Genome-Wide Gene-Caffeine Interactions on Risk of Skin Basal Cell Carcinoma2

描述（由申请人提供）：最近，流行病学研究有令人信服的证据表明，较高的咖啡因摄入量与皮肤基底细胞癌（BCC）的风险较低有关。然而，咖啡因预防皮肤癌的生物学机制在很大程度上是未知的。在后基因组时代，现在可以筛选整个基因组，以发现与咖啡因的潜在遗传相互作用。研究基因-咖啡因相互作用可以识别与咖啡因协同作用的新基因，并有助于揭示咖啡因摄入量和BCC之间观察到的负相关的生物学机制。利用现有的一个大的BCC全基因组关联研究（GWAS），我们建议探索基因-咖啡因相互作用对BCC在整个基因组中的影响。除了标准的病例对照方法，我们将采用强大的新鸡尾酒的方法，它已被证明在广泛的相互作用模式下的最大功率，特别是在这项研究中的吸引力，考虑到真正的相互作用的影响没有确定在BCC GWAS。在BCC GWAS中测试基因-咖啡因相互作用也是发现BCC新的遗传易感性位点的一种有希望的方法;通过与咖啡因的相互作用影响BCC的基因可能在传统的GWAS中被遗漏，如果它们的主要影响很小。值得注意的是，咖啡因/咖啡消费的GWAS新发现了一些与咖啡因摄入相关的遗传位点，通过基因-咖啡因相互作用为BCC关联提供了强有力的候选者。因此，我们建议测试这些位点与BCC的关联，并阐明基因-咖啡因相互作用在其总遗传效应中的作用。首先，我们将通过测试它们的边际效应、与咖啡因摄入的相互作用以及边际效应和基因-咖啡因的联合效应来评估它们与BCC的关联 交互.在我们的初步研究中，测试基因-咖啡因相互作用比传统的SNP边缘效应测试显示出更大的功效。咖啡因摄入量的遗传评分将基于所有咖啡相关基因座计算，并用于代表这些基因座的总体影响。此外，我们将采用一种新的中介分析方法，将每个咖啡相关SNP的总遗传效应分解为三个组成部分：对BCC的直接效应，通过咖啡因摄入的间接效应，以及与咖啡因摄入的介导交互效应。这项分析将使基因-咖啡因相互作用的作用更清楚具体地说，我们计划进行两阶段分析，使用现有的2，277例BCC病例和6，716例对照的大型BCC GWAS进行发现，并使用1，000例BCC病例和1，000例对照的额外BCC病例对照研究进行验证。我们的研究将是第一个定位良好的全基因组基因环境相互作用（GWGEI）研究BCC。本提案中测试的统计方法和获得的分析经验也可应用于全球环境工作组关于其他照射和疾病的研究。

DESCRIPTION (provided by applicant): Recently, there has been compelling evidence from epidemiologic studies that higher caffeine intake is associated with lower risk of basal cell carcinoma (BCC) of the skin. However, the biological mechanisms by which caffeine protects against skin cancer are largely unknown. In the post-genomic era, it is now possible to screen the entire genome to uncover potential genetic interactions with caffeine. Examining gene-caffeine interactions could identify novel genes that act synergistically with caffeine and help uncover biological mechanisms underlying the observed inverse association between caffeine intake and BCC. Taking advantage of a large existing genome-wide association study (GWAS) of BCC, we propose to explore the effects of gene- caffeine interactions on BCC in the entire genome. In addition to the standard case-control approach, we will adopt the powerful new cocktail approach, which has demonstrated the greatest power under a wide range of interaction patterns and is particularly appealing in this study, given that the true interaction effects were not identified in BCC GWASs. Testing gene-caffeine interactions in BCC GWAS is also a promising approach to discover novel genetic susceptibility loci for BCC; genes influencing BCC through interactions with caffeine may be missed in traditional GWAS if their main effects are small. Of note, GWASs of caffeine/coffee consumption have newly identified a number of genetic loci associated with caffeine intake, offering strong candidates for BCC association via gene-caffeine interactions. We therefore proposed to test these loci for their associations with BCC and clarify the role of gene-caffeine interactions in their total genetic effects. First, we will evaluate their associations with BCC by testing their marginal effects, interactions with caffeine intake, and the joint effects of both marginal effects and gene-caffeine interactions. In our preliminary study, testing gene-caffeine interactions demonstrated greater power than the traditional test of SNPs' marginal effects for BCC associations. A genetic score of caffeine consumption will be calculated based on all coffee-related loci and used to represent the overall effect of these loci. Furthermore, we will apply a new approach of mediation analysis to decompose the total genetic effect of each coffee-related SNP into three components: the direct effect on BCC, the indirect effect through caffeine intake, and the mediated interactive effect with caffeine intake. This analysis will make clearer the role of gene-caffeine interactions Specifically, we plan to conduct a two-stage analysis using a large existing BCC GWAS of 2,277 BCC cases and 6,716 controls for discovery and an additional BCC case-control study of 1,000 BCC cases and 1,000 controls for validation. Our study would be the first well-positioned genome-wide gene-environment interaction (GWGEI) study on BCC. The statistical approaches tested and analytical experience gained in this proposal can be applied to GWGEI studies on other exposures and diseases as well.