2018-08-012024-05-16https://scholars.lib.ntu.edu.tw/handle/123456789/668220摘要：腹腔內粘黏是腹部手術後常見的病發症，影響全球數百萬人手術後的生活品質。目前並沒有文獻使用全基因體研究(GWAS)，來發掘所有台灣人的術後腹腔內粘黏形成的易感因子以協助預測術後腹腔內粘黏的高危險病患，只有少數的候選基因研究報導有些基因對手術後沾黏有相關。例如：(1) 在43名參與者的研究，攜帶HLA-A24基因增加術後粘黏風險7.4倍；(2) 258名參與者的研究，攜帶mutant Interleukin-1 receptor antagonist基因增加術後粘黏風險2倍。我們過去在手術粘黏部位的gene expression研究，也發現有93個基因有1.86倍的改變，所以我們預測腹腔內粘黏的形成和許多基因有相關。GWAS是一種無偏差比較全基因體有多型性SNP的方法(>65 萬SNP)，已成功的用來找出許多手術後產生副作用的易感因子(例如：術後嘔吐易感因子)。計劃的第一年將會在台大醫院和亞東醫院收腹部手術的案例進行初步GWAS研究，並同時進行系統性論文回顧，以進一步了解手術後腹腔內粘黏和基因的關係。計劃的第二年將進行病例對照研究。由於在短時間內可能無法找到很多手術後腹腔內粘黏的無發病對照組，我們會先使用健康人群當做術後腹腔粘黏的對照組，因為在之前的研究發現使用健康人群做對照組和手術後不發病對照組的結果類似。資料來源將來自臺灣人體生物資料庫已募集的詳細資料。我們將使用疾病風險計分找出跟手術前有相同環境因子和共病症的對照組進行配對。我們的團隊過去使用疾病風險計分分析全民健康保險研究資料庫，已有多篇論文發表，可以勝任這個研究。計劃的第三年將進行replication study，我們將直接比較腹部手術後發生粘黏和不會發生粘黏的病人並對發現的易感遺傳因子進行驗證。 在全基因體相關性研究分析中，我們首先評估每個位點，並將顯著水準訂為p<5 X 10^-6。為了控制假發現(False discovery)，我們還會計算所有p值的q值。此外，我們將建構另一種全基因體相關性研究的分析方法(例如：polygenic risk score)，該方法主要是利用多位點的聯合效應，更能了解基因與術後腹腔粘黏的關係。鑑於我們在術後粘黏的過去經驗，我們有信心成為全球第一個報告術後粘黏患者的GWAS研究，並利用該信息幫助預測術後腹腔內粘黏形成的高風險患者，期以減少手術後腹腔內粘黏的發生。<br> Abstract: Postoperative intra-abdominal adhesions affect the quality of life in millions of people worldwide, but there is no comprehensive report on the genetic susceptibility to this disease. Knowing the disease causing genes can enable testing for high risk patients and allow preventive treatment. Our preliminary literature review only find a few candidate gene studies on postoperative adhesions. For example: (1) Using a cohort of 43 children, it was found that HLA-A24 subtype have 7.4 fold increase risk of post-operative adhesion; (2) Using a cohort of 258 adults, it was found that patients carrying the mutant Interleukin-1 receptor antagonist have 2 fold increase risk in post-operative adhesion. We hypothesized there will be multiple genes related to postoperative intra-abdominal adhesions, as our previous gene expression study found that at least 93 genes showed 1.86 fold change in expression. Therefore, we aimed to use genome-wide association study (GWAS) to scans the entire genome for changes in common single nucleotide polymorphisms (>65 millions) between postoperative intra-abdominal adhesions patients and controls. Although a GWAS study has never been conducted for postoperative intra-abdominal adhesions, this approach has been successfully used to identify susceptible genes in postoperative nausea. In the first year, we will have two aims: enrolling patients that have undergone abdominal surgeries for preliminary GWAS; and conducting a systematic review of all the genetic polymorphism implicated in postoperative intra-abdominal adhesion. In the second year, we will enroll a sufficient number of patients at National Taiwan University Hospital and Far Eastern Memorial Hospital, to conduct a preliminary GWAS analysis using the case control study design. We will be comparing 150 patients with signs of post-operative intra-abdominal adhesion to 750 disease risk score matched population controls, and a large number of unmatched controls. This is because it may be difficult to collect a large number of controls that mimic the demographic and risk factors for post-operative intra-abdominal adhesion, in a short time. The population control will be from Taiwan biobank, which is a longitudinal project that has collected detailed information (such as demographic, life-style information and GWAS information). In the third year, we will enroll a sufficient number of tolerant controls (patients that have undergone abdominal surgeries, but do not develop adhesion). By conducting a replication GWAS study, directly comparing abdominal surgery patients that developed post-operative adhesion and do not develop post-operative adhesion, we can confirm the results in the second year. Finally, for markers identified for post-operative intra-abdominal adhesion in our samples, a validation genotyping will also be conducted.In the analysis of GWAS data, we will first evaluate individual markers with the use of a genome-wide significance cutoff p-value of 5 X 10^-6 or q value as suggestive signals under the assumption of independence among markers. In addition, we will also conduct alternative GWAS-data-analysis approaches (i.e. polygenic risk score) that focus on the combined effects of many loci, each making a small contribution to overall disease susceptibility. The results of this novel experiment might help to identify patients at high risk of postoperative intra-abdominal adhesion.手術後腹腔內粘黏系統性回顧基因多型性臺灣人體生物資料庫全基因體相關性研究疾病風險計分多基因危險因數Postoperative intra-abdominal adhesionsystematic reviewgenetic polymorphismTaiwan Biobankgenome-wide association study (GWAS)polygenic risk score