A Statistical Model for Assessing Genetic Susceptibility as a Risk Factor in Multifactorial Diseases: Lessons from Occupational Asthma

BACKGROUND: Incorporating the influence of genetic variation in the risk assessment process is often considered, but no generalized approach exists. Many common human diseases such as asthma, cancer, and cardiovascular disease are complex in nature, as they are influenced variably by environmental, physiologic, and genetic factors. The genetic components most responsible for differences in individual disease risk are thought to be DNA variants (polymorphisms) that influence the expression or function of mediators involved in the pathological processes. OBJECTIVE: The purpose of this study was to estimate the combinatorial contribution of multiple genetic variants to disease risk. METHODS: We used a logistic regression model to help estimate the joint contribution that multiple genetic variants would have on disease risk. This model was developed using data collected from molecular epidemiology studies of allergic asthma that examined variants in 16 susceptibility genes. RESULTS: Based on the product of single gene variant odds ratios, the risk of developing asthma was assigned to genotype profiles, and the frequency of each profile was estimated for the general population. Our model predicts that multiple disease variants broaden the risk distribution, facilitating the identification of susceptible populations. This model also allows for incorporation of exposure information as an independent variable, which will be important for risk variants associated with specific exposures. CONCLUSION: The present model provided an opportunity to estimate the relative change in risk associated with multiple genetic variants. This will facilitate identification of susceptible populations and help provide a framework to model the genetic contribution in probabilistic risk assessment

Neopterin as a marker for immune system activation in coal workers' pneumoconiosis

WOS: 000252201700005PubMed: 18220157Coal workers' pneumoconiosis (CWP) is an occupational pulmonary disease that occurs by chronic inhalation of coal dust. Coal workers' pneumoconiosis is divided into two categories depending on the extent of the disease as simple pneumoconiosis (SP) and progressive massive fibrosis (PMF). Development of CWP is associated with the activation of the immune system. Neopterin is a predictive biochemical marker of cell-mediated immune activation and elevated levels of neopterin are detected in body fluids of patients with immune-related diseases. The present study was aimed to investigate whether increased serum, urine and bronchoalveolar lavage (BAL) fluid levels of neopterin is associated with the development and/or severity of CWP. Mean serum neopterin levels in SP and PMF patients (10.72 +/- 0.98 nmol/L; 14.08 +/- 3.86 nmol/L, respectively) were significantly higher than those of control group (5.30 +/- 0.47 nmol/L) (P < 0.05). Although urinary neopterin levels were also increased in SP and PMF patients (235.17 +/- 7.40 mu mol/mol creatinine; 256.05 +/- 9.43 mu mol/mol creatinine, respectively) as compared with the control group (140.00 +/- 5.43 mu mol/mol creatinine) (P < 0.01), they were within the normal concentration range. No significant difference was observed between serum and urinary neopterin levels of SP and PMF patients. A correlation was observed between serum and urinary neopterin levels of all subjects (r = 0.525, P < 0.01). Bronchoalveolar lavage fluid neopterin levels were significantly higher in patients with SP and PMF (22.67 +/- 2.9 nmol/L; 41.67 +/- 8.68 nmol/L, respectively) compared with control subjects (6.264 +/- 1.74 nmol/L) (P < 0.05, P < 0.0 1, respectively). The levels of neopterin in BAL fluid were also significantly higher in patients with PMF than in those with SP (P < 0.05). These findings indicate that elevated serum and BAL levels of neopterin may be considered as a suitable biomarker for the assessment of CWP

Relationship of inflammatory cytokines with disease severity in CWP patients

45th Congress of the European-Societies-of-Toxicology -- OCT 05-08, 2008 -- Rhodes, GREECEWOS: 000259252100693European Soc Toxico

Evaluation of antioxidant enzyme levels as biological markers at different stages of pneumoconiosis in coal workers

45th Congress of the European-Societies-of-Toxicology -- OCT 05-08, 2008 -- Rhodes, GREECEWOS: 000259252100711European Soc Toxico

Possible effect of gene polymorphisms on the release of TNF alpha and IL1 cytokines in coal workers' pneumoconiosis

WOS: 000286779300025PubMed: 20005085It has been shown that coal dust exposure stimulates inflammatory response leading to increased release of cytokines from monocytes such as TNF-alpha and IL1 These released cytokines play the key role in the pathogenesis of pneumoconiosis including coal workers' pneumoconiosis. In this study, we investigated TNFA, IL1A, IL1B and IL1RA genes variations on basal, lipopolysaccharide and coal dust-induced cytokine release from blood monocytes of homozygous allele and minor variant allele carriers in Turkish coal workers and CWP patients. According to the genotyping results, TNFA -238 gene polymorphism was found as a risk factor in CWP development (OR=3.79) and to in vitro results; release of both TNF-alpha and IL1 cytokines from the monocytes in CWP patients was significantly increased compared to the healthy workers. Also. LPS and coal dust stimulated release of TNF-alpha, which was significantly higher in allele 2 carriers compared to subjects carrying allele 1 in both the groups. These data suggest that the coal dust-induced release of TNF-alpha from monocytes may be a useful biomarker of CWP. (C) 2009 Elsevier GmbH. All rights reserved.Ankara UniversityAnkara University [20030803036]This study was supported by Research Fund of Ankara University (20030803036)