| 摘要: | 中風是導致全球人口失能與死亡的第三大惡疾，其後續衍生的疾病預後負擔更在經濟層面對全球帶來巨大的衝擊。中風主要分為缺血性中風和出血性中風，並以缺血性中風為大宗。缺血性中風會在兩種狀態下損害個體健康：（1）缺血時所引發的損傷、（2）缺血後再灌流時引起的損傷。在缺血－再灌流的過程中會觸發活性氧化物的過度生成並造成患者更高的氧化壓力，又氧化壓力被指出是影響缺血性中風病理傷害的關鍵因素。先前文獻發現一種可調控粒線體活性氧化物生成的蛋白－解偶聯蛋白(UCP)，目前已鑑定出五種亞型：UCP1、UCP2、UCP3、UCP4以及UCP5。解偶聯蛋白的主要功能是透過誘導質子洩漏使氧化磷酸化過程被輕度解偶聯，進而降低粒線體活性氧化物的產生。故本研究的目的為：從基因多形性、加權基因風險分數、氧化壓力這三種角度來探討UCP1-UCP5基因與缺血性中風不良預後的相關性。
本研究是一項以醫院收案為基礎的病例追蹤型研究，總分析樣本數為567位缺血性中風患者。本研究透過結構式問卷與患者血液檢體來收集研究變項資料，其中修改後雷氏量表(mRS)用於評估患者中風後1個月的預後情形，mRS總分?2定義為中風預後不良。UCP1-5位點之基因分型以PCR-RFLP實驗和iPLEX MassARRAY系統進行鑑定。加權基因風險分數則以UCP1(rs2270565和rs7687015)、UCP2 (rs642154 和 45-bp Ins/Del) 以及UCP3 (rs3781907和rs1800006) 計算獲得。GSH/GSSG Ratio和8-OHdG作為氧化壓力生物標誌。統計方法使用羅吉斯回歸分析UCP1-5基因多形性和UCP1-3加權基因風險分數與缺血性中風1個月不良預後之危險對比值、UCP1-3加權基因風險分數與氧化壓力生物標誌之相關性。此外也利用AUC、NRI、IDI評估模型預測能力以及協同指數判斷交互作用。
本研究發現年齡較高、女性、低教育程度、無吸菸、高血壓、無心臟病、中風史、高中風嚴重度是中風不良預後的危險因子。UCP1 rs2270565和rs7687015、UCP2 rs642154 和 45-bp Ins/Del以及UCP3 rs3781907和rs1800006位點皆符合後續納入計算加權基因風險分數的標準(p-value<0.15)，並在校正潛在中風預後危險因子後與缺血性中風1個月不良預後存在顯著或邊緣性顯著的相關性。UCP1-3高加權基因風險分數也與中風1個月不良預後呈顯著正相關(AOR=1.90，95% CI=1.20-3.02)。在交互作用分析中發現，高基因風險分數和高中風嚴重度對中風1個月不良預後具有顯著正向累加交互作用(S=2.72，95%CI=1.04-7.12)。AUC結果指出合併UCP1-3加權基因風險分數和中風預後危險因子的模型具有最佳預測中風不良預後的能力。氧化壓力分析則觀察到，UCP1-3高加權基因風險分數與GSH/GSSG Ratio<0.78723、8-OHdG>5.055以及高氧化壓力呈正相關。但可能因分析樣本數過小，使得檢定力不足，故以上結果未達統計上的顯著關聯。
本研究發現UCP1-3所組成之加權基因風險分數可作為缺血性中風不良預後的獨立預測因子。UCP1-3高加權基因風險分數與高中風嚴重度對於較差的中風預後具有正向的交互作用。攜帶UCP1-3高加權基因風險分數的患者傾向擁有較高的氧化壓力狀態。因此臨床上對於具有高基因風險之中風患者，特別是中風高嚴重度者需要更加留意其後續之預後發展。
Stroke remains the third-leading cause of worldwide disability and mortality. The most common stroke is ischemic stroke. Ischemic stroke may damage individuals' health from injury caused by ischemia and reperfusion after ischemia. Oxidative stress has been identified as a noteworthy factor affecting the pathological damage of ischemic stroke. Previous studies found that uncoupling proteins (UCPs) may regulate mitochondrial ROS production. There are five subtypes of UCP: UCP1, UCP2, UCP3, UCP4, and UCP5. The main function of UCPs is to induce proton leakage, mildly uncoupling the oxidative phosphorylation process, thereby reducing mitochondrial ROS production. Therefore, our study aimed to investigate the relationship between UCP1-UCP5 genes and poor outcome at 1-month post-stroke through genetic polymorphism, weighted genetic risk scores, and oxidative stress.
Our study is a hospital-based case follow-up study with a total sample size of 567 ischemic stroke patients. Variables were collected by structured questionnaires. The prognosis of stroke was evaluated by modified Rankin Scale scores (mRS) at 1-month post-stroke, and mRS scores?2 were considered as poor outcomes. Genotyping of UCP1-5 genes was performed using the PCR-RFLP and iPLEX MassARRAY systems. A weighted genetic risk score was calculated by UCP1 (rs2270565 and rs7687015), UCP2 (rs642154 and 45-bp Ins/Del), and UCP3 (rs3781907 and rs1800006). GSH/GSSG Ratio and 8-OHdG were biomarkers of oxidative stress. A logistic regression was performed to analyze the associations between UCP1-5 genetic polymorphisms and poor outcomes after stroke by OR and 95% CI. The associations between UCP1-3 weighted genetic risk scores, poor outcomes after stroke, and oxidative stress biomarkers were also performed by logistic regression. Moreover, AUC, NRI, and IDI were used to evaluate the model's predictive ability. A synergy index was used for the analysis of interaction.
Our study found that older age, female, lower education level, non-smoking, hypertension, absence of heart disease, stroke history, and higher stroke severity were risk factors for poor outcome at 1-month post-stroke. High UCP1-3 weighted genetic risk scores were significantly associated with poor outcome after stroke (AOR=1.90, 95% CI=1.20-3.02). We found a significant synergistic interaction between high UCP1-3 weighted genetic risk scores and high stroke severity (S index=2.72, 95% CI=1.04-7.12) on the risk of poor outcome after stroke. According to the results from NRI and IDI, adding UCP1-3 weighted genetic risk scores to the model of stroke prognosis risk factors improved the predictive ability for the poor outcome at 1-month post-stroke. High UCP1-3 weighted genetic risk scores were positively correlated with high oxidative stress. However, the results did not reach statistical significance.
In conclusion, our study found that UCP1-3 weighted genetic risk scores were independent predictors of poor outcomes at 1-month post-stroke. There was a positive interaction effect between high UCP1-3 weighted genetic risk scores and high stroke severity on the risk of poor outcome at 1-month post-stroke. Moreover, patients with high UCP1-3 weighted genetic risk scores had higher oxidative stress levels. Therefore, it's important to pay attention to patients with high genetic risk scores, especially those with high stroke severity. |
