Singapore

Genetic Analyses for Epidemiologic Studies of Respiratory Diseases
(Project: # ES025045 )
London, Stephanie (london2@niehs.nih.gov ) - NIEHS
Abstract: This project describes the role of the lab of Stephanie London in the Laboratory of Respiratory Biology in support of her epidemiologic studies. The laboratory is engaged in selection of polymorphisms for analysis, using bioinformatic methods and genotyping analysis of samples from Dr. London's epidemiologic studies of respiratory disease. In the past year, we have focused on the study of childhood asthma in Mexico City (described under project entitled Genetic And Environmental Factors In Childhood Respiratory Health). The laboratory uses primarily real-time PCR technology to identify genetic polymorphisms in these samples. DIR has recently acquired an Illumina reader. Our lab staff have been trained on the use of this technology and we are planning our first set of genotyping using this technology. The lab staff have also received additional offsite training in haplotype analysis and bioinformatics in service of the labs goals. We are developing plans to collaborate with David Schwartz's group to analyze the Mexico City study for genes involved in innate immunity (1,536 SNPs using an Illumina panel). This work will be done jointly with Huiling Li and the staff of the Schwartz lab using the new core Illumina facility. This panel will also be examined in other studies in the Schwartz lab enabling comparison data. We are collaborating with statistical geneticist Dimitri Zaykin to use Bayesian methods for analyses of these data when they are available to deal with the multiple comparison issue in a manner that maximizes prior information about the genes and SNPs in this panel. In the coming year, we expect to receive samples from asthma cases and controls in the Singapore Chinese Cohort study. We will then examine candidate genes that are relevant to the cohort exposures in addition to genes that we are examining in the Mexico study. This will enable confirmation of findings across multiple populations.

Genetic and Environmental Factors in Adult Respiratory Asthma
(Project: # ES043012 )
London, Stephanie (london2@niehs.nih.gov ) - NIEHS
Abstract: There is evidence that dietary factors may be important in the etiology of asthma and chronic obstructive pulmonary disease (COPD) in both smokers and nonsmokers. However, the existing data on the role of diet in the etiology of asthma and COPD come predominantly from cross-sectional studies. Prospective data are needed to properly address the role of diet in the development of asthma and COPD. Air pollution clearly exacerbates existing lung disease, but a role in the incidence of asthma and COPD in adults is not established. Prospective data are necessary to properly examine this association, but such data are few. Genetic factors are likely to play a role in modulating the effects of diet, smoking, and ambient air pollution on the risk of cardiac and respiratory outcomes in adults. Genetic factors may influence the metabolism of nutrients in food that are responsible for health effects. Both diet and genetics may combine to influence susceptibility to adverse effects of air pollution. Effects of air pollution are likely to be weak when averaged over whole populations and identification of susceptibility factors will help to clarify health consequences of air pollution. I am establishing several high-quality population resources to prospectively investigate effects of air pollution, diet, genetics and their interactions in relation to asthma and COPD in adults. The first population is a cohort of 63,000 older adults of Chinese ethnicity in Singapore. The cohort was established with NCI extramural funding to examine the relationship between diet and cancer. I have expanded the study to include the assessment of asthma and chronic bronchitis and expanded the assessment of environmental exposures. The Singapore Chinese cohort is of particular interest because of the prospective collection of risk factor data. Another major strength of the study is the high quality dietary assessment, which was developed specifically for, and validated in, this population. The Singapore cohort also follows dietary patterns quite distinct from the Western populations included in existing adult respiratory studies. Other strengths of the study are the large proportion of nonsmokers and the availability of genetic samples. In the past year, we published a paper on dietary patterns and chronic bronchitis symptoms which represented the first use of dietary pattern analysis in the study of nonmalignant respiratory disease. We have also found associations between occupational exposures to dusts and solvents in the Singapore Chinese cohort and published these results. The second study is a collaboration with another extramurally funded cohort, the Atherosclerosis Risk in Communities (ARIC) study. We are examining traffic-related air pollution in relation to a range of respiratory and cardiovascular endpoints. The ARIC study is a cohort of 16,000 adults assembled from 1987-1989 in four US communities. ARIC has a wealth of detailed cardiac and respiratory phenotypes including pulmonary function and retinal examination data. We have observed associations between a valid surrogate of traffic related air pollution and both pulmonary function and microvascular retinal abnormalities. We are nearly ready to submit these manuscripts. We have also found evidence of dietary modification of these associations and have received approval from the ARIC manuscript committee to prepare manuscripts on this topic. The third population is the Sister Study. This NIEHS cohort will have 50,000 sisters of women with breast cancer. I have added nonmalignant respiratory disease questions to the questionnaire with the aim of examining gene-environment interaction in relation to respiratory disease in this cohort. Because the respiratory outcomes of interest have proved to be common in analysis of the first 10,000 respondents, I plan to begin analyses of risk factors for asthma and respiratory symptoms after data become available on the first 20,000 respondents. The final population is the Agricultural Health Study (AHS) at NIEHS. I am co-PI with Jane Hoppin on a proposal to create an asthma case-cohort study looking at genetics of adult asthma and gene-environment interaction within the AHS. This was one of the projects recently reviewed as part of the Director's Challenge proposal on which I was the Co-PI with Darryl Zeldin. In collaboration with investigators at the EPA-UNC Human Exposure Facility, I have established a study to follow-up on recent experimental work showing that obese mice have greater respiratory response to ozone than lean mice. We have established an experimental study where centrally obese and lean women will be exposed to ozone and we will measure both spirometric and inflammatory responses to ozone.