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Dive into the research topics where Karoline I. Gaede is active.

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Featured researches published by Karoline I. Gaede.


Nature Genetics | 2005

Sarcoidosis is associated with a truncating splice site mutation in BTNL2.

Ruta Valentonyte; Jochen Hampe; Klaus Huse; Philip Rosenstiel; Mario Albrecht; Annette Stenzel; Marion Nagy; Karoline I. Gaede; Andre Franke; Robert Haesler; Andreas Koch; Thomas Lengauer; Dirk Seegert; Norbert Reiling; Stefan Ehlers; Eberhard Schwinger; Matthias Platzer; Michael Krawczak; Joachim Müller-Quernheim; Manfred Schürmann; Stefan Schreiber

Sarcoidosis is a polygenic immune disorder with predominant manifestation in the lung. Genome-wide linkage analysis previously indicated that the extended major histocompatibility locus on chromosome 6p was linked to susceptibility to sarcoidosis. Here, we carried out a systematic three-stage SNP scan of 16.4 Mb on chromosome 6p21 in as many as 947 independent cases of familial and sporadic sarcoidosis and found that a 15-kb segment of the gene butyrophilin-like 2 (BTNL2) was associated with the disease. The primary disease-associated variant (rs2076530; PTDT = 3 × 10−6, Pcase-control = 1.1 × 10−8; replication PTDT = 0.0018, Pcase-control = 1.8 × 10−6) represents a risk factor that is independent of variation in HLA-DRB1. BTNL2 is a member of the immunoglobulin superfamily and has been implicated as a costimulatory molecule involved in T-cell activation on the basis of its homology to B7-1. The G → A transition constituting rs2076530 leads to the use of a cryptic splice site located 4 bp upstream of the affected wild-type donor site. Transcripts of the risk-associated allele have a premature stop in the spliced mRNA. The resulting protein lacks the C-terminal IgC domain and transmembrane helix, thereby disrupting the membrane localization of the protein, as shown in experiments using green fluorescent protein and V5 fusion proteins.


Clinics in Chest Medicine | 2008

Genetics of Sarcoidosis

Joachim Müller-Quernheim; Manfred Schürmann; Sylvia Hofmann; Karoline I. Gaede; Annegret Fischer; Antje Prasse; Gernot Zissel; Stefan Schreiber

Sarcoidosis is a multigenic and multifactorial disease. Predisposing genes have been identified and fast progress in molecular technologies including systematic genome-wide association studies and large-scale resequencing will aid the discovery of further risk loci and variants. The exploration of the molecular epidemiology of genetic variants in the pathogenesis of sarcoidosis will allow an assessment of their prognostic usefulness. To this end, different granulomatous disorders of known and unknown etiology should be investigated jointly by genetic, immunobiological, and proteomic approaches. The definition of individual genetic risk profiles in sarcoidosis and other chronic inflammatory disorders seems achievable and a useful route for clinical translation.


European Respiratory Journal | 2006

Diagnoses of chronic beryllium disease within cohorts of sarcoidosis patients

Joachim Müller-Quernheim; Karoline I. Gaede; E. Fireman; Gernot Zissel

An increase in chronic beryllium disease (CBD) has been suggested due to higher industrial use of beryllium alloys. Since occupational CBD is a perfect phenocopy of sarcoidosis, it might be misdiagnosed as sarcoidosis. In the current it was hypothesised that CBD exists in cohorts of sarcoidosis patients. In a prospective case study, sarcoidosis patients were evaluated for potential beryllium exposure. In those patients in whom beryllium exposure was confirmed and beryllium hypersensitivity demonstrated, the diagnosis of sarcoidosis was rejected and corrected to CBD. In 84 patients seen for re-evaluation or making a diagnosis of sarcoidosis, beryllium exposure was recognised and a diagnosis of CBD was made in 34 out of 84 patients. The time lag between clinical diagnosis of sarcoidosis and the final diagnosis of CBD ranged 0–18 yrs (median 3 yrs) and the mean (range) age at time of diagnosis of CBD was 43.9(25–80) yrs. Beryllium-contaminated workplaces causing disease encompassed a wide spectrum of industries and technical trades in which beryllium-exposure is generally not perceived as a health hazard. In conclusion, chronic beryllium disease still belongs to the spectrum of differential diagnoses of granulomatous disorders.


