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1.
Diabetes ; 2020 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-33024004

RESUMO

Early and precise identification of individuals with pre-diabetes and type 2 diabetes (T2D) at risk of progressing to chronic kidney disease (CKD) is essential to prevent complications of diabetes. Here, we identify and evaluate prospective metabolite biomarkers and the best set of predictors of CKD in the longitudinal, population-based Cooperative Health Research in the Region of Augsburg (KORA) cohort by targeted metabolomics and machine learning approaches. Out of 125 targeted metabolites, sphingomyelin (SM) C18:1 and phosphatidylcholine diacyl (PC aa) C38:0 were identified as candidate metabolite biomarkers of incident CKD specifically in hyperglycemic individuals followed during 6.5 years. Sets of predictors for incident CKD developed from 125 metabolites and 14 clinical variables showed highly stable performances in all three machine learning approaches and outperformed the currently established clinical algorithm for CKD. The two metabolites in combination with five clinical variables were identified as the best set of predictors and their predictive performance yielded a mean area value under the receiver operating characteristic curve of 0.857. The inclusion of metabolite variables in the clinical prediction of future CKD may thus improve the risk prediction in persons with pre- and T2D. The metabolite link with hyperglycemia-related early kidney dysfunction warrants further investigation.

2.
Cardiovasc Diabetol ; 19(1): 178, 2020 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-33066780

RESUMO

BACKGROUND: High N-terminal pro-brain-type natriuretic peptide levels have been associated with a lower risk of type 2 diabetes mellitus (T2D). However, less is known about other cardiac stress biomarkers in this context. Here we evaluated the association of mid-regional pro-atrial natriuretic peptide (MR-proANP), C-terminal pro-arginine vasopressin (copeptin), C-terminal pro-endothelin-1 (CT-proET-1) and mid-regional pro-adrenomedullin (MR-proADM) with incident T2D and changes in glucose metabolism. METHODS: We performed a prospective cohort study using data from the population-based KORA F4/FF4 study. 1773 participants (52.3% women) with MR-proANP measurements and 960 (52.7% women) with copeptin, CT-proET-1 and MR-proADM measurements were included. We examined associations of circulating plasma levels of MR-proANP, copeptin, CT-proET-1 and MR-proADM with incident T2D, the combined endpoint of incident prediabetes/T2D and with fasting and 2 h-glucose, fasting insulin, HOMA-IR, HOMA-B and HbA1c at follow-up. Logistic and linear regression models adjusted for age, sex, waist circumference, height, hypertension, total/HDL cholesterol ratio, triglycerides, smoking, physical activity and parental history of diabetes were used to compute effect estimates. RESULTS: During a median follow-up time of 6.4 years (25th and 75th percentiles: 6.0 and 6.6, respectively), 119 out of the 1773 participants and 72 out of the 960 participants developed T2D. MR-proANP was inversely associated with incident T2D (odds ratio [95% confidence interval]: 0.75 [0.58; 0.96] per 1-SD increase of log MR-proANP). Copeptin was positively associated with incident prediabetes/T2D (1.29 [1.02; 1.63] per 1-SD increase of log copeptin). Elevated levels of CT-proET-1 were associated with increased HOMA-B at follow-up, while elevated MR-proADM levels were associated with increased fasting insulin, HOMA-IR and HOMA-B at follow-up. These associations were independent of previously described diabetes risk factors. CONCLUSIONS: High plasma concentrations of MR-proANP contributed to a lower risk of incident T2D, whereas high plasma concentrations of copeptin were associated with an increased risk of incident prediabetes/T2D. Furthermore, high plasma concentrations of CT-proET-1 and MR-proADM were associated with increased insulin resistance. Our study provides evidence that biomarkers implicated in cardiac stress are associated with incident T2D and changes in glucose metabolism.

3.
Sci Rep ; 10(1): 15373, 2020 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-32958955

RESUMO

Since family history of diabetes is a very strong risk factor for type 2 diabetes, which is one of the most important risk factors for cardiovascular disease (CVD), it might be also useful to assess the risk for CVD. Therefore, we aimed to investigate the relationship between a familial (parents and siblings) history of diabetes and the risk of incident CVD. Data from four prospective German cohort studies were used: EPIC-Potsdam study (n = 26,054), CARLA study (n = 1,079), SHIP study (n = 3,974), and KORA study (n = 15,777). A multivariable-adjusted Cox regression was performed to estimate associations between familial histories of diabetes, myocardial infarction or stroke and the risk of CVD in each cohort; combined hazard ratios (HRMeta) were derived by conducting a meta-analysis. The history of diabetes in first-degree relatives was not related to the development of CVD (HRMeta 0.99; 95% CI 0.88-1.10). Results were similar for the single outcomes myocardial infarction (MI) (HRMeta 1.07; 95% CI 0.92-1.23) and stroke (HRMeta 1.00; 95% CI 0.86-1.16). In contrast, parental history of MI and stroke were associated with an increased CVD risk. Our study indicates that diabetes in the family might not be a relevant risk factor for the incidence of CVD. However, the study confirmed the relationship between a parental history of MI or stroke and the onset of CVD.

