Karl J Lackner

Johannes Gutenberg-Universität Mainz, Mayence, Rheinland-Pfalz, Germany

Are you Karl J Lackner?

Claim your profile

Publications (268)1636.2 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: To determine the age- and sex-specific prevalence and determinants of Retinal vein occlusions (RVO) in a large populations-based German cohort. The investigation comprised 15,010 participants (35-74 years) from the Gutenberg Health Study (GHS). We determined the prevalence of RVO (central retinal vein occlusion, CRVO; branch retinal vein occlusion, BRVO) for the local population by assessing fundus photographs of 12,954 (86.3%; 49.8% females, 50.2% males) participants. Furthermore, we analyzed the associations of RVO with cardiovascular, anthropometric, and ophthalmic parameters. The weighted prevalences of RVO, CRVO, and BRVO were 0.40%, 0.8%, and 0.32%, respectively. Males were 1.7 times more frequently affected by RVO than females. Prevalence of RVO was 0.2% in participants aged 35-44 and 45-54 years, respectively, 0.48% from 55-64 and 0.92% in participants between 65-74 years. 91.5% of persons with RVO had one or more cardiovascular risk factors or diseases versus 75.9% of persons without RVO. BRVO was associated with arterial hypertension (OR: 2.69; 95%CI: 1.27-5.70) and atrial fibrillation (3.37; 1.24-9.12) and CRVO with higher age (7.02, 1.63-30.19) and a family history of stroke (4.64; 1.18-18.25). Median visual acuity (base 10 logarithm of minimum angle of resolution; logMAR) was 0.2 in persons with RVO versus 0.05 in those without. The prevalence of RVO in this German population was 0.4% and males were 1.7 times more frequently affected than females. CRVO was associated with higher age and a family history of stroke, and BRVO with arterial hypertension and atrial fibrillation. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Journal of Thrombosis and Haemostasis 04/2015; DOI:10.1111/jth.12982 · 5.55 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The inflammatory and immune systems are altered in type 2 diabetes. Here, the aim was to profile the immune and inflammatory response in subjects with prediabetes and diabetes in a large population-representative sample. In total, 15,010 individuals were analyzed from the population-based Gutenberg Health Study. Glucose status was classified according to HbA1c concentration and history of diagnosis. All samples were analyzed for white blood cells (WBCs), granulocytes, lymphocytes, monocytes, platelets, C-reactive protein (CRP), albumin, fibrinogen, and hematocrit. Interleukin-18 (IL-18), IL-1 receptor antagonist (IL-1RA), and neopterin concentrations were determined in a subcohort. In total, 7,584 men and 7,426 women were analyzed (range 35-74 years), with 1,425 and 1,299 having prediabetes and diabetes, respectively. Biomarkers showed varying dynamics from normoglycemic via subjects with prediabetes to subjects with diabetes: 1) gradual increase (WBCs, granulocytes, monocytes, IL-1RA, IL-18, and fibrinogen), 2) increase with subclinical disease only (lymphocytes and CRP), 3) increase from prediabetes to diabetes only (neopterin), and 4) no variation with glucose status (hematocrit). The strongest relative differences were found for CRP, IL-1RA, and fibrinogen concentrations. Several inflammatory and immune markers were associated with the glucose status independent from cardiovascular risk factors and comorbidities, varied with disease severity and the presence of disease-specific complications in the diabetes subcohort. The inflammatory and immune biomarker profile varies with the development and progression of type 2 diabetes. Markers of inflammation and immunity enable differentiation between the early preclinical and clinical phases of the disease, disease complications, and progression. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
    Diabetes care 04/2015; DOI:10.2337/dc14-3008 · 8.57 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Elevated levels of FVIII:c are associated with risk for both venous and arterial thromboembolism. However, no population-based study on the sex-specific distribution and reference ranges of plasma FVIII:c and its cardiovascular determinants is available. FVIII:c was analyzed in a randomly selected sample of 2533 males and 2440 females from the Gutenberg Health Study in Germany. Multivariable regression analyses for FVIII:c were performed under adjustment for genetic determinants, cardiovascular risk factors and cardiovascular disease. Females (126.6% (95% CI: 125.2/128)) showed higher FVIII:c levels than males (121.2% (119.8/122.7)). FVIII:c levels increased with age in both sexes (ß per decade: 5.67% (4.22/7.13) male, 6.15% (4.72/7.57) female; p<0.001). Sex-specific reference limits and categories indicating the grade of deviation from the reference were calculated, and nomograms for FVIII:c were created. FVIII:c was approximately 25% higher in individuals with non-O blood type. Adjusted for sex and age, ABO-blood group accounted for 18.3% of FVIII:c variation. In multivariable analysis, FVIII:c was notably positively associated with diabetes mellitus, obesity, hypertension and dyslipidemia and negatively with current smoking. In a fully adjusted multivariable model, the strongest associations observed were of elevated FVIII:c with diabetes and peripheral artery disease in both sexes and with obesity in males. Effects of SNPs in the vWF, STAB2 and SCARA5 gene were stronger in females than in males. The use of nomograms for valuation of FVIII:c might be useful to identify high-risk cohorts for thromboembolism. Additionally, the prospective evaluation of FVIII:c as a risk predictor becomes feasible. Copyright © 2015. Published by Elsevier Ireland Ltd.
