Cardiac involvement affects ≤40% of patients with sarcoidosis and accounts for ≤25% of deaths. The diagnosis of cardiac sarcoidosis is challenging using the existing screening tests and often relies ...on expensive cardiac magnetic resonance imaging (cMRI) and cardiac 18-fluorodeoxuyglucose positron emission tomography (FDG-cPET). We developed a scoring system using common clinical tests to predict positive imaging findings using cMRI or FDG-cPET. A retrospective chart review of subjects undergoing cMRI or FDG-cPET was performed. The data were extracted and scored using a predetermined system. Our cohort was predominantly white, with a mean age of 55 years, and 60% were women. The scoring system was compared with the findings from cMRI and FDG-cPET to determine the ability to predict the imaging results that define cardiac sarcoidosis. The scoring system for the patients who had undergone both FDG-cPET and cMRI suggested predictability, but the differences were not statistically significant. However, the positive results from just 1 study were as predictive as having positive findings from both studies. A 1-point increase in the total score increased the probability of positive findings from cMRI or FDG-cPET by 14% (95% confidence interval 3% to 25% increase; p = 0.01). The scoring system seemed to be driven more by the findings from cMRI than by those from FDG-cPET. In patients who had undergone cMRI alone, for each 1-point increase in the total score, the probability of positive cMRI findings increased 11% (95% confidence interval 1% decrease to 25% increase, p = 0.08). All screening modalities were analyzed. No modality was sensitive or specific, although major findings (defined in our scoring system) were most predictive of positive imaging findings. In conclusion, commonly available cardiac screening tools used together in a composite score provide reasonable results to predict positive cardiac sarcoidosis findings on imaging, but the system needs refinement. Our data suggest that major findings from screening studies are more likely to correlate with cMRI findings than with findings from FDG-cPET.
Background Most diseases, including asthma, result from the interaction between environmental exposures and genetic variants. Functional variants of CD14 negatively affect lung function in farm ...workers and children exposed to animal allergens and endotoxin. Objective We hypothesized that CD14 polymorphisms interact with inhaled endotoxin, mouse allergen, or both to decrease airways function in laboratory animal workers. Methods Three hundred sixty-nine Caucasian workers completed a symptom and work exposure questionnaire, skin prick testing, and spirometry. Individual exposure estimates for endotoxin and murine allergen were calculated by weighting task-based breathing zone concentrations by time reported for each task and length of time in the current job. Real-time PCR was used to assess CD14 /−1619, −550, and −159 alleles. Multiple linear regression predicting airways function included an interaction term between genotype and exposure. Results Workers at the highest quartile of the natural log-transformed cumulative endotoxin exposure and with the endotoxin-responsive CD14 /−1619 G allele had significantly lower FEV1 and forced expiratory flow, midexpiratory phase (FEF25-75 ) percent predicted compared with workers with an AA genotype, with no significant differences noted at lower endotoxin levels for either genotype. The gene-environment effect was marked for atopic workers. Laboratory animal allergy, murine allergen exposure, CD14 /−159 or −550 genotype, and a gene-exposure interaction term for these genotypes and exposures did not predict changes in lung function. Conclusions A significant gene-environment interaction affects airways function in laboratory animal workers. More highly endotoxin-exposed workers with CD14 /−1619G alleles have significantly lower FEV1 and FEF25-75 percent predicted than those with CD14 /−1619AA alleles. Atopic workers are particularly affected by cumulative endotoxin exposures.
Genetics of Sarcoidosis Fingerlin, Tasha E; Hamzeh, Nabeel; Maier, Lisa A
Clinics in chest medicine,
12/2015, Letnik:
36, Številka:
4
Journal Article
Recenzirano
Sarcoidosis is a disease with highly variable presentation and progression; although it is hypothesized that disease phenotype is related to genetic variation, how much of this variability is driven ...by genetic factors is not known. The HLA region is the most strongly and consistently associated genetic risk factor for sarcoidosis, supporting the notion that sarcoidosis is an exposure-mediated immunologic disease. Most of the genetic etiology of sarcoidosis remains unknown in terms of the specific variants that increase risk in various populations, their biologic functions, and how they interact with environmental exposures.
