Utilization of Biomarker Data for Clinical and Environmental Intervention.

Of the 189 air toxics listed in the Clean Air Act, a substantial number are important in potentially causing adverse health effects in several organ systems. Although the major health effects are manifested as respiratory diseases, especially airways disease, these agents may cause cancer and premature mortality, probably from cardiopulmonary disease. Validated biologic markers may be useful in identifying early effects to improve our understanding of exposure-response relationships and clarify susceptibility. However, the knowledge obtained from epidemiologic studies utilizing these new molecular tools will reduce morbidity and mortality from air toxics only when they can be applied effectively in the prevention and control of disease. Intervention strategies using these markers can be used to identify etiologic factors and assess the effectiveness of exposure reduction, and, in some instances, chemoprevention. This paper illustrates examples of these intervention strategies and reviews the current strengths and limitations of environmental molecular epidemiology in controlling disease caused by air toxics

East meets West: ethnic differences in epidemiology and clinical behaviors of lung cancer between East Asians and Caucasians

Lung cancer is the leading cause of cancer death worldwide, with large variation of the incidence and mortality across regions. Although the mortality of lung cancer has been decreasing, or steady in the US, it has been increasing in Asia for the past two decades. Smoking is the leading cause of lung cancer, and other risk factors such as indoor coal burning, cooking fumes, and infections may play important roles in the development of lung cancer among Asian never smoking women. The median age of diagnosis in Asian patients with lung cancer is generally younger than Caucasian patients, particularly among never-smokers. Asians and Caucasians may have different genetic susceptibilities to lung cancer, as evidenced from candidate polymorphisms and genome-wide association studies. Recent epidemiologic studies and clinical trials have shown consistently that Asian ethnicity is a favorable prognostic factor for overall survival in non-small cell lung cancer (NSCLC), independent of smoking status. Compared with Caucasian patients with NSCLC, East Asian patients have a much higher prevalence of epidermal growth factor receptor (EGFR) mutation (approximately 30% vs. 7%, predominantly among patients with adenocarcinoma and never-smokers), a lower prevalence of K-Ras mutation (less than 10% vs. 18%, predominantly among patients with adenocarcinoma and smokers), and higher proportion of patients who are responsive to EGFR tyrosine kinase inhibitors. The ethnic differences in epidemiology and clinical behaviors should be taken into account when conducting global clinical trials that include different ethnic populations

TEGS-CN: A Statistical Method for Pathway Analysis of Genome-wide Copy Number Profile

The effects of copy number alterations make up a significant part of the tumor genome profile, but pathway analyses of these alterations are still not well established. We proposed a novel method to analyze multiple copy numbers of genes within a pathway, termed Test for the Effect of a Gene Set with Copy Number data (TEGS-CN). TEGS-CN was adapted from TEGS, a method that we previously developed for gene expression data using a variance component score test. With additional development, we extend the method to analyze DNA copy number data, accounting for different sizes and thus various numbers of copy number probes in genes. The test statistic follows a mixture of X2 distributions that can be obtained using permutation with scaled X2 approximation. We conducted simulation studies to evaluate the size and the power of TEGS-CN and to compare its performance with TEGS. We analyzed a genome-wide copy number data from 264 patients of non-small-cell lung cancer. With the Molecular Signatures Database (MSigDB) pathway database, the genome-wide copy number data can be classified into 1814 biological pathways or gene sets. We investigated associations of the copy number profile of the 1814 gene sets with pack-years of cigarette smoking. Our analysis revealed five pathways with significant P values after Bonferroni adjustment (<2.8 × 10−5), including the PTEN pathway (7.8 × 10−7), the gene set up-regulated under heat shock (3.6 × 10−6), the gene sets involved in the immune profile for rejection of kidney transplantation (9.2 × 10−6) and for transcriptional control of leukocytes (2.2 × 10−5), and the ganglioside biosynthesis pathway (2.7 × 10−5). In conclusion, we present a new method for pathway analyses of copy number data, and causal mechanisms of the five pathways require further study

Gene-environment interaction effects on lung function- a genome-wide association study within the Framingham heart study