    International journal of cardiology 03/2015; 187:166-174. DOI:10.1016/j.ijcard.2015.03.330 · 6.18 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Objective to establish and critically evaluate the 99th percentile upper reference limit (URL) for high-sensitivity cardiac troponin I (hs-cTnI) in a large healthy European cohort using different selection criteria. Methods 1368 presumably healthy individuals from 9 countries were evaluated with surrogate biomarkers for diabetes (glycated hemoglobin [HbA1c] < 48 mmoL/mol), myocardial (B-type natriuretic peptide [BNP] < 35 pg/mL) and renal dysfunction (estimated glomerular filtration rate [eGFR] > 60 mL/min/1.73 m2), and dyslipidemia to refine the healthy cohort. The 99th percentile URLs were independently determined by the non-parametric and robust methods. Results The use of biomarker selection criteria resulted in a decrease of the 99th percentile URL for hs-cTnI from 23.7 to 14.1 ng/L and from 11.2 to 7.1 ng/L, when using the non-parametric percentile and robust methods, respectively; a further reduction after exclusion of individuals with dyslipidemia was noted. Male gender, BNP, HbA1c and smoking status were independently associated with hs-cTnI concentration in the presumably healthy population, while the impact of age, present in the univariate analysis, decreased after adjustments for gender and surrogate biomarkers. The BNP-based inclusion criterion had the most pronounced effect on the 99th percentile URL, excluding 21% of the study participants and decreasing its value to 11.0 (7.1) ng/L according to the non-parametric (robust) method. Gender, but not age-specific, differences at 99th percentile URL have been identified. Conclusion The selection of a reference population has a critical impact on the 99th percentile value for hs-cTnI. A uniform protocol for the selection of the healthy reference population is needed.
    International Journal of Cardiology 03/2015; 187. DOI:10.1016/j.ijcard.2015.03.282 · 6.18 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: This paper describes the study design, methodology, cohort profile and self-reported diseases in the ophthalmological branch of the Gutenberg Health Study (GHS). The GHS is an ongoing, prospective, interdisciplinary, single-center, population-based cohort study in Germany. The main goals of the ophthalmological section are to assess the prevalence and incidence of ocular diseases and to explore risk factors, genetic determinants and associations with systemic diseases and conditions. The eye examination at baseline included a medical history, self-reported eye diseases, visual acuity, refractive errors, intraocular pressure, visual field, pachymetry, keratometry, fundus photography and tear sampling. The 5-year follow-up visit additionally encompassed optical coherence tomography, anterior segment imaging and optical biometry. The general examination included anthropometry; blood pressure measurement; carotid artery ultrasound; electrocardiogram; echocardiography; spirometry; cognitive tests; questionnaires; assessment of mental conditions; and DNA, RNA, blood and urine sampling. Of 15,010 participants (aged 35-74 years at the time of inclusion), ocular data are available for 14,700 subjects (97.9%). The mean visual acuity (standard deviation), mean spherical equivalent, median decimal visual acuity, and mean intraocular pressure were 0.08 (0.17) logMar, -0.42 (2.43) diopters, 0.9 and 14.24 (2.79) mm Hg, respectively. The frequencies of self-reported strabismus, glaucoma, surgery for retinal detachment and retinal vascular occlusions were 2.7%, 2.3%, 0.2% and 0.4%, respectively. The GHS is the most extensive dataset of ophthalmic diseases and conditions and their risk factors in Germany and one of the largest cohorts worldwide. This dataset will provide new insight in the epidemiology of ophthalmic diseases and related medical specialties.
