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

全基因组基因-咖啡因相互作用对皮肤基底细胞癌风险的影响2

• 批准号: 8772437
• 负责人: JIALI HAN
• 金额: $ 8.81万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-08 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8772437
• 关键词: ATR protein kinase; Adopted; Apoptosis; Basal Cell; Basal cell carcinoma; Biological; Caffeine; Case-Control Studies; Cells; Coffee; Confidence Intervals; Consumption; DNA biosynthesis; Development; Disease; Drug Targeting; Epidemiologic Studies; Genes; Genetic; Genetic Determinism; Genetic Predisposition to Disease; Genome; Genomics; Health Professional; Individual; Intake; Intervention; Joints; Mediating; Mediation; Meta-Analysis; Methods; Mus; Nurses' Health Study; Oral; Participant; Pattern; Phosphotransferases; Play; Positioning Attribute; Prevention strategy; Publishing; Relative Risks; Risk; Role; Single Nucleotide Polymorphism; Skin; Skin Cancer; Skin Carcinoma; Staging; Tea; Testing; Validation; Variant; Work; analytical method; base; case control; cohort; experience; follow-up; gene environment interaction; genetic profiling; genetic variant; genome wide association study; genome-wide; innovation; keratinocyte; novel; novel strategies; protective effect; public health relevance; ultraviolet damage

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.

描述（由申请人提供）：最近，流行病学研究中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。但是，咖啡因预防皮肤癌的生物学机制在很大程度上尚不清楚。在基因组后时代，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。检查基因 - 咖啡因相互作用可以鉴定出与咖啡因协同作用的新型基因，并有助于发现咖啡因摄入与BCC之间观察到的反相关性的生物学机制。利用BCC的大量现有基因组关联研究（GWAS），我们建议探索基因 - 咖啡因相互作用对整个基因组中BCC的影响。除了标准案例对照方法外，我们还将采用强大的新鸡尾酒方法，该方法在广泛的互动模式下表现出最大的力量，并且在这项研究中尤其吸引人，鉴于未识别出真正的互动效果BCC GWASS。在BCC GWAS中测试基因咖啡因相互作用也是一种发现BCC的新遗传易感基因座的有前途的方法。如果传统GWA的主要作用很小，则通过与咖啡因相互作用影响BCC的基因可能会错过。值得注意的是，咖啡因/咖啡消耗的GWASS新发现了许多与咖啡因摄入相关的遗传基因座，通过基因咖啡因相互作用为BCC关联提供了强大的候选者。因此，我们建议测试这些基因座与它们与BCC的关联，并阐明基因咖啡因相互作用在其总遗传作用中的作用。首先，我们将通过测试其边际影响，与咖啡因摄入的相互作用以及边缘效应和基因咖啡因的关节作用来评估它们与BCC的关联。 互动。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对BCC关联的边际效应的测试表现出更大的功率。将根据所有与咖啡相关的基因座计算咖啡因消耗的遗传评分，并用于代表这些基因座的整体效果。此外，我们将采用一种新的调解分析方法将每个与咖啡相关的SNP的总遗传效应分解为三个组成部分：直接对BCC的影响，通过咖啡因摄入量的间接效应以及与咖啡因摄入的介导的互动效果。该分析将更清楚地表明基因咖啡因相互作用的作用，我们计划使用2,277个BCC病例的大型BCC GWA和6,716个对照进行发现的两阶段分析，并进行了1,000个BCC病例研究的其他BCC病例对照。和1,000个控制验证的控件。我们的研究将是BCC上首次拟合良好的全基因组基因环境相互作用（GWGEI）研究。该提案中测试的统计方法和分析经验也可以应用于有关其他暴露和疾病的GWGEI研究。