Research Unit of Molecular Epidemiology

German, Germany

Research Unit of Molecular Epidemiology

German, Germany

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Li J.,Children's Hospital of Philadelphia | Jorgensen S.F.,University of Oslo | Maggadottir S.M.,Children's Hospital of Philadelphia | Bakay M.,Children's Hospital of Philadelphia | And 43 more authors.
Nature Communications | Year: 2015

Common variable immunodeficiency disorder (CVID) is the most common symptomatic primary immunodeficiency in adults, characterized by B-cell abnormalities and inadequate antibody response. CVID patients have considerable autoimmune comorbidity and we therefore hypothesized that genetic susceptibility to CVID may overlap with autoimmune disorders. Here, in the largest genetic study performed in CVID to date, we compare 778 CVID cases with 10,999 controls across 123,127 single-nucleotide polymorphisms (SNPs) on the Immunochip. We identify the first non-HLA genome-wide significant risk locus at CLEC16A (rs17806056, P=2.0 × 10-9) and confirm the previously reported human leukocyte antigen (HLA) associations on chromosome 6p21 (rs1049225, P=4.8 × 10-16). Clec16a knockdown (KD) mice showed reduced number of B cells and elevated IgM levels compared with controls, suggesting that CLEC16A may be involved in immune regulatory pathways of relevance to CVID. In conclusion, the CLEC16A associations in CVID represent the first robust evidence of non-HLA associations in this immunodeficiency condition. © 2015 Macmillan Publishers Limited. All rights reserved.


Gaye A.,University of Bristol | Marcon Y.,McGill University | Isaeva J.,Norwegian Institute of Public Health | Laflamme P.,McGill University | And 51 more authors.
International Journal of Epidemiology | Year: 2014

Background: Research in modern biomedicine and social science requires sample sizes so large that they can often only be achieved through a pooled co-analysis of data from several studies. But the pooling of information from individuals in a central database that may be queried by researchers raises important ethico-legal questions and can be controversial. In the UK this has been highlighted by recent debate and controversy relating to the UK's proposed 'care.data' initiative, and these issues reflect important societal and professional concerns about privacy, confidentiality and intellectual property. DataSHIELD provides a novel technological solution that can circumvent some of the most basic challenges in facilitating the access of researchers and other healthcare professionals to individual-level data. Methods: Commands are sent from a central analysis computer (AC) to several data computers (DCs) storing the data to be co-analysed. The data sets are analysed simultaneously but in parallel. The separate parallelized analyses are linked by non-disclosive summary statistics and commands transmitted back and forth between the DCs and the AC. This paper describes the technical implementation of DataSHIELD using a modified R statistical environment linked to an Opal database deployed behind the computer firewall of each DC. Analysis is controlled through a standard R environment at the AC. Results: Based on this Opal/R implementation, DataSHIELD is currently used by the Healthy Obese Project and the Environmental Core Project (BioSHaRE-EU) for the federated analysis of 10 data sets across eight European countries, and this illustrates the opportunities and challenges presented by the DataSHIELD approach. Conclusions: DataSHIELD facilitates important research in settings where: (i) a co-analysis of individual-level data from several studies is scientifically necessary but governance restrictions prohibit the release or sharing of some of the required data, and/or render data access unacceptably slow; (ii) a research group (e.g. in a developing nation) is particularly vulnerable to loss of intellectual property-the researchers want to fully share the information held in their data with national and international collaborators, but do not wish to hand over the physical data themselves; and (iii) a data set is to be included in an individual-level co-analysis but the physical size of the data precludes direct transfer to a new site for analysis. © The Author 2014; all rights reserved.


