Involvement of T-cell receptor-β alterations in the development of otosclerosis linked to OTSC2

Schrauwen, Isabelle; Venken, Koen; Vanderstraeten, Kathleen; Thys, Melissa; Hendrickx, Jan; Fransén, Erik; Laer, Lut Van; Govaerts, Paul; Verstreken, M.; Schatteman, Isabelle; Stinissen, Piet; Hellings, Niels; Camp, Guy Van

doi:10.1038/gene.2010.3

Cited by 15 publications

(22 citation statements)

References 47 publications

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“…Furthermore, another class of diseases in the network, myeloproliferative disorders, contains precancer and cancer, and includes polycythemia vera and chronic myelogenous leukemia, among others. The final constituent is otosclerosis, a disease causing hearing loss that has been found to be a T cell-mediated autoimmune disorder involving abnormal bone growth in the middle ear 29. Interestingly, both neuroblastoma and neoplasms of the testis are found in younger patients and most commonly involve germline mutations of specific genes that cause these phenotypes.…”

Section: Resultsmentioning

confidence: 99%

Complex-disease networks of trait-associated single-nucleotide polymorphisms (SNPs) unveiled by information theory

Lee

Chen

et al. 2012

J Am Med Inform Assoc

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ObjectiveThousands of complex-disease single-nucleotide polymorphisms (SNPs) have been discovered in genome-wide association studies (GWAS). However, these intragenic SNPs have not been collectively mined to unveil the genetic architecture between complex clinical traits. The authors hypothesize that biological annotations of host genes of trait-associated SNPs may reveal the biomolecular modularity across complex-disease traits and offer insights for drug repositioning.MethodsTrait-to-polymorphism (SNPs) associations confirmed in GWAS were used. A novel method to quantify trait–trait similarity anchored in Gene Ontology annotations of human proteins and information theory was developed. The results were then validated with the shortest paths of physical protein interactions between biologically similar traits.ResultsA network was constructed consisting of 280 significant intertrait similarities among 177 disease traits, which covered 1438 well-validated disease-associated SNPs. Thirty-nine percent of intertrait connections were confirmed by curators, and the following additional studies demonstrated the validity of a proportion of the remainder. On a phenotypic trait level, higher Gene Ontology similarity between proteins correlated with smaller ‘shortest distance’ in protein interaction networks of complexly inherited diseases (Spearman p<2.2×10−16). Further, ‘cancer traits’ were similar to one another, as were ‘metabolic syndrome traits’ (Fisher's exact test p=0.001 and 3.5×10−7, respectively).ConclusionAn imputed disease network by information-anchored functional similarity from GWAS trait-associated SNPs is reported. It is also demonstrated that small shortest paths of protein interactions correlate with complex-disease function. Taken together, these findings provide the framework for investigating drug targets with unbiased functional biomolecular networks rather than worn-out single-gene and subjective canonical pathway approaches.

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Section: Resultsmentioning

confidence: 99%

Complex-disease networks of trait-associated single-nucleotide polymorphisms (SNPs) unveiled by information theory

Lee

Chen

et al. 2012

J Am Med Inform Assoc

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“…Genetic investigations in large families segregating autosomal dominant otosclerosis identified seven loci ( OTSC1–5 , OTSC7 , OTSC8 ) (Tomek et al, 1998; Van Den Bogaert et al, 2001; Chen et al, 2002; Van Den Bogaert et al, 2004; Brownstein et al, 2006; Thys et al, 2007b; Bel Hadj Ali et al, 2008), but none of the corresponding genes has been found. However, a recent study suggests the implication of the T‐cell receptor β locus as the causative gene in the OTSC2 region (Schrauwen et al, 2010). Unlike the monogenic form of otosclerosis, sporadic cases without familial background are very common.…”

Section: Introductionmentioning

confidence: 99%

Association of COL1A1 and TGFB1 Polymorphisms with Otosclerosis in a Tunisian Population

Khalfallah

Schrauwen

Mnejja

et al. 2011

Annals of Human Genetics

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SummaryOtosclerosis is a condition characterized by an abnormal bone metabolism in the otic capsule, resulting in conductive and/or sensorineural hearing loss. Otosclerosis is a common disorder in which genes play an important role. Case-control association studies have implicated several genes in the abnormal bone metabolism associated with otosclerosis: COL1A1, TGFB1, BMP2, and BMP4. To investigate the association of these genes with otosclerosis in the Tunisian population, we examined nine single nucleotide polymorphisms (SNPs) in 159 unrelated otosclerosis patients and 155 unrelated controls. We found an association of rs11327935 in COL1A1 with otosclerosis that was shown to be sex specific. The coding polymorphism T263I in TGFB1 was also associated with otosclerosis in the Tunisian population. The effect sizes of both the associations were consistent with previous studies, as the same effect was found in all cases. The association of BMP2 and BMP4 was not significant. However, a trend towards association was found for the BMP4 gene that was consistent with earlier reports. In conclusion, this study replicates and strengthens the evidence for association between polymorphisms of COL1A1 and TGFB1 in the genetic aetiology of otosclerosis.

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“…The human T cell receptor complex fulfills a prominent role in the immune system in the recognition of antigens and subsequent activation of T cells. By further functional exploration, we found a significantly lower TCRβ mRNA expression and lower circulating TCRαβ + T cells in blood from OTSC2 patients compared to controls and sporadic patients 45. Furthermore, we discovered additional significant disturbances in specific T cell subsets in these patients, including an increased CD28 null cell population, which are highly proinflammatory senescent T cells that have lost their CD28 expression.…”

Section: Linkage Studies For Otosclerosismentioning

confidence: 78%

The etiology of otosclerosis: A combination of genes and environment

Schrauwen

Camp

2010

The Laryngoscope

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Otosclerosis is a common form of hearing loss characterized by abnormal bone remodeling in the otic capsule. It is a complex genetic disease, caused by a combination of genetic and environmental factors. During the past decade, several attempts have been made to identify factors for otosclerosis. This review provides an overview of the current understanding of the etiology of otosclerosis and describes the genetic and environmental factors that have been implicated in the disease. Environmental factors include fluoride and viral factors, particularly measles. Genetic association studies for otosclerosis have reported several associations of genetic variants that influence the risk of disease, mainly involving bone remodeling pathways, although their individual risk contributions are small. Rare monogenic forms of otosclerosis also exist, which are caused by a mutation in a single gene leading to a clear familial segregation of the disease. Linkage analysis of large otosclerosis families has led to the identification of seven loci, and recently evidence was found that T cell receptor beta is a gene responsible for familial otosclerosis, suggesting an underlying immunological pathway. However, this might also represent an autoimmune process, a hypothesis that is supported by other data as well. In conclusion, a variety of pathways have been identified to be involved in the development of otosclerosis, showing that distinct mechanisms involving both genetic and environmental risk factors can influence and contribute to a similar disease outcome.

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Involvement of T-cell receptor-β alterations in the development of otosclerosis linked to OTSC2

Cited by 15 publications

References 47 publications

Complex-disease networks of trait-associated single-nucleotide polymorphisms (SNPs) unveiled by information theory

Complex-disease networks of trait-associated single-nucleotide polymorphisms (SNPs) unveiled by information theory

Association of COL1A1 and TGFB1 Polymorphisms with Otosclerosis in a Tunisian Population

The etiology of otosclerosis: A combination of genes and environment

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