    PLoS ONE 03/2015; 10(3):e0120476. DOI:10.1371/journal.pone.0120476 · 3.53 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Primary open-angle glaucoma is the most common optic neuropathy and an important cause of irreversible blindness worldwide. The optic nerve head or optic disc is divided in two parts: a central cup (without nerve fibers) surrounded by the neuroretinal rim (containing axons of the retinal ganglion cells). The International Glaucoma Genetics Consortium conducted a meta-analysis of genome-wide association studies consisting of 17,248 individuals of European ancestry and 6,841 individuals of Asian ancestry. The outcomes of the genome-wide association studies were disc area and cup area. These specific measurements describe optic nerve morphology in another way than the vertical cup-disc ratio, which is a clinically used measurement, and may shed light on new glaucoma mechanisms. We identified 10 new loci associated with disc area (CDC42BPA, F5, DIRC3, RARB, ABI3BP, DCAF4L2, ELP4, TMTC2, NR2F2, and HORMAD2) and another 10 new loci associated with cup area (DHRS3, TRIB2, EFEMP1, FLNB, FAM101, DDHD1, ASB7, KPNB1, BCAS3, and TRIOBP). The new genes participate in a number of pathways and future work is likely to identify more functions related to the pathogenesis of glaucoma. © 2015 WILEY PERIODICALS, INC.
    Genetic Epidemiology 01/2015; 39(3). DOI:10.1002/gepi.21886 · 2.95 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The antiphospholipid syndrome (APS) is an autoimmune disease characterised by thromboembolic events and/or pregnancy morbidity in the presence of antiphospholipid antibodies (aPL). Here we show that three cofactor independent human monoclonal aPL can induce transcription of NLRP3 and caspase-1 resulting in inflammasome activation specific for NLRP3. This depends fully on activation of endosomal NADPH-oxidase-2 (NOX2) by aPL. Activation of NOX2 and subsequent inflammasome activation by aPL are independent from TLR2 or TLR4. While endosomal superoxide production induces caspase-1 and NLRP3 transcription, it does not affect prae-IL-1β transcription. Therefore, release of IL-1β occurs only after activation of additional pathways like TLR7/8 or TLR2. All effects exerted by the monoclonal aPL can be reproduced with IgG fractions of APS patients proving that the monoclonal aPL are representative for the APS. IgG fractions of healthy controls or patients suffering from systemic lupus erythematosus have no effect. In a mouse model of the APS we can show inflammasome activation in vivo. Furthermore, mononuclear cells isolated from patients with the APS show an increased expression of caspase-1 and NLRP3 which is accompanied by a three-fold increased serum concentration of IL-1β suggesting chronic inflammasome activation in APS patients. In summary, we provide further evidence that endosomal NOX2 can be activated by cofactor independent aPL. This leads to induction of the NLRP3 inflammasome. Our data indicate that cofactor independent aPL might contribute significantly to the pathogenesis of the APS.
    Thrombosis and Haemostasis 01/2015; 113(4). DOI:10.1160/TH14-07-0628 · 5.76 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Context: Mutations in the four subunits of succinate dehydrogenase (SDH) are the cause for the hereditary paraganglioma (PGL) syndromes type 1-4 and are associated with multiple and recurrent pheochromocytomas (Pheo) and PGLs. SDHC mutations most frequently result in benign, non-functional head-and neck PGLs (HNPGLs). The malignant potential of SDHC mutations remains unclear to date. Objectives: We report a patient with malignant PGL carrying a SDHC mutation and compare her case with two others of the same genotype but presenting with classic benign HNPGLs. Loss of heterozygosity (LOH) was demonstrated in the malignant PGL tissue. Design: In three unrelated patients referred for routine genetic testing SDHB, SDHC, and SDHD genes were sequenced and gross deletions were excluded by MLPA (MRC Holland). LOH was determined by pyrosequencing-based allele quantification and SDHB immunohistochemistry. Results: In a patient with a non-functioning thoracic PGL metastatic to the bone, the lungs and mediastinal lymph nodes we detected the SDHC mutation c.397C>T predicting a truncated protein due to a premature stop codon (p.Arg133*). We demonstrated LOH and loss of SDHB protein expression in the malignant tumor tissue. The two other patients also carried c.397C>T, p.Arg133*; they differed from each other with respect to their tumor characteristics but both showed benign HNPGLs. Conclusions We describe the first case of a malignant PGL with distant metastases caused by a SDHC germline mutation. The present case shows that SDHC germline mutations can have highly variable phenotypes and may cause malignant PGL even though malignancy is probably rare.
