biomarker in this subpopulation.

8.
J Proteome Res ; 18(4): 1796-1805, 2019 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-30817158

RESUMO

Identification of chronic kidney disease patients at risk of progressing to end-stage renal disease (ESRD) is essential for treatment decision-making and clinical trial design. Here, we explored whether proton nuclear magnetic resonance (NMR) spectroscopy of blood plasma improves the currently best performing kidney failure risk equation, the so-called Tangri score. Our study cohort comprised 4640 participants from the German Chronic Kidney Disease (GCKD) study, of whom 185 (3.99%) progressed over a mean observation time of 3.70 ± 0.88 years to ESRD requiring either dialysis or transplantation. The original four-variable Tangri risk equation yielded a C statistic of 0.863 (95% CI, 0.831-0.900). Upon inclusion of NMR features by state-of-the-art machine learning methods, the C statistic improved to 0.875 (95% CI, 0.850-0.911), thereby outperforming the Tangri score in 94 out of 100 subsampling rounds. Of the 24 NMR features included in the model, creatinine, high-density lipoprotein, valine, acetyl groups of glycoproteins, and Ca2+-EDTA carried the highest weights. In conclusion, proton NMR-based plasma fingerprinting improved markedly the detection of patients at risk of developing ESRD, thus enabling enhanced patient treatment.

9.
Clin J Am Soc Nephrol ; 14(3): 342-353, 2019 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-30733224

RESUMO

BACKGROUND AND OBJECTIVES: Data are scarce on blood metabolite associations with proteinuria, a strong risk factor for adverse kidney outcomes. We sought to investigate associations of proteinuria with serum metabolites identified using untargeted profiling in populations with CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Using stored serum samples from the African American Study of Kidney Disease and Hypertension (AASK; n=962) and the Modification of Diet in Renal Disease (MDRD) study (n=620), two rigorously conducted clinical trials with per-protocol measures of 24-hour proteinuria and GFR, we evaluated cross-sectional associations between urine protein-to-creatinine ratio and 637 known, nondrug metabolites, adjusting for key clinical covariables. Metabolites significantly associated with proteinuria were tested for associations with CKD progression. RESULTS: In the AASK and the MDRD study, respectively, the median urine protein-to-creatinine ratio was 80 (interquartile range [IQR], 28-359) and 188 (IQR, 54-894) mg/g, mean age was 56 and 52 years, 39% and 38% were women, 100% and 7% were black, and median measured GFR was 48 (IQR, 35-57) and 28 (IQR, 18-39) ml/min per 1.73 m2. Linear regression identified 66 serum metabolites associated with proteinuria in one or both studies after Bonferroni correction (P<7.8×10-5), 58 of which were statistically significant in a meta-analysis (P<7.8×10-4). The metabolites with the lowest P values (P<10-27) were 4-hydroxychlorthalonil and 1,5-anhydroglucitol; all six quantified metabolites in the phosphatidylethanolamine pathway were also significant. Of the 58 metabolites associated with proteinuria, four were associated with ESKD in both the AASK and the MDRD study. CONCLUSIONS: We identified 58 serum metabolites with cross-sectional associations with proteinuria, some of which were also associated with CKD progression. PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2019_02_07_CJASNPodcast_19_03_.mp3.

