Use of the Informatics for Integrating Biology and the Bedside (i2b2) Population to Test Serum Bilirubin Levels and Risk for Inflammatory Bowl Diseases and the Involvement of Uridine Glucuronosyltransferase Genes
Use of the Informatics for Integrating Biology and the Bedside (i2b2) Population to Test Serum Bilirubin Levels and Risk for Inflammatory Bowl Diseases and the Involvement of Uridine Glucuronosyltransferase Genes
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利用信息学整合生物学和床旁 (i2b2) 人群来测试血清胆红素水平和炎性碗疾病的风险以及尿苷葡萄糖醛酸基转移酶基因的参与
DOI：
10.1145/3233547.3233638
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Gallagher, Carla J.
中科院分区：
文献类型：
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作者：
Gallagher, Carla J.
与炎症性肠病（IBD）相关的慢性炎症导致氧化应激增加，从而损害结肠微环境。低水平的血清胆红素，一种内源性抗氧化剂，与克罗恩病（CD）的风险增加有关，但没有研究测试另一种常见的IBD溃疡性结肠炎（UC）。胆红素在肝脏中仅通过尿苷葡萄糖醛酸转移酶1A1（UGT 1A1）代谢。遗传变异引起UGT1A1的功能变化，导致高胆红素血症，如果不治疗，可能对组织有毒，并导致特征性黄疸外观。大约10%的高加索人群为微卫星多态性UGT1A1*28纯合子，由于UGT1A1转录效率降低和UGT1A1酶活性总体降低70%，导致血清总胆红素水平升高。本研究的目的是检查胆红素水平是否与溃疡性结肠炎（UC）的风险相关。使用整合生物学和床边信息学（i2b2），从一个三级护理中心，宾夕法尼亚州立大学好时医疗中心（PSU）确定了一个大的病例对照人群。同样，在弗吉尼亚联邦大学医学中心确定了一个验证队列。进行Logistic回归分析，以确定血清胆红素浓度较低时发生UC的风险。从PSU队列中，在手术切除时获得末端回肠组织子集，以分析UGT 1A1基因表达（编码负责胆红素代谢的酶）。与CD患者相似，UC患者也表现出血清总胆红素水平降低。将血清胆红素水平分为四分位数后，UC的风险随着血清胆红素浓度的降低而增加。这些结果在我们的验证队列中得到证实。UGT1A1基因表达在UC患者的回肠末端上调。较低水平的抗氧化剂胆红素可能会降低UC患者清除活性氧的能力，导致肠损伤增加。这些较低胆红素水平的一个潜在解释可能是UGT1A1基因表达的上调，该基因编码参与结合胆红素的唯一酶。减少氧化应激的治疗可能对这些患者有益。
Chronic inflammation associated with inflammatory bowel disease (IBD) results in increased oxidative stress that damages the colonic microenvironment. A low level of serum bilirubin, an endogenous antioxidant, has been associated with increased risk for Crohn's disease (CD), but no study has tested another common IBD ulcerative colitis (UC). Bilirubin is metabolized in the liver by uridine glucuronosyltransferase 1A1 (UGT1A1) exclusively. Genetic variants cause functional changes in UGT1A1 which result in hyperbilirubinemia, which can be toxic to tissues if untreated and results in a characteristic jaundiced appearance. Approximately 10% of the Caucasian population is homozygous for the microsatellite polymorphism UGT1A1*28, which results in increased total serum bilirubin levels due to reduced transcriptional efficiency of UGT1A1 and an overall 70% reduction in UGT1A1 enzymatic activity. The aim of this study was to examine whether bilirubin levels are associated with the risk for ulcerative colitis (UC). Using the Informatics for Integrating Biology and the Bedside (i2b2), a large case-control population was identified from a single tertiary care center, Penn State Hershey Medical Center (PSU). Similarly, a validation cohort was identified at Virginia Commonwealth University Medical Center. Logistic regression analysis was performed to determine the risk of developing UC with lower concentrations of serum bilirubin. From the PSU cohort, a subset of terminal ileum tissue was obtained at the time of surgical resection to analyze UGT1A1 gene expression (which encodes the enzyme responsible for bilirubin metabolism). Similar to CD patients, UC patients also demonstrated reduced levels of total serum bilirubin. Upon segregating serum bilirubin levels into quartiles, risk of UC increased with reduced concentrations of serum bilirubin. These results were confirmed in our validation cohort. UGT1A1 gene expression was up-regulated in the terminal ileum of a subset of UC patients. Lower levels of the antioxidant bilirubin may reduce the capability of UC patients to remove reactive oxygen species leading to an increase in intestinal injury. One potential explanation for these lower bilirubin levels may be up-regulation of UGT1A1 gene expression, which encodes the only enzyme involved in conjugating bilirubin. Therapeutics that reduce oxidative stress may be beneficial for these patients.