Biomedical subjects

Manfred Schürmann

Publications and source records attributed to Manfred Schürmann.

6 recordsLinked to original sources

PubMed2005

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

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.

Adult↗

PubMed2005

Study of C-C chemokine receptor 2 alleles in sarcoidosis, with emphasis on family-based analysis.

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.

Adolescent↗

PubMed2005

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

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.

Bronchoalveolar Lavage↗

PubMed2003

Genetics of sarcoidosis.

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.

Journal Article↗

PubMed2003

Angiotensin-converting enzyme gene polymorphisms in patients with pulmonary sarcoidosis: impact on disease severity.

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.

Animals↗

PubMed2002

CFTR gene mutations in sarcoidosis.

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.

Amino Acid Substitution↗