    The Journal of Clinical Endocrinology and Metabolism 12/2014; 99(3):jc20133486. DOI:10.1210/jc.2013-3486 · 6.31 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Abstract Reference limits are estimators for 'extreme' percentiles of the distribution of a quantitative diagnostic marker in the healthy population. In most cases, interest will be in the 90% or 95% reference intervals. The standard parametric method of determining reference limits consists of computing quantities of the form X̅±c·S. The proportion of covered values in the underlying population coincides with the specificity obtained when a measurement value falling outside the corresponding reference region is classified as diagnostically suspect. Nonparametrically, reference limits are estimated by means of so-called order statistics. In both approaches, the precision of the estimate depends on the sample size. We present computational procedures for calculating minimally required numbers of subjects to be enrolled in a reference study. The much more sophisticated concept of reference bands replacing statistical reference intervals in case of age-dependent diagnostic markers is also discussed.
    Clinical Chemistry and Laboratory Medicine 12/2014; 52(12):1685-94. DOI:10.1515/cclm-2014-0226 · 2.96 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Different biological pathways have been related to atrial fibrillation (AF). Novel biomarkers capturing inflammation, oxidative stress, and neurohumoral activation have not been investigated comprehensively in AF.
    PLoS ONE 11/2014; 9(11):e112486. DOI:10.1371/journal.pone.0112486 · 3.53 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: To identify genetic variants associated with refractive astigmatism in the general population, meta-analyses of genome-wide association studies were performed for: White Europeans aged at least 25 years (20 cohorts, N = 31,968); Asian subjects aged at least 25 years (7 cohorts, N = 9,295); White Europeans aged <25 years (4 cohorts, N = 5,640); and all independent individuals from the above three samples combined with a sample of Chinese subjects aged <25 years (N = 45,931). Participants were classified as cases with refractive astigmatism if the average cylinder power in their two eyes was at least 1.00 diopter and as controls otherwise. Genome-wide association analysis was carried out for each cohort separately using logistic regression. Meta-analysis was conducted using a fixed effects model. In the older European group the most strongly associated marker was downstream of the neurexin-1 (NRXN1) gene (rs1401327, P = 3.92E-8). No other region reached genome-wide significance, and association signals were lower for the younger European group and Asian group. In the meta-analysis of all cohorts, no marker reached genome-wide significance: The most strongly associated regions were, NRXN1 (rs1401327, P = 2.93E-07), TOX (rs7823467, P = 3.47E-07) and LINC00340 (rs12212674, P = 1.49E-06). For 34 markers identified in prior GWAS for spherical equivalent refractive error, the beta coefficients for genotype versus spherical equivalent, and genotype versus refractive astigmatism, were highly correlated (r = -0.59, P = 2.10E-04). This work revealed no consistent or strong genetic signals for refractive astigmatism; however, the TOX gene region previously identified in GWAS for spherical equivalent refractive error was the second most strongly associated region. Analysis of additional markers provided evidence supporting widespread genetic co-susceptibility for spherical and astigmatic refractive errors.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Abstract Background: The 99th percentile of cardiac troponin levels, determined in a reference population, is accepted as threshold for diagnosis of acute myocardial infarction (AMI). However, there is no common consensus of how to define the reference population. The aim of the present study was to determine 99th percentile reference values, determined by a high-sensitivity assay (hsTnI), according to different health status and cardiovascular risk factor prevalence in a large population-based sample. Methods: Troponin I was determined using the Abbott ARCHITECT STAT highly sensitive troponin I immunoassay in 4138 participants of the Gutenberg Health Study. Results: hsTnI was detectable in 81.6% of all individuals. The 99th percentile of the overall population was 27 ng/L. Age and gender had a prominent influence on these values. Exclusion of individuals with elevated natriuretic peptide levels or cardiac abnormalities resulted in lower 99th percentile values, whereas exclusion of individuals with an impaired estimated glomerular filtration rate (eGFR) or with prevalent coronary artery disease/myocardial infarction (CAD/MI) did not result in a meaningful change. Conclusions: Troponin I, measured by a high-sensitivity assay, can be reliably detected in the vast majority of the general population. hsTnI values were dependent on age, gender as well as structural and functional cardiac abnormalities.