Background: Previous studies in occupational exposure and lung function have focused only on the main effect of occupational exposure or genetics on lung function. Some disease-susceptible genes may be missed due to their low marginal effects, despite potential involvement in the disease process through interactions with the environment. Through comprehensive genome-wide gene-environment interaction studies, we can uncover these susceptibility genes. Our objective in this study was to explore gene by occupational exposure interaction effects on lung function using both the individual SNPs approach and the genetic network approach. Methods: The study population comprised the Offspring Cohort and the Third Generation from the Framingham Heart Study. We used forced expiratory volume in one second (FEV1) and ratio of FEV1 to forced vital capacity (FVC) as outcomes. Occupational exposures were classified using a population-specific job exposure matrix. We performed genome-wide gene-environment interaction analysis, using the Affymetrix 550 K mapping array for genotyping. A linear regression-based generalized estimating equation was applied to account for within-family relatedness. Network analysis was conducted using results from single-nucleotide polymorphism (SNP)-level analyses and from gene expression study results. Results: There were 4,785 participants in total. SNP-level analysis and network analysis identified SNP rs9931086 (Pinteraction =1.16 × 10-7) in gene SLC38A8, which may significantly modify the effects of occupational exposure on FEV1. Genes identified from the network analysis included CTLA-4, HDAC, and PPAR-alpha. Conclusions: Our study implies that SNP rs9931086 in SLC38A8 and genes CTLA-4, HDAC, and PPAR-alpha, which are related to inflammatory processes, may modify the effect of occupational exposure on lung function

The Global Contribution of Outdoor Air Pollution to the Incidence, Prevalence, Mortality and Hospital Admission for Chronic Obstructive Pulmonary Disease: A Systematic Review and Meta-Analysis

Objective:: This study aimed to investigate the quantitative effects of outdoor air pollution, represented by 10 µg/m3 increment of PM10, on chronic obstructive pulmonary disease in China, United States and European Union through systematic review and meta-analysis. Methods:: Publications in English and Chinese from PubMed and EMBASE were selected. The Cochrane Review Handbook of Generic Inverse Variance was used to synthesize the pooled effects on incidence, prevalence, mortality and hospital admission. Results:: Outdoor air pollution contributed to higher incidence and prevalence of COPD. Short-term exposure was associated with COPD mortality increased by 6%, 1% and 1% in the European Union, the United States and China, respectively (p < 0.05). Chronic PM exposure produced a 10% increase in mortality. In a short-term exposure to 10 µg/m3 PM10 increment COPD mortality was elevated by 1% in China (p < 0.05) and hospital admission enrollment was increased by 1% in China, 2% in United States and 1% in European Union (p < 0.05). Conclusions:: Outdoor air pollution contributes to the increasing burdens of COPD.10 µg/m3 increase of PM10 produced significant condition of COPD death and exacerbation in China, United States and European Union. Controlling air pollution will have substantial benefit to COPD morbidity and mortality

Should Asbestos in Buildings Be Regulated on an Environmental or Occupational Basis?

The issue of asbestos abatement in buildings may be viewed as part of a larger and more fundamental scientific and social issue: Should asbestos in buildings be regulated on an environmental or an occupational basis? The environmental approach to regulation of hazardous substances has a different emphasis from that of an occupational approach. The environmental approach emphasizes abatement of property damage, while the occupational approach is more concerned with decreased exposure levels and compensation for injuries to health. Similarly, the justifications for the two approaches also have a different emphasis. The need for environmental protection is justified on the basis of diffuse injuries of toxic substances to the general population. In comparison, the justification for regulation of toxic substances in the workplace is based on identifiable injuries to workers. These different justifications have led to some divergence in policy approaches. Thus, this article addresses the issue of abatement of asbestos in buildings in the context of comparing the environmental with the occupational approaches to regulating asbestos in buildings

Accuracy of work history obtained from a spouse

In an evaluation of the usefulness of collecting work exposure information from wives of workers, 26 husband-wife pairs were interviewed separately about exposure of the husband to organic solvents. There was 58% concordance between the husbands and wives for answers to a simple question regarding solvent exposure. Amplification of these answers through the use of a computerized occupation-exposure linkage system yielded 81% concordance. When the analysis was restricted to those reporting exposure to solvents for more than five years, an 88% concordance was achieved with the linkage system. It was concluded that wives can accurately recall their husbands\u27 work histories with respect to jobs having solvent exposure. The exposure specificity of such histories is significantly enhanced by the use of an occupation-exposure linkage system