4.
Transl Psychiatry ; 10(1): 323, 2020 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-32958748

RESUMO

The role of self-perceived general health in predicting morbidity and mortality among older people is established. The predictive value of self-perceived mental health and of its possible biological underpinnings for future depressive symptoms is unexplored. This study aimed to assess the role of mental health-related quality of life (HRQOL) and of its epigenetic markers in predicting depressive symptoms among older people without lifetime history of depression. Data were based on a subgroup (n = 1 492) of participants of the longitudinal ESTHER study. An epigenome-wide association study (EWAS) of mental HRQOL was conducted using DNA from baseline whole blood samples and logistic regression analyses were performed to assess the predictive value of methylation beta values of EWAS identified CpGs for incidence of depressive symptoms in later life. The methylation analyses were replicated in the independent KORA cohort (n = 890) and a meta-analysis of the two studies was conducted. Results of the meta-analysis showed that participants with beta values of cg27115863 within quartile 1 (Q1) had nearly a two-fold increased risk of developing depressive symptoms compared to participants with beta values within Q4 (ORQ1vsQ4 = 1.80; CI 1.25-2.61). In the ESTHER study the predictive value of subjective mental health for future depressive symptoms was also assessed and for 10-unit increase in mental HRQOL scores the odds for incident depressive symptoms were reduced by 54% (OR 0.46; CI 0.40-0.54). These findings suggest that subjective mental health and hypomethylation at cg27115863 are predictive of depressive symptoms, possibly through the activation of inflammatory signaling pathway.

5.
Diabetes ; 2020 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-32928870

RESUMO

With an estimated prevalence of 463 million affected, type 2 diabetes represents a major challenge to health care systems worldwide. Analyzing the plasma proteomes of individuals with type 2 diabetes may illuminate hitherto unknown functional mechanisms underlying disease pathology. We assessed the associations between type 2 diabetes and >1000 plasma proteins in the KORA (Cooperative health research in the Region of Augsburg) F4 cohort (n=993, 110 cases), with subsequent replication in the HUNT3 (Third wave of the Nord-Trøndelag Health Study) cohort (n=940, 149 cases). We computed logistic regression models adjusted for age, sex, BMI, smoking status and hypertension. Additionally, we investigated associations with incident type 2 diabetes and performed two-sample bi-directional Mendelian randomization (MR) analysis to prioritize our results. Association analysis of prevalent type 2 diabetes revealed 24 replicated proteins, of which eight are novel. Proteins showing association with incident type 2 diabetes were aminoacylase-1, growth hormone receptor, and insulin-like growth factor binding protein-2. Aminoacylase-1 was associated with both prevalent and incident type 2 diabetes. MR analysis yielded nominally significant causal effects of type 2 diabetes on cathepsin Z and rennin, both known to have roles in the pathophysiological pathways of cardiovascular disease, and of sex hormone-binding globulin on type 2 diabetes. In conclusion, our high-throughput proteomics study replicated previously reported type 2 diabetes-protein associations, and identified new candidate proteins possibly involved in the pathogenesis of type 2 diabetes.

