Lipid genotypes, phenotypes, and colorectal adenomas: Elucidating mechanisms

脂质基因型、表型和结直肠腺瘤：阐明机制

• 批准号: 8542803
• 负责人: POLLY A NEWCOMB
• 金额: $ 8.27万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-10 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8542803
• 关键词: Address; Adhesions; Adult; Affect; Alleles; Apolipoproteins; Apoptosis; Biological; Blood; Candidate Disease Gene; Carcinogenesis Mechanism; Cardiovascular Diseases; Cardiovascular system; Cell Adhesion; Cholesterol; Chronic Disease; Colonoscopy; Colorectal; Colorectal Adenoma; Colorectal Cancer; Colorectal Neoplasms; DNA; Data; Data Collection; Diet; Dyslipidemias; Epidemiologic Studies; Epidemiology; Etiology; Evaluation; Free Will; Genes; Genetic; Genetic Predisposition to Disease; Genetic Risk; Genotype; Germ Cells; Growth Factor; Health; Health Personnel; Health behavior; High Density Lipoprotein Cholesterol; Hormones; Immune; Individual; Inflammation; Inherited; Investigation; LDL Cholesterol Lipoproteins; Learning; Lesion; Link; Linkage Disequilibrium; Lipids; Lipoproteins; Location; Logistic Regressions; Low-Density Lipoproteins; Malignant Neoplasms; Measurement; Measures; Medical History; Medical Records; Methods; Obesity; Observational Study; Odds Ratio; Outcome; Participant; Pathologist; Pathway interactions; Pharmaceutical Preparations; Pharmacy facility; Phenotype; Plague; Plasma; Play; Polyps; Population; Population Study; Premalignant; Proxy; Publishing; Questionnaires; Randomized; Records; Regulation; Reporting; Risk; Risk Factors; Role; Sampling; Severities; Signal Transduction; Single Nucleotide Polymorphism; Smoking; Smoking Behavior; Stratification; Testing; Transportation; Triglycerides; Variant; Vascular Endothelium; Vitamin D; Washington; adenoma; angiogenesis; base; blood lipid; carcinogenesis; cholesterol control; colorectal cancer prevention; density; epidemiologic data; genetic association; genetic variant; genome wide association study; insight; intestinal epithelium; macromolecule; migration; neoplastic; peroxidation; steroid hormone

DESCRIPTION (provided by applicant): Evidence from epidemiologic studies shows an association between blood lipid concentrations and colorectal adenomas. It has been difficult, however, to determine if this link is indicative of a causal mechanism or is the consequence of shared risk factors for cancer and cardiovascular disease such as diet, obesity, smoking, and physical inactivity. Dyslipidemia is common, affecting up to one-third of the adult US population, and has a strong hereditary component. Some studies have identified associations between genetic loci known to influence lipid levels and the risk of colorectal neoplasia, including PCSK9, ABCG8, and APOE, but these studies have been limited to only a few candidate genes. Many recent genome-wide association studies (GWASs) have been conducted for lipid phenotypes, and nearly 100 loci have been linked to blood lipid levels. Teslovich at al. (2010) conducted a combined analysis of 46 GWASs involving plasma lipid measurements from over 100,000 individuals. Their analysis resulted in a set of 102 single nucleotide polymorphisms (SNPs) related to blood levels of total cholesterol (TC), high- and low-density lipoprotein (HDL, LDL) cholesterol, and triglycerides (TG). Notably, these newly recognized variants affect pathways known to be important for carcinogenesis: inflammation, apoptosis, angiogenesis, cellular signaling, adhesion, migration, hormone synthesis, and growth factor regulation. In the proposed post-GWAS study, we will evaluate the association between adenoma occurrence, lipid phenotypes, and lipid genotypes. Our Mendelian randomization approach, which exploits genetic proxies for observed phenotypes, will help avoid problems with confounding and reverse causation that have hampered previous observational studies of this question. This method has proved to be especially effective for studies of cholesterol and cardiovascular disease. Specifically, our proposed study will: 1) test the association between adenomas and blood concentrations of LDL, HDL, TG, and TC in our study population; 2) determine the association between adenomas and 102 GWAS-identified SNPs related to blood lipids; and 3) evaluate whether these genetic associations with adenoma risk vary according to measured blood lipid concentrations. We will utilize extant biospecimens and questionnaire data from a completed colonoscopy study among enrollees of Group Health (GH), a large healthcare provider in Washington State. Participants underwent colonoscopy for any indication at GH between 1998 and 2007. In total, there were 889 pathologist-confirmed adenoma cases and 1,037 with a polyp-free colonoscopy that serve as controls. New data collection includes: 1) genotyping extracted DNA; 2) measuring lipids from stored plasma or from medical records; and 3) measuring use of cholesterol medication from pharmacy records. Odds ratios for lipid measures will be estimated from logistic regression. Variants will be considered in both single-SNP analyses and as part of genetic risk scores according to mechanistic pathway. Understanding how lipid genes influence adenoma risk may inform mechanisms of carcinogenesis, ultimately helping to reduce the burden of CRC.