10.
JAMA Cardiol ; 4(2): 144-152, 2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30673084

RESUMO

Importance: Increased free thyroxine (FT4) and decreased thyrotropin are associated with increased risk of atrial fibrillation (AF) in observational studies, but direct involvement is unclear. Objective: To evaluate the potential direct involvement of thyroid traits on AF. Design, Setting, and Participants: Study-level mendelian randomization (MR) included 11 studies, and summary-level MR included 55 114 AF cases and 482 295 referents, all of European ancestry. Exposures: Genomewide significant variants were used as instruments for standardized FT4 and thyrotropin levels within the reference range, standardized triiodothyronine (FT3):FT4 ratio, hypothyroidism, standardized thyroid peroxidase antibody levels, and hyperthyroidism. Mendelian randomization used genetic risk scores in study-level analysis or individual single-nucleotide polymorphisms in 2-sample MR for the summary-level data. Main Outcomes and Measures: Prevalent and incident AF. Results: The study-level analysis included 7679 individuals with AF and 49 233 referents (mean age [standard error], 62 [3] years; 15 859 men [29.7%]). In study-level random-effects meta-analysis, the pooled hazard ratio of FT4 levels (nanograms per deciliter) for incident AF was 1.55 (95% CI, 1.09-2.20; P = .02; I2 = 76%) and the pooled odds ratio (OR) for prevalent AF was 2.80 (95% CI, 1.41-5.54; P = .003; I2 = 64%) in multivariable-adjusted analyses. The FT4 genetic risk score was associated with an increase in FT4 by 0.082 SD (standard error, 0.007; P < .001) but not with incident AF (risk ratio, 0.84; 95% CI, 0.62-1.14; P = .27) or prevalent AF (OR, 1.32; 95% CI, 0.64-2.73; P = .46). Similarly, in summary-level inverse-variance weighted random-effects MR, gene-based FT4 within the reference range was not associated with AF (OR, 1.01; 95% CI, 0.89-1.14; P = .88). However, gene-based increased FT3:FT4 ratio, increased thyrotropin within the reference range, and hypothyroidism were associated with AF with inverse-variance weighted random-effects OR of 1.33 (95% CI, 1.08-1.63; P = .006), 0.88 (95% CI, 0.84-0.92; P < .001), and 0.94 (95% CI, 0.90-0.99; P = .009), respectively, and robust to tests of horizontal pleiotropy. However, the subset of hypothyroidism single-nucleotide polymorphisms involved in autoimmunity and thyroid peroxidase antibodies levels were not associated with AF. Gene-based hyperthyroidism was associated with AF with MR-Egger OR of 1.31 (95% CI, 1.05-1.63; P = .02) with evidence of horizontal pleiotropy (P = .045). Conclusions and Relevance: Genetically increased FT3:FT4 ratio and hyperthyroidism, but not FT4 within the reference range, were associated with increased AF, and increased thyrotropin within the reference range and hypothyroidism were associated with decreased AF, supporting a pathway involving the pituitary-thyroid-cardiac axis.

11.
Forensic Sci Int Genet ; 38: 93-104, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30391626

RESUMO

With recent advances in DNA sequencing technologies it has become feasible and cost effective to genotype larger marker sets for forensic purposes. Two technologies that make use of the larger marker sets have come into focus in forensic research and applications; inference of biogeographic ancestry (BGA) and forensic DNA phenotyping (FDP). These methods hold the promise to reveal information about a yet unknown perpetrator from a DNA sample. In contrast, DNA-profiling, that is a standard practice in case work, relies on matching DNA-profiles between crime scene material and suspects on a database of DNA-profiles. Markers for DNA-profiling were developed under the premise to reveal as little additional information about the human source of the profile as possible, the rationale being that personal privacy rights have to be balanced against the public interest in solving a crime. The same argument holds for markers used in BGA and FDP; these markers might also reveal information on off-target phenotypes (OTPs), that go beyond BGA and the phenotypes targeted in FDP. In particular, health related OTPs might shift the balance between privacy protection and public interest. However, to our knowledge, there is currently no convenient resource available to incorporate knowledge on OTPs in BGA and FDP assay design and application. In order to provide such a resource, we performed a systematic search for OTPs associated with a comprehensive set of markers (1766 SNPs) used or suggested to be used for BGA inference and FDP. In this set, we identified a relatively small number of 27 SNPs (1.53%) that convey information on diverse health related OTPs such as cancer risk, induced asthma, or risk of alcoholism. Some of these SNPs are commonly used for FDP and BGA across different marker sets. We conclude that the effects of SNP markers used in FDP and BGA on OTPs are currently limited, with few exceptions that should be considered in a balanced decision on assay design and application.


Assuntos
Predisposição Genética para Doença , Fenótipo , Polimorfismo de Nucleotídeo Único , Marcadores Genéticos , Humanos
12.
JCI Insight ; 3(23)2018 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-30518689

RESUMO

Biallelic loss-of-function mutations in TRIP11, encoding the golgin GMAP-210, cause the lethal human chondrodysplasia achondrogenesis 1A (ACG1A). We now find that a homozygous splice-site mutation of the lamin B receptor (LBR) gene results in the same phenotype. Intrigued by the genetic heterogeneity, we compared GMAP-210- and LBR-deficient primary cells to unravel how particular mutations in LBR cause a phenocopy of ACG1A. We could exclude a regulatory interaction between LBR and GMAP-210 in patients' cells. However, we discovered a common disruption of Golgi apparatus architecture that was accompanied by decreased secretory trafficking in both cases. Deficiency of Golgi-dependent glycan processing indicated a similar downstream effect of the disease-causing mutations upon Golgi function. Unexpectedly, our results thus point to a common pathogenic mechanism in GMAP-210- and LBR-related diseases attributable to defective secretory trafficking at the Golgi apparatus.