6.
Rofo ; 2020 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-32785905

RESUMO

PURPOSE: To determine the association of asymptomatic diverticular disease as assessed by magnetic resonance imaging (MRI) with adipose tissue compartments, hepatic steatosis and constitutional risk factors within a cohort drawn from a Western general population. MATERIALS AND METHODS: Asymptomatic subjects enrolled in a prospective case-control study underwent a 3 Tesla MRI scan, including an isotropic VIBE-Dixon sequence of the entire trunk. The presence and extent of diverticular disease were categorized according to the number of diverticula in each colonic segment in a blinded fashion. The amount of visceral, subcutaneous, and total adipose tissue (VAT, SAT, and TAT) was quantified by MRI. Additionally, the degree of hepatic steatosis, indicated as hepatic proton density fat fraction (hepatic PDFF) was determined using a multi-echo T1w sequence. Constitutional cardiometabolic risk factors were obtained and univariate and multivariate associations were calculated. RESULTS: A total of 371 subjects were included in the analysis (58.2 % male, 56.2 ±â€Š9.2 years). Based on MRI, 154 participants (41.5 %) had diverticular disease with 62 cases (17 %) being advanced diverticular disease. Subjects with advanced diverticular disease had a significantly higher body mass index (BMI) (BMI: 29.9 ±â€Š5.1 vs. 27.5 ±â€Š4.6, p < 0.001; respectively). Furthermore, all adipose tissue compartments were increased in subjects with advanced diverticular disease (e. g. VAT: 6.0 ±â€Š2.8 vs. 4.2 ±â€Š2.6 and SAT: 9.2 ±â€Š3.6 vs. 7.8 ±â€Š3.6, all p < 0.001, respectively). Similarly, subjects with advanced diverticular disease had significantly higher hepatic PDFF (4.9 [2.7, 11.4] vs. 6.1 [5.5, 14.6], p = 0.002). CONCLUSION: Advanced diverticular disease is associated with an increased volume of adipose tissue compartments and BMI, which may suggest a metabolic role in disease development. KEY POINTS: · Diverticular disease is associated with constitutional risk factors such as BMI.. · Excess of adipose tissue compartments and hepatic steatosis are associated with the prevalence of diverticular disease.. · Our results suggest a shared pathological pathway of cardiometabolic alterations and the prevalence of diverticular disease.. · MRI is feasible for the assessment of adipose tissue compartments, hepatic steatosis, and diverticular disease and allows identification of patients who are at risk but in an asymptomatic disease state.. CITATION FORMAT: · Storz C, Rospleszcz S, Askani E et al. Magnetic Resonance Imaging of Diverticular Disease and its Association with Adipose Tissue Compartments and Constitutional Risk Factors in Subjects from a Western General Population. Fortschr Röntgenstr 2020; DOI: 10.1055/a-1212-5669.

7.
BMC Med Genomics ; 13(1): 120, 2020 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-32843070

RESUMO

BACKGROUND: Advanced age-related macular degeneration (AMD) is a leading cause of blindness. While around half of the genetic contribution to advanced AMD has been uncovered, little is known about the genetic architecture of early AMD. METHODS: To identify genetic factors for early AMD, we conducted a genome-wide association study (GWAS) meta-analysis (14,034 cases, 91,214 controls, 11 sources of data including the International AMD Genomics Consortium, IAMDGC, and UK Biobank, UKBB). We ascertained early AMD via color fundus photographs by manual grading for 10 sources and via an automated machine learning approach for > 170,000 photographs from UKBB. We searched for early AMD loci via GWAS and via a candidate approach based on 14 previously suggested early AMD variants. RESULTS: Altogether, we identified 10 independent loci with statistical significance for early AMD: (i) 8 from our GWAS with genome-wide significance (P < 5 × 10- 8), (ii) one previously suggested locus with experiment-wise significance (P < 0.05/14) in our non-overlapping data and with genome-wide significance when combining the reported and our non-overlapping data (together 17,539 cases, 105,395 controls), and (iii) one further previously suggested locus with experiment-wise significance in our non-overlapping data. Of these 10 identified loci, 8 were novel and 2 known for early AMD. Most of the 10 loci overlapped with known advanced AMD loci (near ARMS2/HTRA1, CFH, C2, C3, CETP, TNFRSF10A, VEGFA, APOE), except two that have not yet been identified with statistical significance for any AMD. Among the 17 genes within these two loci, in-silico functional annotation suggested CD46 and TYR as the most likely responsible genes. Presence or absence of an early AMD effect distinguished the known pathways of advanced AMD genetics (complement/lipid pathways versus extracellular matrix metabolism). CONCLUSIONS: Our GWAS on early AMD identified novel loci, highlighted shared and distinct genetics between early and advanced AMD and provides insights into AMD etiology. Our data provide a resource comparable in size to the existing IAMDGC data on advanced AMD genetics enabling a joint view. The biological relevance of this joint view is underscored by the ability of early AMD effects to differentiate the major pathways for advanced AMD.