Baurecht H.,University of Kiel | Hotze M.,University of Kiel | Brand S.,Ludwig Maximilians University of Munich | Buning C.,Hepatology and Endocrinology Charite | And 44 more authors.
American Journal of Human Genetics | Year: 2015

Atopic dermatitis and psoriasis are the two most common immune-mediated inflammatory disorders affecting the skin. Genome-wide studies demonstrate a high degree of genetic overlap, but these diseases have mutually exclusive clinical phenotypes and opposing immune mechanisms. Despite their prevalence, atopic dermatitis and psoriasis very rarely co-occur within one individual. By utilizing genome-wide association study and ImmunoChip data from >19,000 individuals and methodologies developed from meta-analysis, we have identified opposing risk alleles at shared loci as well as independent disease-specific loci within the epidermal differentiation complex (chromosome 1q21.3), the Th2 locus control region (chromosome 5q31.1), and the major histocompatibility complex (chromosome 6p21-22). We further identified previously unreported pleiotropic alleles with opposing effects on atopic dermatitis and psoriasis risk in PRKRA and ANXA6/TNIP1. In contrast, there was no evidence for shared loci with effects operating in the same direction on both diseases. Our results show that atopic dermatitis and psoriasis have distinct genetic mechanisms with opposing effects in shared pathways influencing epidermal differentiation and immune response. The statistical analysis methods developed in the conduct of this study have produced additional insight from previously published data sets. The approach is likely to be applicable to the investigation of the genetic basis of other complex traits with overlapping and distinct clinical features. © 2015 The Authors.


Petersen A.-K.,Institute of Genetic Epidemiology | Zeilinger S.,Research Unit of Molecular Epidemiology | Kastenmuller G.,Institute of Bioinformatics and Systems Biology | Werner R.-M.,Institute of Bioinformatics and Systems Biology | And 20 more authors.
Human Molecular Genetics | Year: 2014

Previously,we reported strong influences of genetic variants on metabolic phenotypes, some of them with clinical relevance. Here, we hypothesize that DNA methylation may have an important and potentially independent effect on human metabolism. Totest this hypothesis,we conducted what is to the best of our knowledge the first epigenome-wide association study (EWAS) between DNA methylation and metabolic traits (metabotypes) in human blood. We assess 649 blood metabolic traits from 1814 participants of the Kooperative Gesundheitsforschung in der Region Augsburg (KORA) population study for association with methylation of 457 004 CpG sites, determined on the Infinium Human Methylation 450 Bead Chip platform. Using the EWAS approach, we identified two types of methylome-metabotype associations. One type is driven by an underlying genetic effect; the other type is independent of genetic variation and potentially driven by common environmental and life-style-dependent factors. We report eight CpG loci atgenome-wide significance that have a genetic variant as confounder (P = 3.9 × 10-20 to 2.0 × 10-108, r2 = 0.036 to 0.221).Seven loci display CpG site-specific associations to metabotypes ,but do not exhibit any underlying genetic signals (P = 9.2 × 10-14 to 2.7 × 10-27, r2 = 0.008 to 0.107). We further identify several groups of CpG loci that associate with a same metabotype, such as 4-vinylphenol sulfate and 4-androsten-3-beta,17-beta-diol disulfate. In these cases, the association between CpG-methylation and metabotype is likely the result of a common external environmental factor, including smoking. Our study shows that analysis of EWAS with large numbers of metabolic traits in large population cohorts are, in principle, feasible. Taken together, our data suggest that DNA methylation plays an important role in regulating human metabolism. © The Author 2013. Published by Oxford University Press.


Then C.,Ludwig Maximilians University of Munich | Kowall B.,Heinrich Heine University Düsseldorf | Lechner A.,Ludwig Maximilians University of Munich | Meisinger C.,Helmholtz Center for Environmental Research | And 6 more authors.
Acta Diabetologica | Year: 2015

Elevated plasma CT-pro-vasopressin (copeptin) has been described as biomarkers for type 2 diabetes (T2D) and the metabolic syndrome (MetS), which, however, was not confirmed by all studies. Here, we analyzed the association of copeptin with T2D, MetS and MetS components in the population-based KORA F4 study. Plasma copeptin concentrations were analyzed in 1,554 study participants. We used fractional polynomial selection procedures to check for nonlinearity of the associations between copeptin and T2D and HbA1c, respectively. In logistic regression models, we investigated associations between copeptin and T2D, MetS and its components according to IDF criteria. In the fractional polynomial approach, linear models fitted best for copeptin. In multivariable adjusted models, copeptin as a continuous variable was associated with T2D and HbA1c only in men (OR = 1.38 per standard deviation, 95 % CI 1.13–1.70 for T2D). Comparing the top quartile Q4 versus Q1–3, elevated copeptin was associated with T2D (OR 2.70, 95 % CI 1.60–4.59) in men but not in women (OR 0.98, 95 % CI 0.52–1.83). Copeptin was not significantly associated with MetS, central obesity, triglycerides and reduced HDL cholesterol. A significant association with copeptin was observed for hypertension in women (OR 1.59, 95 % CI 1.08–2.33) and glucose dysfunction according to IDF criteria in men (OR 1.63, 95 % CI 1.14–2.34). In the KORA F4 study, copeptin was significantly associated with T2D only in men, whereas hypertension was associated with copeptin in women. No other components of the MetS were related to elevated copeptin. © 2014, Springer-Verlag Italia.


