Perioperative pharmacogenetics: Nitrous oxide and anesthetic outcomes

描述(由申请人提供)：术后发病率和死亡率是一个未得到充分认识的重大公共卫生问题。在2004年。1.4%的住院患者术后死亡。心肌梗死是术后死亡率的主要原因。围手术期(药物遗传学)可以通过个体化的治疗选择和药物治疗(“个体化药物”)来减少不良后果。然而，目前研究围手术期药物遗传学的潜在益处的研究非常缺乏。这份K23提案是关于围手术期药物遗传学的职业发展计划。这项研究的核心是一项随机、随机、对照试验，调查已知的一氧化二氮改变的中间代谢途径中的基因变异与术后心肌缺血的关系。一氧化二氮是世界上最常用的全身麻醉剂。它抑制维生素812，增加同型半胱氨酸浓度。慢性同型半胱氨酸血症与不良心脏事件有关。MTHFR 677 C&gt；T基因多态是导致同型半胱氨酸升高的最重要的基因决定因素，也与一氧化二氮麻醉后同型半胱氨酸显著升高有关。因此，这项研究将检验这一假设，即具有该基因变异的患者在一氧化二氮麻醉后术后心肌缺血的发生率高于野生型患者(目标1)。我们还将确定这种风险是否可以通过围手术期盲目、随机补充维生素B12和叶酸来改善(目标2)。这项试验将针对接受重大非心脏手术的心脏事件高危患者。K23提案的教学培训部分将是遗传流行病学的科学硕士课程。总体的长期职业目标是成为围手术期药物遗传学的独立研究者。公共卫生相关性：术后心肌缺血是导致手术发病率和死亡率的最重要因素之一，每年有200-300万美国人面临风险。这项研究将回答一氧化二氮是否是术后心肌缺血的危险因素，以及这种风险是否可以通过B族维生素来改善。因此，这项研究可能成为评估一氧化二氮在高危患者中的安全性的重要证据。

DESCRIPTION (provided by applicant): Postoperative morbidity and mortality is an under-recognized, yet significant public health problem. In 2004. 1.4% of all inpatients died after surgery. Myocardial infarction is a major contributor to postoperative mortality. Perioperative (pharmaco-)genetics may reduce adverse outcomes by individualizing therapeutic options and drug therapy ("personalized medicine"). However, there is currently a significant paucity of Studies investigating the potential benefits of perioperative pharmacogenetics. This K23 proposal is for a career development program in perioperative pharmacogenetics. The research component centers on a randomized blinded controlled trial investigating the association between gene variants in intermediary metabolic pathways known to be altered by nitrous oxide and postoperative myocardial ischemia. Nitrous oxide is the most commonly used general anesthetic in the world. It inhibits vitamin 812 and increase homocysteine concentrations. Chronic homocysteinemia has been associated with adverse cardiac events.The MTHFR 677 C>T polymorphism is the most important genetic determinant for elevated homocysteine and is also associated with significantly higher homocysteine after nitrous oxide anesthesia. Thus, this investigation will test the hypothesis that patients with this gene variant have a higher incidence of postoperative myocardial ischemia after nitrous oxide, anesthesia than wild-type patients (aim 1). We will also determine if this risk can be ameliorated by blinded, randomized perioperative supplementation of vitamin B12 and folate (aim 2). The trial will target patients at high risk for cardiac events undergoing major noncardiac surgery. The didactic training component of the K23 proposal will be the Masters of Science program in Genetic Epidemiology. The overall long-term career objective is to become an independent investigator in perioperative pharmacogenetics. PUBLIC HEALTH RELEVANCE: Postoperative myocardial ischemia is one of the most important contributors to surgical morbidity and mortality with 2-3 million Americans at risk annually. This research will answer if nitrous oxide is a risk factor for postoperative myocardial ischemia and if this risk can be ameliorated by B-vitamins. Thus, this research might serve as important evidence to assess the safety of nitrous oxide in high-risk patients.