Role of Circadian Factors in Inflammation and Colorectal Adenoma Risk

结直肠癌（CRC）是最常见和致命的癌症形式之一。在南卡罗来纳州， 已经记录了《儿童权利公约》的种族差异，超过了全国的比例。大多数结肠肿瘤起源于腺瘤 （腺瘤性息肉）通过筛查结肠镜检查检测。胃肠道（GI）炎症和 异常的DNA甲基化是驱动腺瘤形成和CRC风险的关键过程。睡眠不足和 昼夜节律紊乱可诱导炎症，改变DNA甲基化，并增加CRC风险。非洲- 美国人（AAs）与欧洲-美国人（EAs）在内源性昼夜节律时间方面不同，他们是 比EA更有可能睡眠不佳和压力过大（非稳态超负荷或“风化”）。这个案子- 一项对照研究将检验昼夜节律过程和睡眠的中断与以下假设有关： 接受结肠镜检查的AA和EA患者中炎症和腺瘤的风险。分子 计时是由“时钟基因”控制的，“时钟基因”通过表观遗传机制调节昼夜节律基因的表达。 生物钟基因可以调节炎症（例如，TNFα、IL-6表达），并且它们作为肿瘤抑制因子 (e.g.,“周期”或PER基因）。我们的研究表明，PER中的遗传变异或异常甲基化 基因与腺瘤风险增加有关，睡眠障碍可增加CRC风险。褪黑激素是 一种生物钟调节激素，通过与其受体结合抑制胃肠道炎症和结肠肿瘤生长， 细胞受体（MT-1、RORα）。这项研究将表征生物行为昼夜节律中断指标 （睡眠障碍，社会时差，疲劳，压力），沿着关键的分子相关性（PER 3基因型和 时钟基因[PER 1、PER 2、PER 3];时钟控制基因[MT-1、RORα、TNFα、IL-6]的甲基化;和 整体DNA甲基化[LINE-1]），以确定它们在炎症和腺瘤风险中的作用。一种生物行为 该框架将解决以下具体目标：1）在患者中进行病例对照研究 进行筛选结肠镜检查以确定昼夜节律中断指标（DNA甲基化， 生物行为、遗传）与腺瘤病例状态相关，如果这种关系是 按种族修改（N= 1，000; 400例病例，600例对照）; 2）确定昼夜节律紊乱指标是否 与正常胃肠道组织炎症相关（TNFα、IL-6 mRNA表达）; 3）确定是否 行为和分子昼夜节律紊乱指标相关; 4）在腺瘤病例中，确定是否 腺瘤中候选昼夜节律基因的甲基化不同于正常GI组织。我们的团队拥有强大的 提供高质量结肠镜检查服务的记录，并参与AA和EA社区， research.前瞻性数据收集（相对于结肠镜检查）和使用有效的定量生物行为 并且分子测量将限制偏差的潜在引入。这项研究将严格审查 基于昼夜节律的行为和分子风险因素，因为它们与GI炎症和结直肠 腺瘤风险。基于昼夜节律的风险因素可能成为CRC预防的新的、可修改的目标。

Colorectal cancer (CRC) is among the most common and deadly forms of cancer. In South Carolina, our group has documented racial CRC disparities that exceed national rates. Most colon tumors arise from adenomas (adenomatous polyps) that are detected via a screening colonoscopy. Gastrointestinal (GI) inflammation and aberrant DNA methylation are key processes driving adenoma formation and CRC risk. Sleep loss and circadian rhythm disruption can induce inflammation, alter DNA methylation, and increase CRC risk. African- Americans (AAs) differ from European-Americans (EAs) in their endogenous circadian timing, and they are more likely than EAs to have poor sleep and excessive stress (allostatic overload or ‘weathering’). This case- control study will test the hypothesis that disruption of circadian processes and sleep is associated with inflammation and adenoma risk among AA and EA patients receiving a screening colonoscopy. Molecular timekeeping is controlled by ‘clock genes’ that regulate circadian gene expression via epigenetic mechanisms. Clock genes can modulate inflammation (e.g., TNFα, IL-6 expression), and they act as tumor suppressors (e.g., the ‘Period’ or PER genes). Our research suggests that genetic variation or aberrant methylation in PER genes is associated with increased adenoma risk, and that sleep disorders can increase CRC risk. Melatonin is a clock-regulated hormone that suppresses GI inflammation and inhibits colon tumor growth by binding to its cellular receptors (MT-1, RORα). This study will characterize biobehavioral circadian disruption indicators (sleep disturbances, social jet lag, fatigue, stress), along with key molecular correlates (PER3 genotype and methylation of: clock genes [PER1, PER2, PER3]; clock-controlled genes [MT-1, RORα, TNFα, IL-6]; and global DNA methylation [LINE-1]) to determine their role in inflammation and adenoma risk. A biobehavioral framework will address the following Specific Aims: 1) Conduct a case-control study among patients undergoing a screening colonoscopy to determine whether circadian disruption indicators (DNA methylation, biobehavioral, genetic) are associated with adenoma case status relative to controls, and if the relationship is modified by race (N=1,000; 400 cases, 600 controls); 2) Determine if circadian disruption indicators are associated with inflammation in normal GI tissue (TNFα, IL-6 mRNA expression); 3) Determine whether behavioral and molecular circadian disruption indicators are related; 4) Among adenoma cases, determine if methylation of candidate circadian genes in adenomas differs from normal GI tissue. Our team has a strong track record of providing high quality colonoscopy services and in engaging AA and EA communities in research. Prospective data collection (relative to colonoscopy) and the use of valid, quantitative biobehavioral and molecular measures will limit the potential introduction of bias. This study will rigorously examine circadian-based behavioral and molecular risk factors as they relate to GI inflammation and colorectal adenoma risk. Circadian-based risk factors may serve as novel, modifiable targets for CRC prevention.