13.
Artigo em Inglês | MEDLINE | ID: mdl-30476224

RESUMO

Background: Elevated plasma concentrations of symmetric and asymmetric dimethylarginine (SDMA and ADMA, respectively) and a lower plasma concentration of the structurally related homoarginine are commonly observed in patients with chronic kidney disease (CKD) and independently predict total mortality as well as progression of renal disease. We aimed to identify drugs that may alter this adverse metabolite pattern in a favourable fashion. Methods: Plasma ADMA, SDMA, homoarginine and l-arginine were determined by liquid chromatography-tandem mass spectrometry in 4756 CKD patients ages 18-74 years with an estimated glomerular filtration rate (eGFR) of 30-60 mL/min/1.73 m2 or an eGFR >60 mL/min/1.73 m2 and overt proteinuria who were enrolled in the German Chronic Kidney Disease (GCKD) study. Associations between laboratory, clinical and medication data were assessed. Results: Intake of several commonly used drugs was independently associated with plasma concentrations of homoarginine and/or related metabolites. Among these, the peroxisome proliferator-activated receptor alpha (PPAR-α) agonist fenofibrate was associated with the most profound differences in ADMA, SDMA and homoarginine plasma concentrations: 66 patients taking fenofibrate had a multivariable adjusted odds ratio (OR) of 5.83 [95% confidence interval (CI) 2.82-12.03, P < 0.001] to have a plasma homoarginine concentration above the median. The median homoarginine plasma concentration in patients taking fenofibrate was 2.30 µmol/L versus 1.55 in patients not taking the drug (P < 0.001). In addition, fibrates were significantly associated with lower plasma SDMA and higher l-arginine concentrations. In contrast, glucocorticoids were associated with lower plasma homoarginine, with adjusted ORs of 0.52 (95% CI 0.40-0.67, P < 0.001) and 0.53 (95% CI 0.31-0.90, P = 0.018) for prednisolone and methylprednisolone, respectively. Conclusions: In a large cohort of CKD patients, intake of fenofibrate and glucocorticoids were independently associated with higher and lower plasma homoarginine concentrations, respectively. Effects on plasma homoarginine and methylarginines warrant further investigation as potential mechanisms mediating beneficial or adverse drug effects.

14.
Nat Commun ; 9(1): 4228, 2018 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-30315176

RESUMO

Elevated serum urate levels can cause gout, an excruciating disease with suboptimal treatment. Previous GWAS identified common variants with modest effects on serum urate. Here we report large-scale whole-exome sequencing association studies of serum urate and kidney function among ≤19,517 European ancestry and African-American individuals. We identify aggregate associations of low-frequency damaging variants in the urate transporters SLC22A12 (URAT1; p = 1.3 × 10-56) and SLC2A9 (p = 4.5 × 10-7). Gout risk in rare SLC22A12 variant carriers is halved (OR = 0.5, p = 4.9 × 10-3). Selected rare variants in SLC22A12 are validated in transport studies, confirming three as loss-of-function (R325W, R405C, and T467M) and illustrating the therapeutic potential of the new URAT1-blocker lesinurad. In SLC2A9, mapping of rare variants of large effects onto the predicted protein structure reveals new residues that may affect urate binding. These findings provide new insights into the genetic architecture of serum urate, and highlight molecular targets in SLC22A12 and SLC2A9 for lowering serum urate and preventing gout.

15.
Sci Rep ; 8(1): 13184, 2018 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-30181573

RESUMO

We evaluated genetics of hyperuricemia and gout, their interaction with kidney function and medication intake in chronic kidney disease (CKD) patients. Genome-wide association studies (GWAS) of urate and gout were performed in 4941 CKD patients in the German Chronic Kidney Disease (GCKD) study. Effect estimates of 26 known urate-associated population-based single nucleotide polymorphisms (SNPs) were examined. Interactions of urate-associated variants with urate-altering medications and clinical characteristics of gout were evaluated. Genome-wide significant associations with serum urate and gout were identified for known loci at SLC2A9 and ABCG2, but not for novel loci. Effects of the 26 known SNPs were of similar magnitude in CKD patients compared to population-based individuals, except for SNPs at ABCG2 that showed greater effects in CKD. Gene-medication interactions were not significant when accounting for multiple testing. Associations with gout in specific joints were significant for SLC2A9 rs12498742 in wrists and midfoot joints. Known genetic variants in SLC2A9 and ABCG2 were associated with urate and gout in a CKD cohort, with effect sizes for ABCG2 significantly greater in CKD compared to the general population. CKD patients are at high risk of gout due to reduced kidney function, diuretics intake and genetic predisposition, making treatment to target challenging.