8.
Acad Radiol ; 2020 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-32800693

RESUMO

RATIONALE AND OBJECTIVES: To investigate radiomics features of hepatic fat as potential biomarkers of type 2 diabetes mellitus (T2DM) and metabolic syndrome (MetS) in individuals without overt cardiovascular disease, and benchmarking against hepatic proton density fat fraction (PDFF) and the body mass index (BMI). MATERIALS AND METHODS: This study collected liver radiomics features of 310 individuals that were part of a case-controlled imaging substudy embedded in a prospective cohort. Individuals had known T2DM (n = 39; 12.6 %) and MetS (n = 107; 34.5 %) status, and were divided into stratified training (n = 232; 75 %) and validation (n = 78; 25 %) sets. Six hundred eighty-four MRI radiomics features were extracted for each liver volume of interest (VOI) on T1-weighted dual-echo Dixon relative fat water content (rfwc) maps. Test-retest and inter-rater variance was simulated by additionally extracting radiomics features using noise augmented rfwc maps and deformed volume of interests. One hundred and seventy-one features with test-retest reliability (ICC(1,1)) and inter-rater agreement (ICC(3,k)) of ≥0.85 on the training set were considered stable. To construct predictive random forest (RF) models, stable features were filtered using univariate RF analysis followed by sequential forward aggregation. The predictive performance was evaluated on the independent validation set with area under the curve of the receiver operating characteristic (AUROC) and balanced accuracy (AccuracyB). RESULTS: On the validation set, the radiomics RF models predicted T2DM with AUROC of 0.835 and AccuracyB of 0.822 and MetS with AUROC of 0.838 and AccuracyB of 0.787, outperforming the RF models trained on the benchmark parameters PDFF and BMI. CONCLUSION: Hepatic radiomics features may serve as potential imaging biomarkers for T2DM and MetS.

9.
Genome Med ; 12(1): 74, 2020 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-32825847

RESUMO

BACKGROUND: The concentrations of the highly atherogenic lipoprotein(a) [Lp(a)] are mainly genetically determined by the LPA gene locus. However, up to 70% of the coding sequence is located in the complex so-called kringle IV type 2 (KIV-2) copy number variation, a region hardly accessible by common genotyping and sequencing technologies. Despite its size, little is known about genetic variants in this complex region. The R21X variant is a functional variant located in this region, but it has never been analyzed in large cohorts. METHODS: We typed R21X in 10,910 individuals from three European populations using a newly developed high-throughput allele-specific qPCR assay. R21X allelic location was determined by separating the LPA alleles using pulsed-field gel electrophoresis (PFGE) and typing them separately. Using GWAS data, we identified a proxy SNP located outside of the KIV-2. Linkage disequilibrium was determined both statistically and by long-range haplotyping using PFGE. Worldwide frequencies were determined by reanalyzing the sequencing data of the 1000 Genomes Project with a dedicated pipeline. RESULTS: R21X carriers (frequency 0.016-0.021) showed significantly lower mean Lp(a) concentrations (- 11.7 mg/dL [- 15.5; - 7.82], p = 3.39e-32). The variant is located mostly on medium-sized LPA alleles. In the 1000 Genome data, R21X mostly occurs in Europeans and South Asians, is absent in Africans, and shows varying frequencies in South American populations (0 to 0.022). Of note, the best proxy SNP was another LPA null mutation (rs41272114, D' = 0.958, R2 = 0.281). D' was very high in all 1000G populations (0.986-0.996), although rs41272114 frequency varies considerably (0-0.182). Co-localization of both null mutations on the same allele was confirmed by PFGE-based long-range haplotyping. CONCLUSIONS: We performed the largest epidemiological study on an LPA KIV-2 variant so far, showing that it is possible to assess LPA KIV-2 mutations on a large scale. Surprisingly, in all analyzed populations, R21X was located on the same haplotype as the splice mutation rs41272114, creating "double-null" LPA alleles. Despite being a nonsense variant, the R21X status does not provide additional information beyond the rs41272114 genotype. This has important implications for studies using LPA loss-of-function mutations as genetic instruments and emphasizes the complexity of LPA genetics.

