Statistical Methods For Gene/environment Interaction And Genetic Susceptibility

我们早先对倍增基因-环境相互作用的病例-父母数据的分析方法在两个关键假设下导致了对致因SNP的有效推断。第一个假设是，根据父母的基因类型，儿童的基因分布反映了孟德尔式的分类。第二点是，根据父母的基因型别，孩子的基因型别和接触情况是独立的。最近，我们一直在考虑一项研究设计，包括一个受影响的后代和一个未受影响的后代及其父母。我们称这种结构为四分体。我们的建议是对受影响的后代和父母进行基因分型，并从两个后代那里收集暴露信息，在这种想法下，我们可以使用嵌入的病例-父母-三联体设计来测试遗传和基因-环境交互作用的影响，我们可以使用嵌入的兄弟姐妹对设计来研究暴露。在研究这一设计时，我们了解到，以前提出的基于家庭的基因-环境相互作用测试，当亚群在等位基因频率和暴露流行率方面存在差异，并且研究中的SNP是一个标记而不是导致SNP本身时，可能是有偏见的。这一发现既令人惊讶又令人担忧，因为研究人员此前认为，即使在研究标记时，基于家庭的基因与环境相互作用的研究也会对群体结构的偏差产生强烈的影响。我们已经发表了一篇手稿，详细描述了这些问题，并提出了一种稳健的四分体设计或不协调同胞对的分析方法，当研究中的暴露是二分的时，该方法可以为标记提供关于基因-环境相互作用的有效推断。在一篇相关的手稿中，我们提出了一种仅兄弟姐妹扩增病例的设计，并表明，通过适当的分析，它提供了与我们为四分体和疾病不一致的同胞对设计提出的分析相同的关于基因-环境相互作用的稳健推断。(见Z01 ES040007 BB；Pi Clare Weinberg。) 我们发表了一项交叉饮食研究的结果，寻找与单独高温炸肉或高温炸肉加某些被认为抑制突变的膳食补充剂或低温炸肉有关的DNA诱变性的差异。监测的生物标志物包括彗星试验评估DNA对结肠上皮细胞的损伤，以及平板掺入试验评估尿液和粪便中的诱变性。我们的结果表明，在高温下烹调的肉类增加了尿液和粪便中的致突变性，而酸奶、十字花科蔬菜和叶绿素的消费共同降低了尿液和粪便中的诱变性以及结直肠细胞的DNA损伤。尽管食用高油炸肉类后尿液致突变性增加是众所周知的，但我们的研究首次同时检测了粪便诱变性和结肠上皮细胞的DNA损伤，并证明饮食中的抗突变剂可以改变这些特征。(见Z01 ES49032；PI Jack Taylor，EB。)

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.)