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

基本信息

批准号：
8386849
负责人：
POLLY A NEWCOMB
金额：
$ 8.8万
依托单位：
FRED HUTCHINSON CANCER RESEARCH CENTER
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-10 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8386849
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

项目摘要

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. PUBLIC HEALTH RELEVANCE: This study aims to identify potential mechanisms underlying the association between blood lipid concentrations and the occurrence of colorectal adenomatous polyps. Our findings about the occurrence of adenomas and genes that influence blood lipid phenotypes may inform the mechanisms involved in neoplastic pathways, potentially identifying new avenues of colorectal cancer prevention through cholesterol management for those with inherited susceptibility to dyslipidemia.

描述（由申请人提供）：流行病学研究的证据显示血脂浓度与结直肠腺瘤之间的关联。但是，很难确定此联系是否指示因果机制，还是癌症和心血管疾病（例如饮食，肥胖，吸烟和身体不活动）的共同危险因素的结果。血脂异常很常见，影响了美国成年人口的三分之一，并且具有强大的遗传成分。一些研究已经确定了已知会影响脂质水平的遗传基因座与结直肠瘤的风险，包括PCSK9， ABCG8和APOE，但是这些研究仅限于几个候选基因。已经为脂质表型进行了许多最近的全基因组关联研究（GWASS），并且将近100个基因座与血脂水平有关。特斯洛维奇在al。（2010年）对涉及超过100,000个个体的血浆脂质测量值进行了46个GWASS的联合分析。他们的分析导致一组与总胆固醇（TC），高密度脂蛋白（HDL，LDL）胆固醇和甘油三酸酯（TG）有关的102个单核苷酸多态性（SNP）。值得注意的是，这些新认识的变体会影响已知对癌变重要的途径：炎症，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。我们的孟德尔随机方法利用了观察到的表型利用遗传代理，这将有助于避免混淆和逆转因果关系的问题，这些问题阻碍了先前对这个问题的观察性研究。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。具体而言，我们提出的研究将：1）测试我们研究人群中LDL，HDL，TG和TC的腺瘤与血液浓度之间的关联； 2）确定腺瘤和102个与血脂有关的GWAS识别的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有所不同。我们将利用华盛顿州立大型医疗保健提供商的综合群体卫生（GH）的结肠镜研究中实现现有的生物镜和问卷数据。参与者在1998年至2007年之间进行了结肠镜检查。总共有889例病理学家确认的腺瘤病例，1,037例，无息肉结肠镜检查作为对照。新数据收集包括：1）基因分型提取的DNA； 2）测量来自存储的血浆或病历的脂质； 3）测量药房记录中胆固醇药物的使用。脂质度量的优势比将从逻辑回归中估算。根据机械途径，将在单SNP分析和作为遗传风险评分的一部分中考虑变体。了解脂质基因如何影响腺瘤的风险可能会为癌变机制提供信息，最终有助于减轻CRC的负担。公共卫生相关性：本研究旨在确定血脂浓度与结直肠腺瘤息肉发生之间关联的潜在机制。我们关于影响血脂表型的腺瘤和基因的发生的发现可能会为涉及肿瘤途径的机制提供信息，从而有可能通过胆固醇管理来识别有胆固醇预防的新途径，以至于那些对血脂异常的易感性易感性。