10.
Acta Diabetol ; 2020 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-32748175

RESUMO

AIMS: To identify socioeconomic, behavioral and clinical factors that are associated with prediabetes according to different prediabetes definition criteria. METHODS: Analyses use pooled data of the population-based Cooperative Health Research in the Region of Augsburg (KORA) studies (n = 5312 observations aged ≥ 38 years without diabetes). Prediabetes was defined through either impaired fasting glucose (IFG), impaired glucose tolerance (IGT) or elevated HbA1c according to thresholds of the American Diabetes Association. Explanatory variables were regressed on prediabetes using generalized estimating equations. RESULTS: Mean age was 58.4 years; 50% had prediabetes (33% had IFG, 16% IGT, and 26% elevated HbA1c, 10% fulfilled all three criteria). Age, obesity, hypertension, low education, unemployment, statutory health insurance, urban residence and physical inactivity were associated with prediabetes. Male sex was a stronger risk factor for IFG (OR = 2.5; 95%-CI: 2.2-2.9) than for IGT or elevated HbA1c, and being unemployed was a stronger risk factor for IGT (OR = 3.2 95%-CI: 2.6-4.0) than for IFG or elevated HbA1c. CONCLUSIONS: The overlap of people with IFG, IGT and elevated HbA1c is small, and some factors are associated with only one criterion. Knowledge on sociodemographic and socioeconomic risk factors can be used to effectively target interventions to people at high risk for type 2 diabetes.

11.
Stroke ; 51(9): 2770-2777, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32811388

RESUMO

BACKGROUND AND PURPOSE: Stroke is a common cause of death and a leading cause of disability and morbidity. Stroke risk assessment remains a challenge, but circulating biomarkers may improve risk prediction. Controversial evidence is available on the predictive ability of troponin concentrations and the risk of stroke in the community. Furthermore, reports on the predictive value of troponin concentrations for different stroke subtypes are scarce. METHODS: High-sensitivity cardiac troponin I (hsTnI) concentrations were assessed in 82 881 individuals (median age, 50.7 years; 49.7% men) free of stroke or myocardial infarction at baseline from 9 prospective European community cohorts. We used Cox proportional hazards regression to determine relative risks, followed by measures of discrimination and reclassification using 10-fold cross-validation to control for overoptimism. Follow-up was based upon linkage with national hospitalization registries and causes of death registries. RESULTS: Over a median follow-up of 12.7 years, 3033 individuals were diagnosed with incident nonfatal or fatal stroke (n=1654 ischemic strokes, n=612 hemorrhagic strokes, and n=767 indeterminate strokes). In multivariable regression models, hsTnI concentrations were associated with overall stroke (hazard ratio per 1-SD increase, 1.15 [95% CI, 1.10-1.21]), ischemic stroke (hazard ratio, 1.14 [95% CI, 1.09-1.21]), and hemorrhagic stroke (hazard ratio, 1.10 [95% CI, 1.01-1.20]). Adding hsTnI concentrations to classical cardiovascular risk factors (C indices, 0.809, 0.840, and 0.736 for overall, ischemic, and hemorrhagic stroke, respectively) increased the C index significantly but modestly. In individuals with an intermediate 10-year risk (5%-20%), the net reclassification improvement for overall stroke was 0.038 (P=0.021). CONCLUSIONS: Elevated hsTnI concentrations are associated with an increased risk of incident stroke in the community, irrespective of stroke subtype. Adding hsTnI concentrations to classical risk factors only modestly improved estimation of 10-year risk of stroke in the overall cohort but might be of some value in individuals at an intermediate risk.

12.
Aging (Albany NY) ; 12(16): 16539-16554, 2020 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-32747609

RESUMO

Chronic obstructive pulmonary disease (COPD) is a frequent diagnosis in older individuals and contributor to global morbidity and mortality. Given the link between lung disease and aging, we need to understand how molecular indicators of aging relate to lung function and disease. Using data from the population-based KORA (Cooperative Health Research in the Region of Augsburg) surveys, we associated baseline epigenetic (DNA methylation) age acceleration with incident COPD and lung function. Models were adjusted for age, sex, smoking, height, weight, and baseline lung disease as appropriate. Associations were replicated in the Normative Aging Study. Of 770 KORA participants, 131 developed incident COPD over 7 years. Baseline accelerated epigenetic aging was significantly associated with incident COPD. The change in age acceleration (follow-up - baseline) was more strongly associated with COPD than baseline aging alone. The association between the change in age acceleration between baseline and follow-up and incident COPD replicated in the Normative Aging Study. Associations with spirometric lung function parameters were weaker than those with COPD, but a meta-analysis of both cohorts provide suggestive evidence of associations. Accelerated epigenetic aging, both baseline measures and changes over time, may be a risk factor for COPD and reduced lung function.

