Manfred Schürmann

Publications (15)130.24 Total impact

• Article: 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, [......], Stefan Pabst, Christian Grohé, Johan Grunewald, Marcus Ronninger, Anders Eklund, Philip Rosenstiel, Kerstin Höhne, Gernot Zissel, Joachim Müller-Quernheim, Stefan Schreiber
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  ABSTRACT: Sarcoidosis is a systemic inflammatory disease of unknown etiology, 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, 1,233 controls and 677,619 SNPs were available for an initial screening. 99 SNPs were selected for validation in an independent study panel (1,664 patients, 2,932 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, 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 the ER-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.
  European Respiratory Journal 08/2012; · 5.89 Impact Factor
• Article: 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, [......], Marcus Ronninger, Anders Eklund, Leonid Padyukov, Christian Gieger, H-Erich Wichmann, Almut Nebel, Andre Franke, Joachim Müller-Quernheim, Sylvia Hofmann, Stefan Schreiber
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  ABSTRACT: RATIONALE: Sarcoidosis is a complex inflammatory disease with a heterogeneous clinical picture. Amongst others, an acute and chronic clinical course can be distinguished, for which specific genetic risk factors are known. OBJECTIVES: In order to identify additional risk loci for sarcoidosis and its acute and chronic subforms, we analyzed imputed data from a genome-wide association scan (GWAS) for these phenotypes. METHODS: After quality control, the GWAS 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 1575 controls. 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 ORs ranging from 0.67 to 0.77. This finding was further replicated in two independent European case-control populations from the Czech Republic (OR = 0.75) and from Sweden (OR = 0.79). In a meta-analysis of the included European case-control samples the marker yielded a p value of 2.68x10(-18). The locus was previously reported to be associated with Crohn´s disease, alopecia areata, leprosy and psoriasis. 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. CONCLUSION: 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´s disease and psoriasis.
  American Journal of Respiratory and Critical Care Medicine 07/2012; · 11.08 Impact Factor
• Article: Genetics of sarcoidosis.

  Joachim Müller-Quernheim, Manfred Schürmann, Sylvia Hofmann, Karoline I Gaede, Annegret Fischer, Antje Prasse, Gernot Zissel, Stefan Schreiber
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  ABSTRACT: 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.
  Clinics in Chest Medicine 10/2008; 29(3):391-414, viii. · 3.28 Impact Factor
• Article: Genome-wide association study identifies ANXA11 as a new susceptibility locus for sarcoidosis.

  Sylvia Hofmann, Andre Franke, Annegret Fischer, Gunnar Jacobs, Michael Nothnagel, Karoline I Gaede, Manfred Schürmann, Joachim Müller-Quernheim, Michael Krawczak, Philip Rosenstiel, Stefan Schreiber
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  ABSTRACT: Sarcoidosis is a complex chronic inflammatory disorder with predominant manifestation in the lung. In the first genome-wide association study (> 440,000 SNPs) of this disease, comprising 499 German individuals with sarcoidosis and 490 controls, we detected a series of genetic associations. The strongest association signal maps to the ANXA11 (annexin A11) gene on chromosome 10q22.3. Validation in an independent sample (1,649 cases, 1,832 controls) confirmed the association (SNP rs2789679: P = 3.0 x 10(-13), rs7091565: P = 1.0 x 10(-5), allele-based test). Extensive fine mapping located the association signal to a region between exon 5 and exon 14 of ANXA11. A common nonsynonymous SNP (rs1049550, C > T, [corrected] R230C) was found to be strongly associated with sarcoidosis. The GWAS lead SNP and additional risk variants in the region (rs1953600, rs2573346, rs2784773) were in strong linkage disequilibrium with rs1049550. Annexin A11 has complex and essential functions in several biological pathways, including apoptosis and proliferation.
  Nature Genetics 09/2008; 40(9):1103-6. · 35.53 Impact Factor
• Article: Genome-wide association analysis in sarcoidosis and Crohn's disease unravels a common susceptibility locus on 10p12.2.

