Statistical Methods For Gene/environment Interaction And Genetic Susceptibility

点击翻译按钮获取中文摘要

Our earlier approach to analyzing case-parents data for multiplicative gene-environment interaction leads to valid inference for a causative SNP 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. Recently, we have been considering a study design that involves one affected and one unaffected offspring and their parents. We call this structure a tetrad. Our proposal is to genotype the affected offspring and the parents and to collect exposure information from both offspring under that idea that we could test genetic and gene-environment interaction effects using the embedded case-parent-triad design and we could study exposure using the embedded sibling-pair design. In studying this design, we learned that previously proposed family-based tests of gene-environment interaction can be biased when subpopulations differ in both allele frequency and exposure prevalence and when the SNP under study is a marker and not itself the causative SNP. This finding was both surprising and troubling, as researchers had previously believed that family-based studies of gene-environment interaction would robust to bias from population structure even when studying markers. We have published a manuscript that describes these issues in detail and proposes a robust method of analysis for tetrad designs or discordant sib-pairs that can provide valid inference about gene-environment interactions for markers when the exposure under study is dichotomous. In a related manuscript, we have proposed a sibling-augmented case-only design and showed that, with appropriate analysis, it provides the same robust inferences for gene-environment interactions as the analyses we proposed for the tetrad and disease-discordant sib-pair designs. (see Z01 ES040007 BB; PI Clare Weinberg.) We have published results from a crossover dietary study looking 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. Our results indicated that meat cooked at high temperature increased mutagenicity in urine and feces and that consumption of yogurt, cruciferous vegetables, and chlorphyllin together reduced urinary and fecal mutagenicity as well as colorectal cell DNA damage. Although increased urinary mutagenicity following consumption of highly fried meat is well established, our study is the first to concurrently measure both fecal mutagenicity and DNA damage in colon epithelium and to demonstrate that dietary antimutagens can alter these characteristics. (see Z01 ES49032; PI Jack Taylor, EB.)