Journal of Molecular Medicine | 2001

Gene polymorphisms of immunoregulatory cytokines and angiotensin-converting enzyme in Wegener's granulomatosis

Gabriella Murakozy; Karoline I. Gaede; Bertram Ruprecht; Oliver Gutzeit; Manfred Schürmann; Armin Schnabel; Max Schlaak; Wolfgang L. Gross; Joachim Müller-Quernheim

Wegeners granulomatosis is a granulomatous and vasculitic disease of unknown origin. Gene polymorphisms are known to affect phenotypes of numerous diseases. Polymorphisms within the angiotensin-converting enzyme (ACE), transforming growth factor-β1 (TGF-β1), and interleukin-10 (IL-10) genes are suspected to modify the course of granulomatous disorders. We examined whether the genotype frequencies of the named polymorphisms differ in Wegeners granulomatosis from those in healthy controls. Thirty-nine patients with Wegeners granulomatosis were genotyped for the deletion/insertion polymorphism in intron 16 of the ACE gene, a biallelic polymorphism in codon 25 of the TGF-β1 gene and a biallelic polymorphism at position –1082 of the IL-10 gene and compared with healthy blood donors. For the ACE polymorphism no significant differences were detected neither in the allele frequencies nor in the genotype frequencies. For TGF-β1 a trend to genotype CG was found. The most interesting result was the observed, significant shift to genotype AA of the IL-10 polymorphism in Wegeners granulomatosis. IL-10 and TGF-β1, immunoregulatory cytokines capable of down-regulating T helper cell type 1 response, showed a significant shift or a trend, respectively towards genotypes associated with reduced cytokine release, leading to the hypothesis that different immunoregulatory cytokine patterns dependent on gene polymorphisms might be involved in the pathogenesis of Wegeners granulomatosis.


Clinical Immunology | 2003

Different gender-associated genotype risks of Wegener's granulomatosis and microscopic polyangiitis

Zoltán Bártfai; Karoline I. Gaede; Kimberly A. Russell; Gabriella Murakozy; Joachim Müller-Quernheim; Ulrich Specks

Wegeners granulomatosis (WG) and microscopic polyangiitis (MPA) are systemic small vessel vasculitides associated with ANCA (AAV). Predominant Th1 and Th2 cytokine patterns have been reported for WG and MPA, respectively. Consequently, genotypes suppressing Th1 responses or augmenting Th2 responses may be more frequent in MPA than in WG. Transforming growth beta1 (TGF-beta1) and interleukin-10 (IL-10) genes may modify the course of vasculitis. Therefore, we investigated associations between genotype frequencies of functional polymorphisms of these cytokine genes and clinical manifestations in AAV. One hundred sixty-one AAV patients and 153 healthy blood donors were genotyped for the biallelic polymorphism in codon 25 of the TGF-beta1 gene and the biallelic polymorphism at position -1082 of the IL-10 gene. No difference was found for TGF-beta1 codon 25 polymorphism between control and patient groups. In contrast, a significant shift toward the homozygous AA genotype of the IL-10 (-1082) polymorphism was found in WG (25%, p<0.005) and MPA patients (39%; p<0.00001) compared to controls (10.5%). Furthermore, in MPA the AA homozygous genotype was significantly more frequent in females (62.5%) compared to males (20%, p<0.05). A contribution of the TGF-beta1 codon 25 polymorphism to the susceptibility-defining genetic backgrounds of AAV appears unlikely. In contrast, our findings suggest a role of the enhanced IL-10 (-1082) PM in WG and MPA with a significant gender difference in MPA.


Respiration | 2003

Systemic Immune Cell Activation in a Subgroup of Patients with Idiopathic Pulmonary Fibrosis

Jiri Homolka; Manfred W. Ziegenhagen; Karoline I. Gaede; Peter Entzian; Gernot Zissel; Joachim Müller-Quernheim

Background: The prognosis of idiopathic pulmonary fibrosis (IPF/UIP) is poor and its immunopathogenesis is insufficiently understood. Objectives: The aim of our study was to elucidate the compartmentalization of cell activation and the influence of corticosteroid therapy upon this activation in IPF/UIP. We determined the concentrations of proinflammatory cytokines released by bronchoalveolar lavage (BAL) cells and peripheral blood mononuclear cells (PBMNC) in treated and untreated patients with IPF/UIP. We chose tumor necrosis factor-α (TNFα) since it is a cytokine predominantly secreted by cells of the monocyte/macrophage lineage and interleukin-2 (IL-2) exclusively by T lymphocytes. Methods: The release of TNFα and IL-2 by BAL cells and PBMNC was measured in cell culture supernatants of 72 treated and untreated IPF/UIP patients. Additionally, in the blood compartment serological parameters reflecting the monocyte/macrophage and lymphocyte activation, such as neopterin and soluble IL-2 receptor (sIL-2R), were determined. Results: The TNFα release by BAL cells was significantly elevated in both groups compared to controls but did not differ between treated and untreated patients with IPF/UIP. In 7 of 19 untreated patients with IPF, PBMNC were activated and released increased amounts of TNFα. In only 1 of 17 treated patients with IPF, TNFα release by PBMNC could be found. The serum level of neopterin, a marker of cell activation of the monocyte/macrophage lineage did not differ between treated and untreated patients. The BAL lymphocyte and PBMNC IL-2 release was significantly elevated in IPF/UIP patients without therapy compared to controls (p < 0.05). In contrast, no IL-2 release of BAL cells or PBMNC was observed in treated IPF/UIP patients. Lymphocyte activation was furthermore identified in untreated IPF patients by elevated soluble IL-2 receptor serum concentrations (p < 0.0001). Conclusions: Cells of the monocyte/macrophage lineage and T lymphocytes are activated in BAL cells and PBMNC of patients with IPF/UIP. During treatment, the systemic and local activation of T cells is suppressed. BAL macrophages, however, maintain their activated status, which might be the cause for the frequent chronic progression of the disease.