13.
PLoS One ; 15(8): e0237364, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32764816

RESUMO

OBJECTIVES: Uromodulin has been associated with arterial hypertension in genome-wide association studies, but data from clinical and preclinical studies are inconsistent. We here analyzed the association of serum uromodulin (sUmod) with arterial hypertension and vasoactive hormones in a population-based study. METHODS: In 1108 participants of the KORA F4 study aged 62-81 years, sUmod was measured and the association of sUmod with arterial hypertension was assessed using logistic regression models. The associations of sUmod with renin and aldosterone and with the vasoconstrictive prohormone C-terminal pro-endothelin-1 (CT-proET-1) were analyzed in 1079 participants and in 618 participants, respectively, using linear regression models. RESULTS: After multivariable adjustment including sex, age, eGFR, BMI, fasting glucose, current smoking, previous stroke and myocardial infarction, sUmod was inversely associated with arterial hypertension (OR 0.78; 95% CI 0.68-0.91; p = 0.001). SUmod was not significantly associated with renin and aldosterone after adjustment for sex, age and eGFR. However, sUmod was inversely associated with CT-proET-1 (ß -0.19 ± 0.04; p < 0.001) after adjustment for sex, age, eGFR, BMI, arterial hypertension, fasting glucose, current smoking, previous stroke and myocardial infarction. The association with CT-proET-1 was stronger in participants with hypertension (ß -0.22 ± 0.04) than in normotensive participants (ß -0.13 ± 0.06; p for interaction hypertension = 0.003 in the model adjusted for hypertension). CONCLUSIONS: SUmod was inversely associated with arterial hypertension and the vasoconstrictive prohormone CT-proET-1, suggesting direct or indirect effects of sUmod on blood pressure regulation.


Assuntos
Endotelina-1/sangue , Hipertensão/sangue , Fragmentos de Peptídeos/sangue , Uromodulina/sangue , Idoso , Aldosterona/sangue , Feminino , Humanos , Hipertensão/epidemiologia , Masculino , Renina/sangue
14.
Artigo em Inglês | MEDLINE | ID: mdl-32822252

RESUMO

Background - The P-wave duration (PWD) is an electrocardiographic (ECG) measurement that represents cardiac conduction in the atria. Shortened or prolonged PWD is associated with atrial fibrillation (AF). We used exome chip data to examine the associations between common and rare variants with PWD. Methods - Fifteen studies comprising 64,440 individuals (56,943 European, 5,681 African, 1,186 Hispanic, 630 Asian), and ~230,000 variants were used to examine associations with maximum PWD across the 12-lead ECG. Meta-analyses summarized association results for common variants; gene-based burden and SKAT tests examined low-frequency variant-PWD associations. Additionally, we examined the associations between PWD loci and AF using previous AF GWAS. Results - We identified 21 common and low-frequency genetic loci (14 novel) associated with maximum PWD, including several AF loci (TTN, CAND2, SCN10A, PITX2, CAV1, SYNPO2L, SOX5, TBX5, MYH6, RPL3L). The top variants at known sarcomere genes (TTN, MYH6) were associated with longer PWD and increased AF risk. However, top variants at other loci (e.g., PITX2 and SCN10A) were associated with longer PWD but lower AF risk. Conclusions - Our results highlight multiple novel genetic loci associated with PWD, and underscore the shared mechanisms of atrial conduction and AF. Prolonged PWD may be an endophenotype for several different genetic mechanisms of AF.

15.
Econ Hum Biol ; 38: 100893, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32653545

RESUMO

Retirement is a major life event potentially associated with changes in relevant risk factors for cardiovascular and metabolic conditions. This study analyzes the effect of retirement on behavioral and biomedical risk factors for chronic disease, together with subjective health parameters using Southern German epidemiological data. We used panel data from the KORA cohort study, consisting of 11,168 observations for individuals 45-80 years old. Outcomes included health behavior (alcohol, smoking, physical activity), biomedical risk factors (body-mass-index (BMI), waist-to-hip ratio (WHR), glycosylated hemoglobin (HbA1c), total cholesterol/HDL quotient, systolic/diastolic blood pressure), and subjective health (SF12 mental and physical scales, self-rated health). We applied a parametric regression discontinuity design based on age thresholds for pension eligibility. Robust results after p-value corrections for multiple testing showed an increase in BMI in early retirees (at the age of 60) [ß = 1.11, corrected p-val. < 0.05] and an increase in CHO/HDL in regular retirees (age 65) [ß = 0.47, corrected p-val. < 0.05]. Stratified analyses indicate that the increase in BMI might be driven by women and low educated individuals retiring early, despite increasing physical activity. The increase in CHO/HDL might be driven by men retiring regularly, alongside an increase in subjective physical health. Blood pressure also increased, but the effect differs by retirement timing and sex and is not always robust to sensitivity analysis checks. Our study indicates that retirement has an impact on different risk factors for chronic disease, depending on timing, sex and education. Regular male, early female, and low educated retirees should be further investigated as potential high-risk groups for worsening risk factors after retirement. Future research should investigate if and how these results are linked: in fact, especially in the last two groups, the increase in leisure time physical activity might not be enough to compensate for the loss of work-related physical activity, leading thus to an increase in BMI.

