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

描述（由申请人提供）：最近，来自流行病学研究的令人信服的证据表明，较高的咖啡因摄入量与较低的皮肤基底细胞癌（BCC）风险相关。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，现在有可能筛选整个基因组，以发现咖啡因与基因的潜在相互作用。研究基因与咖啡因的相互作用可以识别出与咖啡因协同作用的新基因，并有助于揭示咖啡因摄入与基底细胞癌之间所观察到的负相关的生物学机制。利用现有的BCC全基因组关联研究（GWAS），我们提出探索基因-咖啡因相互作用对整个基因组BCC的影响。除了标准的病例对照方法外，我们将采用强大的新鸡尾酒方法，该方法在广泛的相互作用模式下显示出最大的功效，并且在本研究中特别有吸引力，因为在BCC GWASs中没有发现真正的相互作用效应。在BCC GWAS中检测基因-咖啡因相互作用也是发现BCC新的遗传易感位点的一种很有前途的方法；如果传统GWAS的主要影响很小，那么通过与咖啡因相互作用影响BCC的基因可能会被遗漏。值得注意的是，咖啡因/咖啡摄入的GWASs最近发现了一些与咖啡因摄入相关的基因位点，这为通过基因-咖啡因相互作用与BCC相关提供了强有力的候选基因。因此，我们建议测试这些基因座与BCC的关联，并阐明基因-咖啡因相互作用在其总体遗传效应中的作用。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的关系

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.