Statistical Methods For Gene/environment Interaction And Genetic Susceptibility

我们早期的方法来分析的情况下，父母的数据倍增的基因环境相互作用，导致有效的推理下的两个关键假设的致病SNP。第一个假设是，以父母的基因型为条件，子女的基因型分布反映孟德尔分类。第二，在父母基因型的条件下，孩子的基因型和暴露是独立的。最近，我们一直在考虑一项研究设计，涉及一个受影响的和一个未受影响的后代和他们的父母。 我们称这种结构为四分体。 我们的建议是基因型的受影响的后代和父母，并收集暴露信息，从两个后代的想法，我们可以测试遗传和基因-环境的相互作用的影响，使用嵌入式的情况下，父母三重设计，我们可以研究暴露使用嵌入式同胞对设计。 在研究这种设计时，我们了解到，以前提出的基于家庭的基因-环境相互作用的测试可能会有偏见，当亚群在等位基因频率和暴露患病率方面存在差异时，以及当研究中的SNP是一种标记而不是其本身的致病SNP时。 这一发现既令人惊讶又令人不安，因为研究人员以前认为，即使在研究标记物时，基于家族的基因-环境相互作用研究也会受到群体结构偏差的影响。 我们已经发表了一份手稿，详细描述了这些问题，并提出了一个强大的四分体设计或不一致的同胞对，可以提供有效的推断标记的基因-环境相互作用时，暴露在研究中是二分的分析方法。 在相关的手稿中，我们提出了一个同胞增强的情况下，只有设计，并表明，通过适当的分析，它提供了相同的强大的推断基因-环境相互作用的分析，我们提出的四分体和疾病不一致的同胞对设计。(see Z 01 ES 040007 BB; PI克莱尔温伯格。） 我们已经发表了一项交叉饮食研究的结果，该研究旨在寻找与高温单独与高温油炸肉加某些被认为抑制致突变性的膳食补充剂或低温油炸肉相关的DNA致突变性差异。监测的生物标志物包括结肠上皮细胞DNA损伤的彗星试验评估，以及尿液和粪便中致突变性的平板掺入试验评估。我们的研究结果表明，在高温下煮熟的肉增加了尿液和粪便中的致突变性，酸奶，十字花科蔬菜和叶绿酸的消费减少了尿液和粪便的致突变性以及结直肠细胞DNA损伤。 虽然高度油炸肉类消费后尿致突变性增加是公认的，我们的研究是第一个同时测量粪便致突变性和结肠上皮DNA损伤，并证明饮食抗突变剂可以改变这些特性。(see Z01 ES 49032; 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.)