Heterogeneity of familial risk in sarcoidosis

Rybicki, Benjamin A.; Harrington, Douglas S.; Major, Marcie; Simoff, Michael; Popovich, John; Maliarik, Mary J.; Iannuzzi, Michael C.

doi:10.1002/(sici)1098-2272(1996)13:1<23::aid-gepi3>3.0.co;2-7

Cited by 62 publications

(30 citation statements)

References 15 publications

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“…Cumulative incidence estimates predict a lifetime risk of sarcoidosis of 0.85 and 2.4% for U.S. whites and blacks, respectively (3). Familial clustering of the disease has provided evidence that genetic predisposition may be an important risk factor, with loci that influence T cell function, regulation of Ag recognition, and processing or regulation of matrix deposition and granuloma formation representing the most likely candidate genes (4,5). In particular, individuals with specific HLA-DR genotypes appear to be at higher risk (6 -10).…”

contrasting

confidence: 92%

Role of IL-18 in CD4+ T Lymphocyte Activation in Sarcoidosis

Greene

Meachery

Taggart

et al. 2000

The Journal of Immunology

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Sarcoidosis is a granulomatous disease of unknown etiology associated with the expansion of IL-2-producing activated CD4+ T lymphocytes. A number of factors including the recently described IL-18 have been implicated in IL-2 expression in vitro. We investigated the role of IL-18 in IL-2 expression in sarcoidosis. Eighteen individuals with sarcoidosis and 15 normal controls were studied. IL-18R expression and epithelial lining fluid (ELF) concentrations of IL-18 were significantly elevated in the sarcoid group (p = 0.0143 and 0.0024, respectively). Both AP1 and NF-κB, transcription factors that regulate IL-2 gene expression, were activated in vivo in sarcoid pulmonary CD4+ T lymphocytes. Transcription factor activity was not detected in pulmonary CD4+ T lymphocytes from normal controls or from peripheral blood CD4+ T lymphocytes from individuals with sarcoidosis, further evidence of compartmentalization of the lymphoproliferative process in this condition. We examined the effects of IL-18 on AP1 and NF-κB in Jurkat T cells in vitro. These effects were both time and dose dependent. Examination of transcription factor activation and IL-2 gene expression in Jurkat T cells revealed that sarcoid but not normal ELF activated AP1 and NF-κB, induced IL-2 gene transcription, and up-regulated IL-2 protein production. Addition of IL-18 to normal ELF also induced IL-2 mRNA accumulation, whereas correspondent depletion of IL-18 from sarcoid ELF using neutralizing Abs abrogated all of the effects. These data strongly implicate IL-18 in the pathogenesis of sarcoidosis via activation of AP1 and NF-κB, leading to enhanced IL-2 gene expression and IL-2 protein production and concomitant T cell activation.

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confidence: 92%

Role of IL-18 in CD4+ T Lymphocyte Activation in Sarcoidosis

Greene

Meachery

Taggart

et al. 2000

The Journal of Immunology

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“…However, both studies were weakened by a number of problems, including limited sample size. To address this point, RYBICKI et al [39] examined 3,395 siblings and parents of 558 index cases of sarcoidosis (361 African-Americans and 197 Caucasians). They used individual risk probabilities based on age, sex, and race specific disease prevalence to evaluate risk in parents and siblings of sarcoidosis patients.…”

Section: Familial Aggregation Of Sarcoidosismentioning

confidence: 99%

Genetic aspects in sarcoidosis

Luisetti¹,

Beretta²,

Casali³

2000

Eur Respir J

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Sarcoidosis is an immune-mediated, multiorgan, granulomatous disorder thought to be triggered by an intricate combination of environmental and genetic factors. Two robust lines of evidence support the hypothesis of a genetic component in the pathogenesis of sarcoidosis: racial variation in its epidemiology and familial clustering of cases. The relationship between epidemiology and environmental factors affecting variations in sarcoidosis incidence/prevalence and presentation are reviewed, as well as strategies to be pursued in the search for susceptibility genes for the disorder.Pathogenic processes leading to sarcoid granuloma formation and maintenance have prompted investigators interested in the genetics of sarcoidosis to focus mainly on major histocompatibility complex genes, and indeed a remarkable amount of data has been accumulated during the last two decades. Whilst in contrast with some autoimmune disorders a clear association between human leukocyte antigen (HLA) and sarcoidosis is still a controversial issue, there is, however, a general agreement that some HLA genes are related to phenotypic variations of the disease. Some genetic investigators have focused on T-cell receptor genes, immunoglobulin genes, angiotensin converting enzyme gene, chemokine genes and others.From a review of studies performed in different racial and ethnic groups, a reasonable suggestion arises that genetic factors are the major determinant in the racial variations in the epidemiology of the disorder. This assumption is, however, so far limited by lack of studies considering both genetic and environmental factors simultaneously. Eur Respir J 2000; 16: 768±780.

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“…Therefore, the ACE genotype might be a genetic marker (Furuya et al 1996;Tomita et al 1997;Biller et al 2009;Papadopoulos et al 2000;Sharma and Alam 1995;Salobir et al 2007;Tahir et al 2007). Along with the detection of familial sarcoidosis, research on genetic predisposition to sarcoidosis has gained momentum (Fite et al 1998;Rybicki et al 1996;Sverrild et al 2008). However, contradictory results were obtained using different ethnic groups; therefore, further studies are required to test whether the ACE genotype is linked to sarcoidosis predisposition (Maliarik et al 1998;McGrath et al 2001;Alia et al 2005;Kruit et al 2010;Schurmann et al 2001;Hatemi et al 2001).…”

Section: Introductionmentioning

confidence: 99%

Association between I/D polymorphism in the ACE gene and sarcoidosis in Turkish patients

Sarı¹,

Kurt

Saydam

et al. 2014

Cytotechnology

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Sarcoidosis is a chronic inflammatory disease with a complex pathogenesis and unknown etiology characterized by noncaseating granulomas that invade the lungs, eyes, liver and other organs. Insertion (I)/deletion (D) polymorphism in the gene encoding the angiotensin-converting enzyme (ACE) has been studied to examine the genetic predisposition to sarcoidosis in different populations, but the results have been inconsistent and inconclusive. This study aimed to determine the frequencies of the genotypes and alleles of I/D polymorphism in the ACE gene in Turkish patients as a distinct ethnic group and to investigate whether such polymorphism is associated with predisposition to sarcoidosis. Genomic DNA samples obtained from 154 individuals (70 patients with sarcoidosis and 84 healthy controls) were used in the study. The DNA was amplified using polymerase chain reactions using allele-specific primers. The amplified products were analyzed by 2 % agarose gel electrophoresis followed by UV transillumination. The allele frequencies and genotype distribution of the groups were analyzed using the Chi square test. There were no significant differences between the controls and sarcoidosis cases with respect to genotype distribution (v 2 = 4.202, p = 0.122) and allele frequencies (v 2 = 1.358, p = 0.244). Our results suggest that I/D polymorphism in the ACE gene does not cause a genetic predisposition to sarcoidosis in Turkish patients.

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Heterogeneity of familial risk in sarcoidosis

Cited by 62 publications

References 15 publications

Role of IL-18 in CD4+ T Lymphocyte Activation in Sarcoidosis

Role of IL-18 in CD4+ T Lymphocyte Activation in Sarcoidosis

Genetic aspects in sarcoidosis

Association between I/D polymorphism in the ACE gene and sarcoidosis in Turkish patients

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