Then C.,Ludwig Maximilians University of Munich | Rottenkolber M.,Ludwig Maximilians University of Munich | Lechner A.,Ludwig Maximilians University of Munich | Meisinger C.,Helmholtz Center for Environmental Research | And 10 more authors.
Atherosclerosis | Year: 2016

Background and aims The exact mechanism of premature atherosclerosis in diabetes is still unclear. Inappropriate activation of the renin-aldosterone-angiotensin system may be an important risk factor for cardiovascular disease. We investigated whether renin and aldosterone are associated with vasoactive peptides midregional-pro atrial natriuretic peptide (MR-proANP) and midregional-pro adrenomedullin (MR-proADM), or with intima media thickness (IMT) as a marker for early atherosclerotic alterations in the general community and in subjects with type 2 diabetes. Methods In 1261 participants in the KORA F4 study, the associations of renin, aldosterone and aldosterone to renin ratio with MR-proANP, MR-proADM and IMT were assessed using linear regression models stratified for the presence of prediabetes and type 2 diabetes. Results After adjustment for confounding factors, an inverse association of MR-proANP with renin (p = 0.002) and aldosterone (p = 0.021) and a direct association of MR-proADM with renin (p < 0.001) and aldosterone (p = 0.019) were seen in nondiabetic individuals. In diabetic subjects, there was no significant correlation of MR-proANP or MR-proADM with renin or aldosterone. Renin and aldosterone were not directly associated with IMT in non-diabetic subjects and the total cohort, whereas aldosterone was associated with IMT in diabetic participants (p = 0.005). Conclusions This study shows associations between renin, aldosterone and MR-proANP/MR-proADM plasma levels that are altered in type 2 diabetes. Plasma renin and aldosterone are not independent biomarkers for early atherosclerotic damages of the carotid arteries in the general community. © 2016 Elsevier Ireland Ltd


Then C.,Ludwig Maximilians University of Munich | Kowall B.,Heinrich Heine University Düsseldorf | Lechner A.,Ludwig Maximilians University of Munich | Meisinger C.,Helmholtz Center for Environmental Research | And 7 more authors.
Atherosclerosis | Year: 2013

Objective: Subjects with metabolic syndrome (MetS) and individuals with type 2 diabetes are at high risk for vascular complications. Hormones acting on vascular endothelium may be involved in the atherogenic process associated with metabolic disorders. The objective of this study was to determine the correlation of pro-atrial natriuretic hormone (proANP) with the presence of subclinical atherosclerosis. Methods: In 1272 subjects participating in the KORA F4 study, we determined plasma levels of mid-regional proANP (MR-proANP) and the intima-media thickness (IMT) of the carotid artery. We used logistic regression models to investigate the relation of MR-proANP with components of MetS and IMT. Results: In multiple adjusted regression models, MR-proANP levels were inversely associated with MetS (OR=0.66, 95% CI 0.47-0.93), central obesity (OR=0.67, 95% CI 0.46-0.96), raised triglyceride levels (OR=0.53, 95% CI 0.37-0.77), prediabetes (OR=0.62, 95%, CI 0.44-0.87) and type 2 diabetes (OR=0.55, 95% CI 0.35-0.88) when comparing the top quartile vs. the lower three quartiles. Furthermore, there was an inverse relationship between MR-proANP and IMT. After adjustment for traditional cardiovascular risk markers, individuals with high MR-proANP plasma levels in the top quartile (Q4) had significantly lower IMT values (Q4 vs. Q1-Q3: β-0.0178, 95% CI-0.0344;-0.0013). Conclusions: In this population-based study, high plasma concentrations of MR-proANP were significantly associated with a lower incidence of MetS components and lower measures of early atherosclerosis. The data suggest a link between MR-proANP levels and the development of vascular complications. © 2013 Elsevier Ireland Ltd.