17.
Pediatr Res ; 2018 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-30140068

RESUMO

BACKGROUND: Genome-wide association studies (GWAS) in healthy populations have identified variants associated with erythrocyte traits, but genetic causes of hemoglobin variation in children with CKD are incompletely understood. METHODS: The Pediatric Investigation of Genetic Factors Linked with Renal Progression (PediGFR) Consortium comprises three pediatric CKD cohorts: Chronic Kidney Disease in Children (CKiD), Effect of Strict Blood Pressure Control and ACE Inhibition on the Progression of CRF in Pediatric Patients (ESCAPE), and Cardiovascular Comorbidity in Children with CKD (4C). We performed cross-sectional and longitudinal association studies of single-nucleotide polymorphisms (SNPs) in 1125 patients. RESULTS: Children of European (n = 725) or Turkish (n = 400) ancestry (EA or TA) were included. In cross-sectional analysis, two SNPs (rs10758658 and rs12718597) previously associated with RBC traits were significantly associated with hemoglobin levels in children of EA and TA. In longitudinal analysis, SNP rs2540917 was nominally associated with hemoglobin in EA and TA children. CONCLUSIONS: SNPs associated with erythrocyte traits in healthy populations were marginally significant for an association with hemoglobin. Further analyses/replication studies are needed in larger CKD cohorts to investigate SNPs of unknown significance associated with hemoglobin. Functional studies will be required to confirm that the observed associations between SNPs and clinical phenotype are causal.

18.
PLoS One ; 13(8): e0202604, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30125326

RESUMO

We assessed the prevalence, awareness, treatment and control of hypertension in patients with moderate chronic kidney disease (CKD) under nephrological care in Germany. In the German Chronic Kidney Disease (GCKD) study, 5217 patients under nephrology specialist care were enrolled from 2010 to 2012 in a prospective observational cohort study. Inclusion criteria were an estimated glomerular filtration rate (eGFR) of 30-60 mL/min/1.73 m2 or overt proteinuria in the presence of an eGFR>60 mL/min/1.73 m2. Office blood pressure was measured by trained study personnel in a standardized way and hypertension awareness and medication were assessed during standardized interviews. Blood pressure was considered as controlled if systolic < 140 and diastolic < 90 mmHg. In 5183 patients in whom measurements were available, mean blood pressure was 139.5 ± 20.4 / 79.3 ± 11.8 mmHg; 4985 (96.2%) of the patients were hypertensive. Awareness and treatment rates were > 90%. However, only 2456 (49.3%) of the hypertensive patients had controlled blood pressure. About half (51.0%) of the patients with uncontrolled blood pressure met criteria for resistant hypertension. Factors associated with better odds for controlled blood pressure in multivariate analyses included younger age, female sex, higher income, low or absent proteinuria, and use of certain classes of antihypertensive medication. We conclude that blood pressure control of CKD patients remains challenging even in the setting of nephrology specialist care, despite high rates of awareness and medication use.

20.
Europace ; 20(12): 2003-2013, 2018 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-29947763

RESUMO

Aims: Characterization of the cardiac phenotype associated with the novel LMNA nonsense mutation c.544C>T, p.Q182*, which we have identified in a large five-generation family. Methods and results: A family tree was constructed. Clinical data [arrhythmia, syncope, sudden cardiac death (SCD), New York Heart Association (NYHA) class] were collected from living and deceased family members. DNA of 23 living family members was analysed for mutations in LMNA. Additionally, dilated cardiomyopathy multi-gene-panel testing and whole exome sequencing were performed in some family members to identify potential phenotype-modifiers. In this five-generation family (n = 65), 17 SCDs occurred at 49.3 ± 10.0 years. Furthermore, we identified eight additional mutation-carriers, seven symptomatic (44 ± 13 years), and one asymptomatic (44 years). First signs of disease [sinus bradycardia with atrioventricular (AV)-block I°] occurred at 36.5 ± 8.1 years. Paroxysmal atrial fibrillation (AF) (onset at 41.8 ± 5.7 years) rapidly progressed to permanent AF (46.2 ± 9.8 years). Subsequently, AV-conduction worsened, syncope, pacemaker-dependence, and non-sustained ventricular tachycardia (43.3 ± 8.2 years) followed. Ventricular arrhythmia caused SCD in patients without implantable cardioverter-defibrillator (ICD). Patients protected by ICD developed rapidly progressive heart failure (45.2 ± 10.6 years). A different phenotype was seen in a sub-family in three patients with early onset of rapidly decompensating heart failure and only minor prior arrhythmia-related symptoms. One patient received high-urgency heart transplantation (HTX) at 32 years, while two died prior to HTX. One of them developed lethal peripartum-associated heart failure. Possible disease-modifiers were identified in this 'heart failure sub-family'. Conclusion: The novel LMNA nonsense mutation c.544C>T causes a severe arrhythmogenic phenotype manifesting with high incidence of SCD in most patients; and in one sub-family, a distinct phenotype with fast progressing heart failure, indicating the need for early consideration of ICD-implantation and listing for heart-transplantation.

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