  Andre Franke, Annegret Fischer, Michael Nothnagel, Christian Becker, Nils Grabe, Andreas Till, Tim Lu, Joachim Müller-Quernheim, Michael Wittig, Alexander Hermann, [......], Regina Niemiec, Sabrina Schulz, Jochen Hampe, Susanna Nikolaus, Peter Nürnberg, Michael Krawczak, Manfred Schürmann, Philip Rosenstiel, Almut Nebel, Stefan Schreiber
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  ABSTRACT: Crohn's disease (CD) and sarcoidosis (SA) are chronic inflammatory barrier diseases that share several clinical and immunological features, including the occurrence of granulomas. A 100k genome-wide association study with 83,360 single-nucleotide polymorphisms (SNPs) was performed on 382 CD patients, 398 SA patients, and 394 control individuals. The 24 SNPs that were most strongly associated in the combined CD/SA phenotype were selected for verification in an independent sample of 1,317 patients (660 CD and 657 SA) and 1,091 controls. The most significant association (Bonferroni corrected P = .036) was obtained at SNP rs1398024 on chromosome 10p12.2, with an odds ratio (OR) for both diseases of 0.81 (95% confidence interval [CI], 0.69-0.96) for carriership of the rarer allele A. The P value in the overall combined sample was 4.24 x 10(-6). During further follow-up, a moderate association (OR, 0.83; 95% CI, 0.72-0.96; P = .015) was observed between rs1398024 and ulcerative colitis (1,080 patients vs 1,091 controls), the second main subphenotype of inflammatory bowel disease in addition to CD. Extensive fine mapping of the 10p12.2 locus points to yet unidentified variants in the C10ORF67 gene region as the most likely underlying risk factors. Our study demonstrates that the combined analysis of different, albeit clinically related, phenotypes can lead to the identification of common susceptibility loci.
  Gastroenterology 08/2008; 135(4):1207-15. · 11.68 Impact Factor
• Article: Female-specific association of C-C chemokine receptor 5 gene polymorphisms with Löfgren's syndrome.

  Annegret Fischer, Ruta Valentonyte, Almut Nebel, Michael Nothnagel, Joachim Müller-Quernheim, Manfred Schürmann, Stefan Schreiber
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  ABSTRACT: C-C chemokine receptors have been suggested to play an important role in sarcoidosis pathogenesis. Previous investigation of the C-C chemokine receptor 5 (CCR5) gene revealed the association of the HHC haplotype with "persistent lung involvement" in two European sarcoidosis populations. Based on this finding, we investigated a possible association of the HHC haplotype and its marker alleles in an extended German sarcoidosis sample that comprised 995 German sarcoidosis families including individuals with the chronic and acute form of the disease, further refined to patients with and without Löfgren's syndrome. We genotyped this sample and 538 healthy control subjects for 8 single nucleotide polymorphisms (SNPs) that define the HHC haplotype in the CCR5 genomic region. Analysis of 3 sarcoidosis phenotypes (chronic, acute and Löfgren's syndrome) revealed that the HHC haplotype was not associated with chronic sarcoidosis although a substantial overlap can be assumed between the chronic form examined in our study and "persistent parenchymal lung involvement", the phenotype for which an association was previously established. However, 2 marker alleles in the putative CCR5 promoter, which are part of the HHC haplotype, are associated with Löfgren's syndrome. Strikingly, the association is restricted to females. This finding is consistent with recently described sex-specific manifestations of Löfgren's syndrome and with previous functional studies suggesting an estrogen-dependent CCR5 expression. The female-specific association of SNPs in the putative CCR5 promoter region with Löfgren's syndrome raises the possibility that the dysregulated, sex-specific modification of CCR5 expression could contribute to the increased risk of women to develop the disease.
  Journal of Molecular Medicine 06/2008; 86(5):553-61. · 4.67 Impact Factor
• Article: Function associated transforming growth factor-beta gene polymorphism in chronic beryllium disease.

