Toll-like receptor (TLR) 4 polymorphisms are associated with a chronic course of sarcoidosis

Pabst, Stefan; Baumgarten, Georg; Stremmel, A.; Lennarz, Martina; Knüfermann, P.; Gillissen, Adrian; Vetter, Hans; Grohé, Christian

doi:10.1111/j.1365-2249.2006.03008.x

Cited by 95 publications

(60 citation statements)

References 57 publications

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“…In prior studies, the course of sarcoidosis disease has been characterised as chronic if disease activity persisted beyond 2 years [11][12][13][14][15][16]. As such, the 2-year threshold was incorporated into our classification schema.…”

Section: Study Subjectsmentioning

confidence: 99%

Longitudinal analysis of sarcoidosis blood transcriptomic signatures and disease outcomes

Su¹,

Li²,

Bhakta³

et al. 2014

Eur Respir J

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Previously, we demonstrated concordance in differentially expressed genes in sarcoidosis blood and lung, implicating shared dysfunction of specific immune pathways. In the present study, we hypothesised that expression levels of candidate genes in sarcoidosis blood could predict and track with disease outcomes longitudinally.We applied Ingenuity Pathway Analysis to a cross-sectional derivation microarray dataset (n538) to identify canonical pathways and candidate genes associated with sarcoidosis. In a separate longitudinal sarcoidosis cohort (n5103), we serially measured 48 candidate gene transcripts, and assessed their relation to disease chronicity and severity.In the cross-sectional derivation study, pathway analysis showed upregulation of genes related to interferon signalling and the role of pattern recognition receptors, and downregulation of T-cell receptor (TCR) signalling pathways in sarcoidosis. In the longitudinal cohort, factor analysis confirmed coregulation of genes marking these pathways and identified CXCL9 as an additional candidate pathway. CXCL9 and TCR factors discriminated between chronic versus nonprogressive disease, and CXCL9 predicted disease outcomes longitudinally. Interferon factor was similarly increased in both disease phenotypes. Factors associated with lung function decline included decreased TCR factor and increased CXCL9.These findings demonstrate blood transcriptomic signatures reflecting TCR signalling and CXCL9 predict sarcoidosis chronicity and correlate with disease severity longitudinally. @ERSpublications Blood gene transcript measurements predict sarcoidosis chronicity and severity longitudinally

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Section: Study Subjectsmentioning

confidence: 99%

Longitudinal analysis of sarcoidosis blood transcriptomic signatures and disease outcomes

Su¹,

Li²,

Bhakta³

et al. 2014

Eur Respir J

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“…For sarcoidosis, polymorphisms in several genes (NRAMP, TLR4, HLA, Vitamin D receptor) involved in the immune response to exogenous pathogens have been investigated [1,[35][36][37], suggesting that exposure to environmental factors capable of eliciting these pathways may be important in development of sarcoidosis. Polymorphisms in the vitamin D receptor are intriguing, and have been used in conjunction with an internal phenotype (Vitamin D deficiency) to suggest the presence of a gene-environment interaction between diet and VDR for risk of pulmonary tuberculosis among Gujaratis [38].…”

Section: Modeling Interactionsmentioning

confidence: 99%

Gene-environment interactions in sarcoidosis: challenge and opportunity

Culver¹,

Newman²,

Kavuru³

2007

Clinics in Dermatology

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Susceptibility to most human diseases is polygenic, with complex interactions between functional polymorphisms of single genes governing disease incidence, phenotype, or both. In this context, the contribution of any discrete gene is generally modest for a single individual, but may confer substantial attributable risk on a population level. Environmental exposure can modify the effects of a polymorphism, either by providing a necessary substrate for development of human disease or because the effects of a given exposure modulate the effects of the gene. In several diseases, genetic polymorphisms have been shown to be context-dependent, i.e. the effects of a genetic variant are realized only in the setting of a relevant exposure. Since sarcoidosis susceptibility is dependent on both genetic and environmental modifiers, the study of gene-environment interactions may yield important pathogenetic information and will likely be crucial for uncovering the range of genetic susceptibility loci. However, the complexity of these relationships implies that investigations of geneenvironment interactions will require the study of large cohorts with carefully-defined exposures and similar clinical phenotypes. A general principle is that the study of gene-environment interactions requires a sample size at least several-fold greater than for either factor alone. To date, the presence of environmental modifiers has been demonstrated for one sarcoidosis susceptibility locus, HLA-DQB1, in African-American families. This article reviews general considerations obtaining for the study of gene-environment interactions in sarcoidosis. It also describes the limited current understanding of the role of environmental influences on sarcoidosis susceptibility genes.

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“…[62] Several studies in German and Dutch cohorts have investigated the potential association of polymorphisms in the TLR4, TLR2 and TLR9 genes with sarcoidosis but found no association with the risk of sarcoidosis. [63][64][65][66][67] One study in a German cohort suggested an association with chronic sarcoidosis. [63] In a Dutch cohort, SNPs rs1109695 and rs7658893 in the TLR-10 gene and rs57436004 and rs5743594 in the TLR-1 gene were associated with the risk of sarcoidosis.…”

Section: Toll-like Receptorsmentioning

confidence: 99%

“…[63][64][65][66][67] One study in a German cohort suggested an association with chronic sarcoidosis. [63] In a Dutch cohort, SNPs rs1109695 and rs7658893 in the TLR-10 gene and rs57436004 and rs5743594 in the TLR-1 gene were associated with the risk of sarcoidosis. [68] None of the 4 SNPs were significantly different between remitting and chronic disease but they did differ significantly between healthy controls and sarcoidosis patients with chronic/progressive disease.…”

Section: Toll-like Receptorsmentioning

confidence: 99%