    Clinical Chemistry and Laboratory Medicine 10/2014; 53(5). DOI:10.1515/cclm-2014-0619 · 2.96 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Objectives: Estimation of the attributable risk for fatal diseases by combining two different data sources. Methods: We derive a method to estimate the attributable risks of different risk factors by combining general mortality risks with up-to-date prevalences of the risk factors using estimates from a risk prediction model and cross-sectional data of a cohort study. Partial attributable risks have been used to illustrate the proportions of the different risk factors for the attributable risk. In addition we derive standard errors for the attributable risk based on the Taylor series expansion. Since the data of our cohort study was sampled with the same size in each 10 years age stratum which does not reflect the age-structure of the general population, the attributable risk and its standard errors are calculated using an approach that allows the weighting of the data according to population proportions of age. The formula for the standard errors has been evaluated using bootstrap-techniques. Results: We successfully implemented the method for the estimation of the attributable risk and its standard errors by integrating risk information using data of the HeartScore Germany and cross-sectional data emerging from the Gutenberg Health Study. The attributable risk can now be calculated without using the information of the overall disease rate. The bootstrap method shows, that the formula for the standard errors is useful. Conclusion: Our method allows for the combination of different data sources in order to estimate attributable risks and our formula for the standard errors seems to yield a good approximation. But the validity of our method highly depends on the validity of the underlying data sources.
    Methods of Information in Medicine 09/2014; 53(5). DOI:10.3414/ME13-01-0088 · 1.08 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: -Dimethylarginines (DMA) interfere with nitric oxide (NO) formation by inhibiting NO synthase (asymmetric dimethylarginine, ADMA) and L-arginine uptake into the cell (ADMA and symmetric dimethylarginine, SDMA). In prospective clinical studies ADMA has been characterized as a cardiovascular risk marker whereas SDMA is a novel marker for renal function and associated with all-cause mortality after ischemic stroke. The aim of the current study was to characterise the environmental and genetic contributions to inter-individual variability of these biomarkers.
    Circulation Cardiovascular Genetics 09/2014; 7(6). DOI:10.1161/CIRCGENETICS.113.000264 · 6.73 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Elevated intraocular pressure (IOP) is an important risk factor in developing glaucoma, and variability in IOP might herald glaucomatous development or progression. We report the results of a genome-wide association study meta-analysis of 18 population cohorts from the International Glaucoma Genetics Consortium (IGGC), comprising 35,296 multi-ancestry participants for IOP. We confirm genetic association of known loci for IOP and primary open-angle glaucoma (POAG) and identify four new IOP-associated loci located on chromosome 3q25.31 within the FNDC3B gene (P = 4.19 × 10(-8) for rs6445055), two on chromosome 9 (P = 2.80 × 10(-11) for rs2472493 near ABCA1 and P = 6.39 × 10(-11) for rs8176693 within ABO) and one on chromosome 11p11.2 (best P = 1.04 × 10(-11) for rs747782). Separate meta-analyses of 4 independent POAG cohorts, totaling 4,284 cases and 95,560 controls, showed that 3 of these loci for IOP were also associated with POAG.
    Nature Genetics 08/2014; DOI:10.1038/ng.3087 · 29.65 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: ObjectivesWhile a bidirectional relationship between diabetes and depression has been established, there is little knowledge if the associations are due to somatic-affective or cognitive-affective dimensions of depression.Research Design and MethodsIn a population-based, representative survey of 15.010 participants we therefore studied the associations of the two dimensions of depression with diabetes and health care utilization among depressed and diabetic participants. Depression was assessed by the Patient Health Questionnaire PHQ-9.ResultsWe found a linear and consistent association between the intensity of depression and the presence of diabetes increasing from 6.9% in no or minimal depression to 7.6% in mild, 9% in moderate and 10.5% in severe depression. There was a strong positive association between somatic-affective symptoms but not with cognitive-affective symptoms and diabetes. Depression and diabetes were both independently related to somatic health care utilisation.ConclusionsDiabetes and depression are associated, and the association is primarily driven by the somatic-affective component of depression. The main limitation of our study pertains to the cross-sectional data acquisition. Further longitudinal work on the relationship of obesity and diabetes should differentiate the somatic and the cognitive symptoms of depression.