16.
BMC Public Health ; 20(1): 1049, 2020 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-32616004

RESUMO

BACKGROUND: Hypertension remains a significant modifiable risk factor for cardiovascular diseases and a major determinant of morbidity and mortality. We aimed to describe sex-stratified age-standardized estimates of prevalence, awareness, treatment and control of hypertension, and their associated factors in older adults. METHODS: The KORA-Age1 is a population-based cross-sectional survey carried out in 2008/2009 on individuals aged 65-94 years in Augsburg region, Germany. Blood pressure measurements were available for 1052 out of 1079 persons who participated in the physical examination. Factors associated with prevalence, awareness and control of hypertension were investigated by multivariable logistic regression. RESULTS: The overall prevalence of hypertension (≥140/90 mmHg) was 73.8% [95% confidence interval (CI), 69.3-77.9], representing 74.8% (95% CI, 68.4-80.2) in men and 73.5% (95% CI, 66.8-79.3) in women. Among those with hypertension, 80.2% (95% CI, 75.3-84.4) were aware of their hypertensive condition and 74.4% (95% CI, 69.2-79.1) were on treatment for hypertension. Among those aware of their hypertension status, 92.8% (95% CI, 88.8-95.6) were on treatment and 53.7% (95% CI, 47.0-60.1) had their blood pressure controlled. Hypertension was more frequent in individuals who were older, obese, or had diabetes. Higher education attainment or presence of comorbidities was associated with higher level of hypertension awareness. Individuals taking three antihypertensive drug classes were more likely to have controlled hypertension compared with those taking one antihypertensive drug class, odds ratio (OR), 1.85 (95% CI, 1.14-2.99). CONCLUSION: Our findings identified high prevalence of hypertension and relevant health gaps on awareness, treatment and suboptimal control of hypertension in older adults in Germany. Screening for hypertension should especially target older adults with low educational attainment and 'healthy' elderly with less contact to physicians.

17.
Artigo em Inglês | MEDLINE | ID: mdl-32690629

RESUMO

INTRODUCTION: Peripheral arterial tonometry (PAT) is an operator-independent and non-invasive measurement method to assess microvascular endothelial function in the fingertips. PAT-derived measures of endothelial function were associated with type 2 diabetes in cross-sectional studies. However, longitudinal studies are lacking. The study aims to investigate the association of two PAT-derived endothelial function parameters reactive hyperemia index (RHI) and mean baseline amplitude (MBA) with follow-up glucose and insulin parameters and the development of (pre)diabetes and type 2 diabetes. RESEARCH DESIGN AND METHODS: The study included 673 participants initially without diabetes (328 men and 345 women) aged 52-71 years from the prospective population-based Cooperative Health Research in the Region of Augsburg F4/FF4 cohort study conducted in Southern Germany (baseline examination F4: 2006-2008; follow-up FF4: 2013-2014). An oral glucose tolerance test was performed at baseline and follow-up to define type 2 diabetes, prediabetes, fasting glucose, fasting insulin, 2-hour glucose, homeostasis model assessment of insulin resistance (HOMA-IR), homeostasis model assessment of beta-cell function and hemoglobin A1c. RESULTS: In multivariable adjusted logistic/linear regression models, a 1 SD increase in baseline RHI was inversely associated with incident type 2 diabetes (OR 0.69 (95% CI 0.48 to 0.97)) as well as with fasting insulin (ß -0.069 (95% CI -0.131 to -0.007)) and HOMA-IR (ß -0.072 (95% CI -0.133 to -0.010)) at follow-up in participants with initial normoglycemia. A 1 SD increase in baseline MBA was positively associated with incident (pre)diabetes (OR 1.62 (95% CI 1.25 to 2.11)) and fasting glucose (ß 0.096 (95% CI 0.047 to 0.146)) at follow-up in participants with initial normoglycemia. CONCLUSIONS: Microvascular endothelial dysfunction seems to be involved in the development of early derangements in glucose metabolism and insulin resistance and could thereby trigger the development of prediabetes and type 2 diabetes.

