Statistical Methods For Gene/environment Interaction And Genetic Susceptibility

我们分析基因-环境交互作用的病例-父母数据的方法使用对数线性模型，并在两个关键假设下得出有效的推断。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。我们最近扩展了我们早期的纯遗传效应估计工作，使用了一种杂交设计，该设计招募病例父母三合一并对其进行基因分型，但只控制父母，而不是他们的后代。我们提出的替代杂交设计用对照母子二元取代对照双亲。这种替代混合设计的优势在于，不需要控制之父，而控制之父有时很难招募到，同时保留了我们原始混合设计的力量和灵活性。我们目前正在努力扩展这种混合设计，用于分析基因与环境的相互作用。此外，我们正在开发评估单倍型-环境相互作用的方法。(见Z01 ES040007-12 BB；Pi Clare Weinberg)。 我们最近使用一种基于辐射诱导的H2A.X焦点的分析方法，评估了候选非同义SNPs在双链断裂修复中的表型差异。尽管该分析在跟踪病灶的形成和消失方面是敏感的，但我们无法在对照细胞系和携带多态的细胞系之间看到任何一致的差异。在正在进行的工作中，我们正在使用单细胞电泳(彗星试验)来评估90个不同的细胞株在暴露于两种DNA损伤剂--甲烷磺酸甲酯(MMS)、烷化剂或过氧化氢(H202)--氧化剂后的DNA损伤水平。作为环境基因组计划的一部分，这些细胞系的大约30个参与碱基切除修复途径的基因已经重新测序。使用基于重新测序数据指定的单倍型，我们正试图将彗星试验测量的DNA损伤与DNA修复基因的多态联系起来。我们还在分析一项交叉饮食研究，以了解单独高温与高温油炸肉加某些被认为抑制突变的膳食补充剂或低温油炸肉有关的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。(见Z01 ES49032-12；PI Jack Taylor，EB)。

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). 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).