Statistical Methods For Gene/environment Interaction And Genetic Susceptibility

National Institute Of Environmental Health Sciences

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Abstract

Our approach to analyzing case-parents data for gene-environment interaction uses loglinear models and leads to valid inference under two crucial assumptions. The first assumption is that, conditional on parents' genotypes, the genotype distributions of children reflect Mendelian assortment. The second is that, conditional on parents' genotypes, a child's genotype and exposure are independent. We have recently extended our earlier work on estimating purely genetic effects using a hybrid design that recruits and genotypes case-parent triads but only control parents, not their offspring. Our proposed alternative hybrid design substitutes control mother-offspring dyads for controls parents. This alternative hybrid design has the advantage of not requiring fathers of controls, who are sometimes hard to recruit, while preserving the power and flexibility of our original hybrid design. We are currently working to extend this hybrid design for the analysis of gene-environment interactions. In addition, we are developing methods for assessing haplotype-environment interactions. (see Z01 ES040007-12 BB; PI Clare Weinberg). [unreadable] [unreadable] We have recently assessed candidate non-synonymous SNPs for phenotypic differences in double-strand break repair using an assay based on radiation-induced H2A.X foci. Although the assay was sensitive in following the formation and disappearance of foci, we were unable to see any consistent differences between control cell lines and those carrying polymorphisms. In ongoing work, we are using single cell electrophoresis (Comet assay) to assess DNA damage levels in 90 distinct cell lines after exposure to two DNA damaging agents, methyl-methanesulfonate (MMS), an alkylating agent, or hydrogen peroxide (H202) an oxidizing agent. About 30 genes involved in the Base Excision Repair pathway have been resequenced for these cell lines as part of the Environmental Genome Project. Using haplotypes assigned based on that resequencing data, we are attempting to correlate DNA damage measured by the Comet assay with polymorphisms in DNA repair genes. We are also analyzing a crossover dietary study for differences in DNA mutagenicity associated with high-temperature alone vs. either high-temperature fried meat plus certain dietary supplements thought to inhibit mutagenicity or low-temperature fried meat. The biomarkers monitored include Comet assay assessment of DNA damage to colon epithelial cells, and plate-incorporation assay assessment of mutagenicity in urine and in stool. (see Z01 ES49032-12; PI Jack Taylor, EB).