  Karoline I Gaede, Massimo Amicosante, Manfred Schürmann, Elisabeth Fireman, Cesare Saltini, Joachim Müller-Quernheim
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  ABSTRACT: 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 beta 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) beta(1) genes are suspected to modify the course of granulomatous disorders. We analyzed the TGF-beta(1) (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-beta(1) (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-beta(1) (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-beta(1) (codon 25) PM genotype frequency associated with a low TGF-beta release suggests that immunoregulatory cytokines such as TGF-beta 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-alpha and TGF-beta(1), 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.
  Journal of Molecular Medicine 06/2005; 83(5):397-405. · 4.67 Impact Factor
• Article: Study of C-C chemokine receptor 2 alleles in sarcoidosis, with emphasis on family-based analysis.

  Ruta Valentonyte, Jochen Hampe, Peter J P Croucher, Joachim Müller-Quernheim, Eberhard Schwinger, Stefan Schreiber, Manfred Schürmann
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  ABSTRACT: Prevailing models of sarcoidosis pathogenesis involve the activation of alveolar macrophages, aggregation of CD4+ T lymphocytes, and their accumulation in epithelioid cell granulomas. Increasing evidence suggests that each of these steps is modified by the host genetic constitution. Consequently, candidate susceptibility genes have been selected based on their potential function under this model. The C-C chemokine receptor 2 (CCR2) is involved in Th1 immune activity by recruiting competent cells and possibly by balancing response. CCR2 gene variants have been shown to be associated with sarcoidosis or, more specifically, with Löfgren's syndrome, a distinct form of acute sarcoidosis. We have studied three CCR2 gene polymorphisms (c.190G>A, c.840C>T, and c.4385A>T) in an extended sample of 1,203 patients with sarcoidosis and their relatives. Case-control comparisons and family-based genetic analyses did not support previous findings of an association between CCR2 gene variability and the risk of sarcoidosis. However, they confirmed linkage disequilibrium and showed positive linkage results (p = 0.034) and therefore suggest a susceptibility gene in the surrounding chromosomal region.
  American Journal of Respiratory and Critical Care Medicine 06/2005; 171(10):1136-41. · 11.08 Impact Factor
• Source

  Available from: Philip Rosenstiel

  Article: 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, [......], Thomas Lengauer, Dirk Seegert, Norbert Reiling, Stefan Ehlers, Eberhard Schwinger, Matthias Platzer, Michael Krawczak, Joachim Müller-Quernheim, Manfred Schürmann, Stefan Schreiber
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  ABSTRACT: 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; P(TDT) = 3 x 10(-6), P(case-control) = 1.1 x 10(-8); replication P(TDT) = 0.0018, P(case-control) = 1.8 x 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.
  Nature Genetics 05/2005; 37(4):357-64. · 35.53 Impact Factor
• Article: Genetics of sarcoidosis.

  Manfred Schürmann
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  ABSTRACT: Sarcoidosis is a systemic disorder of granulomatous inflammation that primarily affects the lung and lymph system, although all organs can be involved. Two principal presentations of the disorder can be defined; an acute form, often with short duration and complete restitution, and a more insidious course with multiorgan involvement and a higher risk of progressive organ damage. Sarcoidosis affects mainly young adults. The etiology of sarcoidosis is unknown, and current concepts assume one or more environmental triggers that start in a host with an inherited susceptibility to a dysbalanced immune response. Candidate susceptibility genes include genes with a function in antigen recognition, T cell activation, T-helper 1/2 (TH1/TH2) cell balance, and granuloma formation. A few genetic linkage analyses and numerous association studies with a focus on the region of the major histocompatibility complex genes have been performed, which have so far yielded no breakthrough. They have, rather, verified the assumption of a complex and possibly heterogeneous character of the genetics of sarcoidosis.
  Seminars in Respiratory and Critical Care Medicine 05/2003; 24(2):213-22. · 2.43 Impact Factor
• Article: Angiotensin-converting enzyme gene polymorphisms in patients with pulmonary sarcoidosis: impact on disease severity.