描述（由申请人提供）：流行病学研究的证据表明血脂浓度与结直肠腺瘤之间存在关联。然而，很难确定这种联系是否表明了因果机制，或者是癌症和心血管疾病的共同危险因素（例如饮食、肥胖、吸烟和缺乏身体活动）的结果。血脂异常很常见，影响着多达三分之一的美国成年人，并且具有很强的遗传性。一些研究已经确定了已知影响脂质水平的基因位点与结直肠肿瘤风险之间的关联，包括 PCSK9、 ABCG8 和 APOE，但这些研究仅限于少数候选基因。最近针对脂质表型进行了许多全基因组关联研究 (GWAS)，近 100 个基因座已与血脂水平相关。特斯洛维奇等人。 (2010) 对 46 个 GWAS 进行了综合分析，涉及超过 100,000 人的血浆脂质测量。他们的分析得出了一组 102 个单核苷酸多态性 (SNP)，它们与血液中总胆固醇 (TC)、高密度脂蛋白和低密度脂蛋白 (HDL、LDL) 胆固醇和甘油三酯 (TG) 的水平相关。值得注意的是，这些新认识的变异影响已知对癌发生重要的途径：炎症、细胞凋亡、血管生成、细胞信号传导、粘附、迁移、激素合成和生长因子调节。在拟议的 GWAS 后研究中，我们将评估腺瘤发生、脂质表型和脂质基因型之间的关联。我们的孟德尔随机化方法利用观察到的表型的遗传代理，将有助于避免混淆和反向因果关系的问题，这些问题阻碍了之前对该问题的观察研究。事实证明，这种方法对于胆固醇和心血管疾病的研究特别有效。具体来说，我们提出的研究将：1）测试我们研究人群中腺瘤与 LDL、HDL、TG 和 TC 血液浓度之间的关联； 2) 确定腺瘤与 102 个 GWAS 鉴定的血脂相关 SNP 之间的关联； 3) 评估这些与腺瘤风险的遗传关联是否根据测量的血脂浓度而变化。我们将利用华盛顿州大型医疗保健提供商 Group Health (GH) 的参与者完成的结肠镜检查研究中现有的生物样本和问卷数据。 1998 年至 2007 年间，参与者在 GH 接受了任何适应症的结肠镜检查。总共有 889 例经病理学家确诊的腺瘤病例和 1,037 例接受无息肉结肠镜检查的病例作为对照。新的数据收集包括：1）对提取的 DNA 进行基因分型； 2) 从储存的血浆或医疗记录中测量脂质； 3) 根据药房记录测量胆固醇药物的使用情况。脂质测量的优势比将通过逻辑回归估计。变异将被考虑在单 SNP 分析中，并根据机制途径作为遗传风险评分的一部分。了解脂质基因如何影响腺瘤风险可能有助于了解致癌机制，最终有助于减轻结直肠癌的负担。