American Journal of Respiratory and Critical Care Medicine | 2012

A Novel Sarcoidosis Risk Locus for Europeans on Chromosome 11q13.1

Annegret Fischer; Benjamin Schmid; David Ellinghaus; Michael Nothnagel; Karoline I. Gaede; Manfred Schürmann; Simone Lipinski; Philip Rosenstiel; Gernot Zissel; Kerstin Höhne; Martin Petrek; Vitezslav Kolek; Stefan Pabst; Christian Grohé; Johan Grunewald; Marcus Ronninger; Anders Eklund; Leonid Padyukov; Christian Gieger; H.-Erich Wichmann; Almut Nebel; Andre Franke; Joachim Müller-Quernheim; Sylvia Hofmann; Stefan Schreiber

RATIONALE Sarcoidosis is a complex inflammatory disease with a heterogeneous clinical picture. Among others, an acute and chronic clinical course can be distinguished, for which specific genetic risk factors are known. OBJECTIVES To identify additional risk loci for sarcoidosis and its acute and chronic subforms, we analyzed imputed data from a genome-wide association scan for these phenotypes. METHODS After quality control, the genome-wide association scan comprised nearly 1.3 million imputed single-nucleotide polymorphisms based on an Affymetrix 6.0 Gene Chip dataset of 564 German sarcoidosis cases, including 176 acute and 354 chronic cases and 1,575 control subjects. MEASUREMENTS AND MAIN RESULTS We identified chromosome 11q13.1 (rs479777) as a novel locus influencing susceptibility to sarcoidosis with genome-wide significance. The marker was significantly associated in three distinct German case-control populations and in an additional German family sample with odds ratios ranging from 0.67 to 0.77. This finding was further replicated in two independent European case-control populations from the Czech Republic (odds ratio, 0.75) and from Sweden (odds ratio, 0.79). In a meta-analysis of the included European case-control samples the marker yielded a P value of 2.68 × 10(-18). The locus was previously reported to be associated with Crohn disease, psoriasis, alopecia areata, and leprosy. For sarcoidosis, fine-mapping and expression analysis suggest KCNK4, PRDX5, PCLB3, and most promising CCDC88B as candidates for the underlying risk gene in the associated region. CONCLUSIONS This study provides striking evidence for association of chromosome 11q13.1 with sarcoidosis in Europeans, and thus identified a further genetic risk locus shared by sarcoidosis, Crohn disease and psoriasis.


European Respiratory Journal | 2011

Association of inflammatory bowel disease risk loci with sarcoidosis, and its acute and chronic subphenotypes

Annegret Fischer; Michael Nothnagel; Andre Franke; Gunnar Jacobs; Hamid Reza Saadati; Karoline I. Gaede; Philip Rosenstiel; Manfred Schürmann; Joachim Müller-Quernheim; Stefan Schreiber; Sylvia Hofmann

Sarcoidosis is a complex granulomatous inflammatory disorder that shares several clinical and pathogenic features with inflammatory bowel disease (IBD). Postulating a common genetic basis of inflammatory diseases, we tested 106 single-nucleotide polymorphisms (SNPs) that are known or have been suggested to be associated with IBD for a potential association with sarcoidosis and its acute and chronic subphenotypes. We genotyped 1,996 German sarcoidosis patients, comprising 648 acutely and 1,161 chronically affected individuals, 2,622 control subjects, and 342 German trios with affected offspring using SNPlex™ technology. The nonsynonymous SNP rs11209026 (Arg381Gln) in the interleukin (IL)-23 receptor (IL23R) gene was associated with chronic sarcoidosis (OR 0.63; p = 5.58×10−5), which was supported by the result of a transmission disequilibrium test analysis in the independent family sample (OR 0.50; p = 0.031). Marker rs12035082 located at chromosome 1q24.3 was found to be associated with the acute subphenotype (OR 1.36; p = 6.80×10−7) and rs916977 (HERC2 locus; OR 1.30; p = 4.49×10−5) was associated with sarcoidosis. Our results highlight the potential importance of the IL-23 signalling pathway for the development of chronic sarcoidosis. The finding links sarcoidosis pathogenesis to other inflammatory conditions and may contribute to new hypotheses on disease mechanisms.