18.
Aging (Albany NY) ; 12(14): 14092-14124, 2020 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-32697766

RESUMO

DNA methylation has fundamental roles in gene programming and aging that may help predict mortality. However, no large-scale study has investigated whether site-specific DNA methylation predicts all-cause mortality. We used the Illumina-HumanMethylation450-BeadChip to identify blood DNA methylation sites associated with all-cause mortality for 12, 300 participants in 12 Cohorts of the Heart and Aging Research in Genetic Epidemiology (CHARGE) Consortium. Over an average 10-year follow-up, there were 2,561 deaths across the cohorts. Nine sites mapping to three intergenic and six gene-specific regions were associated with mortality (P < 9.3x10-7) independently of age and other mortality predictors. Six sites (cg14866069, cg23666362, cg20045320, cg07839457, cg07677157, cg09615688)-mapping respectively to BMPR1B, MIR1973, IFITM3, NLRC5, and two intergenic regions-were associated with reduced mortality risk. The remaining three sites (cg17086398, cg12619262, cg18424841)-mapping respectively to SERINC2, CHST12, and an intergenic region-were associated with increased mortality risk. DNA methylation at each site predicted 5%-15% of all deaths. We also assessed the causal association of those sites to age-related chronic diseases by using Mendelian randomization, identifying weak causal relationship between cg18424841 and cg09615688 with coronary heart disease. Of the nine sites, three (cg20045320, cg07839457, cg07677157) were associated with lower incidence of heart disease risk and two (cg20045320, cg07839457) with smoking and inflammation in prior CHARGE analyses. Methylation of cg20045320, cg07839457, and cg17086398 was associated with decreased expression of nearby genes (IFITM3, IRF, NLRC5, MT1, MT2, MARCKSL1) linked to immune responses and cardiometabolic diseases. These sites may serve as useful clinical tools for mortality risk assessment and preventative care.

19.
Geroscience ; 42(5): 1365-1376, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32648237

RESUMO

Immunostimulation by chronic infection has been linked to an increased risk for different non-communicable diseases, which in turn are leading causes of death in high- and middle-income countries. Thus, we investigated if a positive serostatus for pathogens responsible for common chronic infections is individually or synergistically related to reduced overall survival in community dwelling elderly. We used data of 365 individuals from the German MEMO (Memory and Morbidity in Augsburg Elderly) cohort study with a median age of 73 years at baseline and a median follow-up of 14 years. We examined the effect of a positive serostatus at baseline for selected pathogens associated with chronic infections (Helicobacter pylori, Borrelia burgdorferi sensu lato, Toxoplasma gondii, cytomegalovirus, Epstein-Barr virus, herpes simplex virus 1/2, and human herpesvirus 6) on all-cause mortality with multivariable parametric survival models. We found a reduced survival time in individuals with a positive serostatus for Helicobacter pylori (accelerated failure time (AFT) - 15.92, 95% CI - 29.96; - 1.88), cytomegalovirus (AFT - 22.81, 95% CI - 36.41; - 9.22) and Borrelia burgdorferi sensu lato (AFT - 25.25, 95% CI - 43.40; - 7.10), after adjusting for potential confounders. The number of infectious agents an individual was seropositive for had a linear effect on all-cause mortality (AFT per additional infection - 12.42 95% CI - 18.55; - 6.30). Our results suggest an effect of seropositivity for Helicobacter pylori, cytomegalovirus, and Borrelia burgdorferi sensu lato on all-cause mortality in older community dwelling individuals. Further research with larger cohorts and additional biomarkers is required, to assess mediators and molecular pathways of this effect.

20.
Artigo em Inglês | MEDLINE | ID: mdl-32619440

RESUMO

Lifestyle, obesity, and the gut microbiome are important risk factors for metabolic disorders. We demonstrate in 1,976 subjects of a German population cohort (KORA) that specific microbiota members show 24-h oscillations in their relative abundance and identified 13 taxa with disrupted rhythmicity in type 2 diabetes (T2D). Cross-validated prediction models based on this signature similarly classified T2D. In an independent cohort (FoCus), disruption of microbial oscillation and the model for T2D classification was confirmed in 1,363 subjects. This arrhythmic risk signature was able to predict T2D in 699 KORA subjects 5 years after initial sampling, being most effective in combination with BMI. Shotgun metagenomic analysis functionally linked 26 metabolic pathways to the diurnal oscillation of gut bacteria. Thus, a cohort-specific risk pattern of arrhythmic taxa enables classification and prediction of T2D, suggesting a functional link between circadian rhythms and the microbiome in metabolic diseases.

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