    PLoS ONE 08/2014; 9(8):e105499. DOI:10.1371/journal.pone.0105499 · 3.53 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Abstract Background: The utility of HbA1c for the diagnosis of type 2 diabetes requires an accurate, precise and robust test measurement system. Currently, immunoassay and HPLC are the most popular methods for HbA1c quantification, noting however the limitations associated with some platforms, such as imprecision or interference from common hemoglobin variants. Abbott Diagnostics has introduced a fully automated direct enzymatic method for the quantification of HbA1c from whole blood on the ARCHITECT chemistry system. Methods: Here we completed a method evaluation of the ARCHITECT HbA1c enzymatic assay for imprecision, accuracy, method comparison, interference from hemoglobin variants and specimen stability. This was completed at three independent clinical laboratories in North America and Europe. Results: The total imprecision ranged from 0.5% to 2.2% CV with low and high level control materials. Around the diagnostic cut-off of 48 mmol/mol, the total imprecision was 0.6% CV. Mean bias using reference samples from IFCC and CAP ranged from -1.1 to 1.0 mmol/mol. The enzymatic assay also showed excellent agreement with HPLC methods, with slopes of 1.01 and correlation coefficients ranging from 0.984 to 0.996 compared to Menarini Adams HA-8160, Bio-Rad Variant II and Variant II Turbo instruments. Finally, no significant effect was observed for erythrocyte sedimentation or interference from common hemoglobin variants in patient samples containing heterozygous HbS, HbC, HbD, HbE, and up to 10% HbF. Conclusions: The ARCHITECT enzymatic assay for HbA1c is a robust and fully automated method that meets the performance requirements to support the diagnosis of type 2 diabetes.
    Clinical Chemistry and Laboratory Medicine 08/2014; DOI:10.1515/cclm-2014-0310 · 2.96 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background Despite their high prevalence, sleep disorders often remain unrecognized and untreated because of barriers to assessment and management. The aims of the present study were to examine associations of complaints of sleep disturbances with cardiovascular disease, related risk factors, and inflammation in the community and to determine the contribution of sleep disturbances to self-perceived physical health. Method The sample consists of n = 10.000 participants, aged 35 to 74 years of a population based community sample in Germany. Cross-sectional associations of complaints of sleep disturbances with cardiovascular risk factors and disease, biomarkers of inflammation, depression, anxiety, and physical health status were analyzed. Results 19% of our sample endorsed clinically significant sleep disturbances. In the unadjusted analyses severity of sleep disturbances increased with female sex, low socioeconomic status, living without a partnership, cardiovascular disease, depression, anxiety, poor physical health, increased levels of C-reactive protein and fibrinogen. After multivariate adjustment robust associations with coronary heart disease, myocardial infarction and dyslipidemia remained. Complaints of sleep disturbances were strong and independent contributors to self-perceived poor physical health beyond depression, anxiety and medical disease burden. Conclusions Given the high prevalence of complaints of sleep disturbances and their strong impact on health status, increased efforts should be undertaken for their identification and treatment.
    PLoS ONE 08/2014; 9(8):e104324. DOI:10.1371/journal.pone.0104324 · 3.53 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background Adrenomedullin (ADM) is a circulating vasoactive peptide involved in vascular homeostasis and endothelial function. Single nucleotide polymorphisms of the ADM gene are associated with blood pressure variability, and elevated levels of plasma midregional proadrenomedullin (MR-pro-ADM) are associated with cardiovascular diseases. Methods and Results We investigated the sources of variability of ADM gene expression and plasma MR-pro-ADM concentrations in the general population, and their relationship with markers of atherosclerosis. MR-pro-ADM levels were assessed in 4155 individuals who underwent evaluation of carotid intima-media thickness and arterial rigidity (reflection index and stiffness index). In a subsample of 1372 individuals, ADM gene expression was assessed as part of a transcriptomic study of circulating monocytes. Nongenetic factors explained 45.8% and 7.5% of MR-pro-ADM and ADM expression variability, respectively. ADM expression correlated with plasma C-reactive protein, interleukin-receptor 1A, and myeloperoxidase, whereas MR-pro-ADM levels correlated with C-terminal proendothelin-1, creatinine, and N-terminal pro-B-type natriuretic peptide. Genome-wide association study of ADM expression and MR-pro-ADM levels both identified a single locus encompassing the ADM gene. ADM expression was associated with 1 single nucleotide polymorphism rs11042717 (P=2.36x10(-12)), whereas MR-pro-ADM was associated with 2 single nucleotide polymorphisms with additive effects, rs2957692 (P=1.54x10(-13)) and rs2957717 (P=4.24x10(-8)). Reflection index was independently associated with rs11042717 (P<10(-4)) and ADM expression (P=0.0002) but not with MR-pro-ADM. Weaker associations were observed for stiffness index. Intima-media thickness was not related to ADM single nucleotide polymorphisms or expression. Conclusions These results support an involvement of the ADM gene in the modulation of peripheral vascular tone.
