This project provides genetic analyses for epidemiologic studies being conducted by Stephanie London through the epidemiology branch. The epidemiologic projects are referencedand described under the following Z01 project numbers - 49017, 49019, 43012. In brief, these are epidemiology studies of lung cancer (49017), childhood respiratory illness (49019, including asthma and impaired lung function) and adult nonmalignant respiratory illness (43012). These studies are being conducted in various ethnic groups. The studies of lung cancer are in African-Americans, Caucasians, and Shanghai, Chinese. The studies of childhood respiratory illness include populations in Southern California, Wuhan China and Mexico City and the study of nonmalignant respiratory disease is in Singapore. These international populations are of interest because rates of asthma vary widely. We are pursuing a candidate gene approach selecting polymorphisms in genes with potential relevance to asthma based on their function and, in some instances additional their location in regions of linkage for asthma. The emphasis is on functionally significant polymorphisms. We have nominated genes for screening for polymorphisms through the Environmental Genome Project. Once these candidate genes are screened, we would follow-up any polymorphisms in the epidemiologic studies as well as screening for functional significance. This past year has been devoted to setting up the laboratory and hiring/training a technician and postdoc. We have done this with the help of Doug Bell. We have completed laboratory analysis of three polymorphisms involved in DNA repair in the lung cancer study - two in the XRCC1 gene and one in the XPD gene. We will be examining additional lung cancer candidate genes. With respect to asthma, we are currently establishing assays for two polymorphisms recently described in the IL-13 gene which appear to influence function. One is in the promoter region at -1055 and one in the coding region (exon 4) leads to an amino acid substitution (Arg 130Gln). We will be pursuing additional candidate genes for asthma in this next year. In addition to asthma candidates based on previous linkage results, we are interested in examining polymorphisms in the Tlr4 gene that appear to involved in response to endotoxin, ozone and particles , an exposure which is high for both the Mexico City and Wuhan studies, and for the Mexico City study, ozone. Mexico City has the highest ozone levels in North America. The laboratory techniques involved include RFLP/PCR and TaqMan PCR.
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