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: 8889237
• 负责人: JIALI HAN
• 金额: $ 8.31万
• 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/8889237
• 关键词: ATR gene; 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; Genetic screening method; Genome; Genomics; Health; Health Professional; Individual; Intake; 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; personalized intervention; protective effect; 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(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，现在有可能对整个基因组进行筛选，以发现与咖啡因潜在的遗传相互作用。检测基因-咖啡因的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基底细胞癌之间观察到的反向关联的生物学机制。利用BCC现有的大型全基因组关联研究，我们建议在整个基因组中探索基因-咖啡因相互作用对BCC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方法，这种方法在广泛的相互作用模式下表现出最大的威力，在本研究中特别吸引人，因为在BCC GWAS中没有发现真正的相互作用效应。检测基底细胞癌基因与咖啡因的相互作用也是发现基底细胞癌新的遗传易感基因的一种有希望的方法；在传统的基底细胞癌中，通过与咖啡因相互作用而影响基底细胞癌的基因，如果其主要作用很小，则可能被遗漏。值得注意的是，咖啡因/咖啡消费的GWASs最近发现了一些与咖啡因摄取相关的遗传位点，为通过基因-咖啡因相互作用与基底细胞癌关联提供了强有力的候选。因此，我们建议测试这些基因座与基底细胞癌的关联，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基底细胞癌的关联。 互动。在我们的初步研究中，测试基因-咖啡因的相互作用比传统的SNPs对基底细胞癌关联的边际影响测试显示出更大的威力。咖啡因摄入的遗传得分将基于所有与咖啡相关的基因座来计算，并用于代表这些基因座的整体影响。此外，我们将应用一种新的中介分析方法，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：对BCC的直接影响，通过咖啡因摄取的间接影响，以及与咖啡因摄入量的中介交互作用。这一分析将使基因-咖啡因相互作用的作用更加明确。具体地说，我们计划利用现有的大型BCC GWA进行两阶段分析，其中包括2,277例BCC病例和6,716例对照，用于发现；另一项BCC病例对照研究，用于验证1,000例BCC病例和1,000例对照。我们的研究将是第一个定位良好的关于基底细胞癌的全基因组基因-环境相互作用(GWGEI)研究。在这项建议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卫生倡议关于其他接触和疾病的研究。