  Manfred Schürmann
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  ABSTRACT: Angiotensin converting enzyme (ACE) is a metallopeptidase with a key function in the regulation of blood pressure and volume. The ACE1 gene, on chromosome 17, contains a insertion/deletion (I/D) polymorphism in intron 16. The D allele of this polymorphism is linked with raised serum ACE (sACE) levels. Sarcoidosis is a systemic disease of granulomatous inflammation that primarily affects the lung and lymph system. It is often accompanied by elevated sACE related to ACE production from granuloma cells. The ACE I/D polymorphism has been tested for association or linkage with the risk of sarcoidosis. Though published results are conflicting, there seems to be suggestive evidence of a minor pro-inflammatory influence of the ACE D allele in sarcoidosis. At present, a more accurate interpretation of sACE levels in diagnosis and monitoring of sarcoidosis seems to be the main value of ACE I/D genotyping.
  American Journal of PharmacoGenomics 02/2003; 3(4):233-43.
• Article: CFTR gene mutations in sarcoidosis.

  Manfred Schürmann, Melanie Albrecht, Eberhard Schwinger, Manfred Stuhrmann
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  ABSTRACT: Sarcoidosis is a complex disease of multiorgan granulomatous inflammation. Genetic susceptibility is involved in the pathogenesis of the disorder. Two successive studies from Italy have shown a high frequency of mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene in patients suffering from sarcoidosis. We have genotyped a panel of 63 families with two or more affected siblings for the CFTR gene mutation R75Q, which was found to be present in three of 26 cases of the Italian study. Although R75Q was present in seven families, it was neither associated with the sarcoidosis phenotype in the German population (P=0.5), nor was it linked to sarcoidosis (P=0.54). In addition, a screening for 34 functional CFTR mutations was performed in a subset of 54 patients from 25 families. These patients were known to be concordant for at least one parental copy of the CFTR gene. With the exception of the mayor CF mutation deltaF508, which was present in three patients and absent in one patient from two families, we did not find any other CF mutation in these 54 patients. Our results do not support the hypothesis that CFTR mutations have a major influence on the pathogenesis of sarcoidosis.
  European Journal of HumanGenetics 12/2002; 10(11):729-32. · 4.40 Impact Factor
• Article: Testing for linkage of eye tracking dysfunction and schizophrenia to markers on chromosomes 6, 8, 9, 20, and 22 in families multiply affected with schizophrenia

  Volker Arolt, Rebekka Lencer, Sabine Purmann, Manfred Schürmann, Bertram Müller-Myhsok, Katja Krecker, Eberhard Schwinger
  American Journal of Medical Genetics 04/2000; 88(6):603 - 606.
• Article: Eye tracking dysfunction is a putative phenotypic susceptibility marker of schizophrenia and maps to a locus on chromosome 6p in families with multiple occurrence of the disease

  Volker Arolt, Rebekka Lencer, Achim Nolte, Bertram Müller-Myhsok, Sabine Purmann, Manfred Schürmann, Jutta Leutelt, Marlene Pinnow, Eberhard Schwinger
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  ABSTRACT: The difficulties in defining the borders of the schizophrenia spectrum is one major source of variance in linkage studies of schizophrenia. The employment of biological markers may prove advantageous. Due to empirical evidence, eye tracking dysfunction (ETD) has been discussed to be the most promising marker for genetic liability to schizophrenia. With respect to the recent progress in genomic scans, which have pointed to the short arm of chromosome 6, we carried out a scan of the 6p21–23 region with 16 microsatellite markers to test for linkage between chromosomal markers and ETD as well as schizophrenia. We tested 5 models of inheritance of ETD and found maximum two-point lod scores of 3.51 for D6S271 and 3.44 for D6S282. By including these markers in a multipoint analysis, a lod score of 4.02 was obtained. In the case of schizophrenia, 7 models were tested; however, with non-significant results. Our findings, together with another recent linkage report, point to the possibility of a second susceptibility locus for schizophrenia which may be located centromeric to the HLA region. Also, the evidence of ETD being a susceptibility marker for schizophrenia receives further support.
  American Journal of Medical Genetics 12/1998; 67(6):564 - 579.
• Article: 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, [......], Thomas Lengauer, Dirk Seegert, Norbert Reiling, Stefan Ehlers, Eberhard Schwinger, Mathias Platzer, Michael Krawczak, Joachim Müller-Quernheim, Manfred Schürmann, Stefan Schreiber
  Nature Genetics, v.37, 357-364 (2005).