    Circulation Cardiovascular Genetics 07/2014; 7(5). DOI:10.1161/CIRCGENETICS.113.000456 · 6.73 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: We report on our patient (case 2) who experienced a first acute episode of thrombotic thrombocytopenic purpura (TTP) at the age of 19 years during her first pregnancy in 1976 which ended in a spontaneous abortion in the 30th gestational week. Treatment with red blood cell concentrates was implemented and splenectomy was performed. After having suffered from several TTP episodes in 1977, possibly mitigated by acetylsalicylic acid therapy, an interruption and sterilization were performed in 1980 in her second pregnancy thereby avoiding another disease flare-up. Her elder sister (case 1) had been diagnosed with TTP in 1974, also during her first pregnancy. She died in 1977 during her second pregnancy from a second acute TTP episode. Diagnosis: In 2013 a severe ADAMTS13 deficiency of <10% without detectable ADAMTS13 inhibitor was repeatedly found. Investigation of the ADAMTS13 gene showed that the severe ADAMTS13 deficiency was caused by compound heterozygous ADAMTS13 mutations: a premature stop codon in exon 2 (p.Q44X), and a missense mutation in exon 24 (p.R1060W) associated with low but measurable ADAMTS13 activity. Conclusion: Genetic analysis of the ADAMTS13 gene is important in TTP patients of all ages if an ADAMTS13 inhibitor has been excluded.
    Hamostaseologie 07/2014; 34(3). DOI:10.5482/HAMO-14-03-0023 · 1.59 Impact Factor

Publication Stats

7k Citations
1,636.20 Total Impact Points

Institutions

  • 2001–2015
    • Johannes Gutenberg-Universität Mainz
      • • III. Department of Medicine
      • • Institut für Klinische Chemie und Laboratoriumsmedizin
      Mayence, Rheinland-Pfalz, Germany
  • 2013
    • Queen Mary, University of London
      • Barts and The London School of Medicine and Dentistry
      Londinium, England, United Kingdom
  • 2011–2013
    • Universitätsmedizin der Johannes Gutenberg-Universität Mainz
      • Institute of Clinical Chemistry and Laboratory Medicine (Central Laboratory)
      Mainz, Rhineland-Palatinate, Germany
  • 2012
    • Goethe-Universität Frankfurt am Main
      • Center for Internal Medicine
      Frankfurt, Hesse, Germany
  • 2005–2012
    • Pierre and Marie Curie University - Paris 6
      Lutetia Parisorum, Île-de-France, France
    • Charité Universitätsmedizin Berlin
      • Institute of Clinical Physiology
      Berlin, Land Berlin, Germany
  • 2009–2011
    • Universitätsklinikum Freiburg
      • Institute of Clinical Chemistry and Laboratory Medicine
      Freiburg an der Elbe, Lower Saxony, Germany
    • Boston University
      Boston, Massachusetts, United States
  • 2008
    • Technische Universität Dresden
      Dresden, Saxony, Germany
  • 2007
    • University of California, San Diego
      San Diego, California, United States
  • 2004–2005
    • State University of New York Downstate Medical Center
      • Department of Cell Biology
      Brooklyn, New York, United States
  • 1997–2003
    • Universität Regensburg
      • • Department of Internal Medicine I
      • • Department of Clinical Chemistry and Laboratory Medicine
      Ratisbon, Bavaria, Germany
  • 1998–2001
    • University Hospital Regensburg
      • Klinik und Poliklinik für Innere Medizin I
      Ratisbon, Bavaria, Germany
  • 1999
    • Friedrich-Alexander Universität Erlangen-Nürnberg
      • Department of Ophthalmology
      Erlangen, Bavaria, Germany
  • 1994
    • Deutsche Vereinte Gesellschaft für Klinische Chemie und Laboratoriumsmedizin e.V.
      Ratisbon, Bavaria, Germany
  • 1993
    • National Food and Nutrition Institute
      Warszawa, Masovian Voivodeship, Poland