Then C.,Ludwig Maximilians University of Munich | Kowall B.,Heinrich Heine University Düsseldorf | Lechner A.,Ludwig Maximilians University of Munich | Meisinger C.,Helmholtz Center for Environmental Research | And 7 more authors.
Cardiovascular Diabetology | Year: 2013

Background: Elevated plasma preprovasopressin (copeptin) levels are associated with cardiovascular complications as well as with an increased risk for type 2 diabetes (T2D). Here, we studied, whether plasma copeptin is related to carotid intima-media thickness (IMT), a measure of early atherosclerosis, and may thus be one explanation for the high cardiovascular risk in T2D.Methods: Plasma concentrations of copeptin and IMT of the common carotid artery were determined in 1275 participants of the population-based KORA F4 study. We used linear regression models to investigate associations between copeptin levels and IMT.Results: In the whole study group, copeptin levels were not significantly associated with IMT after adjustment for age and sex. Copeptin and IMT were significantly inversely associated after multivariable adjustment in the total cohort (β = -0.020 mm, 95% CI: -0.037 mm; -0.003 mm), in men (β = -0.035 mm, 95% CI: -0.061 mm; -0.009 mm) and in study participants with prediabetes (β = -0.041 mm, 95% CI: -0.078 mm; -0.005 mm) comparing quartile 4 vs quartile 1. The negative association of copeptin and IMT in men was present after adjustment for age alone. In women and patients with T2D, copeptin was not significantly associated with IMT.Conclusions: Plasma copeptin was not associated with an increased IMT in our study cohort. In contrast, copeptin levels were related to a lower IMT in men and subjects with prediabetes, suggesting that elevated copeptin concentrations do not exert proatherogenic effects on carotid arteries. © 2013 Then et al.; licensee BioMed Central Ltd.


Then C.,Ludwig Maximilians University of Munich | Wahl S.,Research Unit of Molecular Epidemiology | Kirchhofer A.,Ludwig Maximilians University of Munich | Grallert H.,Ludwig Maximilians University of Munich | And 25 more authors.
PLoS ONE | Year: 2013

Aims/Hypothesis:Polymorphisms in the transcription factor 7-like 2 (TCF7L2) gene have been shown to display a powerful association with type 2 diabetes. The aim of the present study was to evaluate metabolic alterations in carriers of a common TCF7L2 risk variant.Methods:Seventeen non-diabetic subjects carrying the T risk allele at the rs7903146 TCF7L2 locus and 24 subjects carrying no risk allele were submitted to intravenous glucose tolerance test and euglycemic-hyperinsulinemic clamp. Plasma samples were analysed for concentrations of 163 metabolites through targeted mass spectrometry.Results:TCF7L2 risk allele carriers had a reduced first-phase insulin response and normal insulin sensitivity. Under fasting conditions, carriers of TCF7L2 rs7903146 exhibited a non-significant increase of plasma sphingomyelins (SMs), phosphatidylcholines (PCs) and lysophosphatidylcholines (lysoPCs) species. A significant genotype effect was detected in response to challenge tests in 6 SMs (C16:0, C16:1, C18:0, C18:1, C24:0, C24:1), 5 hydroxy-SMs (C14:1, C16:1, C22:1, C22:2, C24:1), 4 lysoPCs (C14:0, C16:0, C16:1, C17:0), 3 diacyl-PCs (C28:1, C36:6, C40:4) and 4 long-chain acyl-alkyl-PCs (C40:2, C40:5, C44:5, C44:6).Discussion:Plasma metabolomic profiling identified alterations of phospholipid metabolism in response to challenge tests in subjects with TCF7L2 rs7903146 genotype. This may reflect a genotype-mediated link to early metabolic abnormalities prior to the development of disturbed glucose tolerance. © 2013 Then et al.

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