Background Researchers and technicians working with laboratory animals (LAs) are exposed to animal allergen and endotoxin, which can interact to potentiate or inhibit symptoms or allergic responses. ...We hypothesized that functional genetic variants of Toll-like receptor 4 (TLR4), a key surface receptor for endotoxin, interface between worker and workplace and affect animal sensitization, symptoms, or both. Objective We sought to determine whether TLR4 /8551 variants alter the risk for LA sensitization, symptoms, or both. Methods Three hundred thirty-five researchers, 195 of whom worked with animals, completed questions on workplace practices and symptoms and underwent skin prick tests or RASTs to common and animal allergens. Real-time PCR assessed TLR4 /8551 and TLR4 /8851 variants. Nominal logistic regression was used to analyze the contribution of demographic, exposure, and genetic variables to outcomes of interest. Results Twenty-one percent of workers were LA sensitized, and 29% reported 1 or more symptoms to LAs. The TLR4 /8551 G variant, which is less responsive to endotoxin, was detected in 9% and in linkage disequilibrium with the TLR4 /8851 T allele. The G variant significantly associated with atopy and LA sensitization. Workers with the G variant spent significantly longer hours in high endotoxin/animal allergen tasks compared with those with the AA variant, which is perhaps less affected by endotoxin exposures. In multivariate analyses the G variant and longer animal research hours increased the risk of LA sensitization. Job tasks and LA sensitization, but not TLR4 variants, were predictors of LA-induced symptoms. Conclusion Workers with TLR4 variants that reduce responsiveness to endotoxin have higher risks for LA and other allergen sensitization but spend longer hours in tasks with high endotoxin and animal allergen exposures.
Background Sarcoidosis is a disease that is associated with occupational and environmental antigens, in the setting of a susceptible host. The aim of this study was to examine the association between ...sarcoidosis mortality and previously reported occupational exposures based on sex and race. Methods The decedents enrolled in this study were derived from United States death certificates from 1988-1999. Cause of death was coded according to ICD-9 and ICD-10. The usual occupation was coded with Bureau of the Census Occupation Codes. Mortality odds ratio (MOR) were determined and multiple Poisson regression were performed to evaluate the independent exposure effects after adjustment for age, sex, race and other occupational exposures. Results Of the 7,118,535 decedents in our study, 3,393 were identified as sarcoidosis-related, including 1,579 identified as sarcoidosis being the underlying cause of death. The sarcoidosis-related MOR of any occupational exposure was 1.52 (95% CI, 1.35-1.71). Women with any exposure demonstrated an increased MOR compared to women without (MOR 1.65, 95% CI, 1.45-1.89). The mortality risk was significantly elevated in those with employment involving metal working, health care, teaching, sales, banking, and administration. Higher sarcoidosis-related mortality risks associated with specific exposures were noted in women vs men and blacks vs whites. Conclusions Findings of prior occupations and risk of sarcoidosis were verified using sarcoidosis mortality rates. There were significant differences in risk for sarcoidosis mortality by occupational exposures based on sex and race.
Background Beryllium stimulates TNF-α from chronic beryllium disease (CBD) bronchoalveolar lavage (BAL) cells. Objective We sought to relate TNF polymorphisms to beryllium-stimulated TNF-α ...production, to the development of CBD, and to the risk of more severe CBD over time. Methods We recruited 147 patients with CBD, 112 beryllium-sensitized subjects, and 323 control subjects; genotyped 5 TNF promoter polymorphisms; and measured beryllium-stimulated and unstimulated BAL cell TNF-α production from a subset of subjects. Results Beryllium-stimulated, but not beryllium-unstimulated, BAL cell TNF-α production was significantly increased in patients with CBD compared with that seen in those only sensitized ( P = .0002). Those subjects with the TNF –857T allele and the only haplotype (haplotype 4) containing this allele demonstrated significantly lower unstimulated BAL cell TNF-α production compared with that seen in noncarriers ( P = .009). Patients with CBD alone and combined with sensitized subjects carrying the TNF haplotype 1 compared with those without this haplotype had significantly increased beryllium-stimulated BAL cell TNF-α levels ( P = .02). We found no significant association between patients with CBD, sensitized subjects, and control subjects with any of the TNF promoter polymorphisms or haplotypes. A greater decrease in Pa o2 at maximum exercise was noted in patients with CBD with the −1031C allele ( P = .03) and with haplotypes other than the TNF haplotype 1 ( P = .01), 3 (from 5) of which contain the −1031C allele. Conclusions The −857T allele and haplotype 1 are associated with BAL cell TNF-α production, indicating a potential role of TNF promoter variants in regulation of TNF production in sensitized subjects and patients with CBD. Clinical implications TNF promoter variants are not risk factors for CBD or sensitization.
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