European Respiratory Journal | 2013

Genome-wide association analysis reveals 12q13.3–q14.1 as new risk locus for sarcoidosis

Sylvia Hofmann; Annegret Fischer; Michael Nothnagel; Gunnar Jacobs; Benjamin Schmid; Michael Wittig; Andre Franke; Karoline I. Gaede; Manfred Schürmann; Martin Petrek; Frantisek Mrazek; Stefan Pabst; Christian Grohé; Johan Grunewald; Marcus Ronninger; Anders Eklund; Philip Rosenstiel; Kerstin Höhne; Gernot Zissel; Joachim Müller-Quernheim; Stefan Schreiber

Sarcoidosis is a systemic inflammatory disease of unknown aetiology, influenced by genetic and environmental factors. However, the loci so far identified for sarcoidosis explain only a part of its assumed heritability. To identify further susceptibility loci, we performed a genome-wide association analysis using the Affymetrix 6.0 Human GeneChip followed by validation and replication stages. After quality control, 637 cases, 1233 controls and 677 619 single-nucleotide polymorphisms (SNPs) were available for an initial screening. 99 SNPs were selected for validation in an independent study panel (1664 patients, 2932 controls). SNP rs1050045 was significantly associated with sarcoidosis (corrected p=0.0215) in the validation panel and yielded a p-value of 9.22×10−8 (OR 1.24) in the meta-analysis of the screening and validation stage. A meta-analysis of three populations from Germany, the Czech Republic and Sweden confirmed this finding (p=0.024; OR 1.14). Fine-mapping and mRNA expression studies pointed to osteosarcoma amplified 9 (OS9) as the most likely candidate for the underlying risk factor. The OS9 protein plays an important role in endoplasmic reticulum-associated protein degradation and acts during Toll-like receptor induced activation of myeloid cells. Expression analyses of OS9 mRNA provide evidence for a functional mechanism underlying the detected association signal.


Journal of Molecular Medicine | 2005

Function associated transforming growth factor-β gene polymorphism in chronic beryllium disease

Karoline I. Gaede; Massimo Amicosante; Manfred Schürmann; Elisabeth Fireman; Cesare Saltini; Joachim Müller-Quernheim

Chronic beryllium disease (CBD) is a rare occupational, granulomatous lung disease clinically resembling sarcoidosis. The immune response to beryllium is thought to depend on genetic susceptibility. Although a glutamic acid in position 69 of the human leukocyte antigen-DP β chain (HLA-DPB1-Glu69) is associated with the development of CBD, it cannot fully explain susceptibility. It is likely that additionally other genes are involved in regulating the immune and inflammatory response in the pathogenesis of this disease. Functional gene polymorphisms (PMs) of the tumor necrosis factor (TNF)A and transforming growth factor (TGF) β1 genes are suspected to modify the course of granulomatous disorders. We analyzed the TGF-β1 (codon 25) PM in 59 patients with CBD and 164 matched healthy controls, from two groups of European/Israeli and United States origin. Additionally, patients were genotyped for HLA class II gene variants and the TNFA (−308) PM. The most significant results were found for the TGF-β1 (codon 25) PM with a shift towards the low producing non-GG genotypes in the subgroup of European and Israeli patients with CBD (62.50% vs. 13.82% in healthy controls; P<0.001). This phenomenon was not observed in the group from the United States. Moreover, TGF-β1 (codon 25) PM genotype frequencies from United States CBD patients differed significantly from those of European and Israeli patients. In contrast, increased frequencies for the high producing TNFA2 allele were found only in the patients from the United States (28.20% vs. 8.96% in healthy controls; P<0.005) but not in the group of Europe and Israel. In conclusion, the increase in TGF-β1 (codon 25) PM genotype frequency associated with a low TGF-β release suggests that immunoregulatory cytokines such as TGF-β are involved in the pathogenesis of CBD. Moreover, based on the interaction of gene PMs associated with the control of the immune response, such as TNF-α and TGF-β1, with a specific immune response gene such as HLA-DPB1-Glu69 or other HLA-class II PMs driving the immune response to Be, the present data suggest that a combination of different genetic backgrounds determine susceptibility for the same immunopathological reaction and disease.

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