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被充分认识的重要公共卫生问题。2004年术后死亡率为1.4%。心肌梗死是术后死亡的主要原因。围手术期（药物）遗传学可以通过个体化治疗选择和药物治疗（“个性化医疗”）减少不良结局。然而，目前研究围手术期药物遗传学潜在益处的研究非常缺乏。这个K23的建议是在围手术期药物遗传学的职业发展计划。研究内容集中在一项随机盲法对照试验上，研究已知被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之间的关联。氧化亚氮是世界上最常用的全身麻醉剂。它抑制维生素812和增加同型半胱氨酸浓度。MTHFR 677 C>T多态性是同型半胱氨酸升高的最重要的遗传决定因素，也与一氧化二氮麻醉后同型半胱氨酸显著升高相关。因此，本研究将检验这一假设，即具有该基因变体的患者在一氧化二氮麻醉后比野生型患者术后心肌缺血的发生率更高（目的1）。我们还将确定这种风险是否可以通过盲法随机围手术期补充维生素B12和叶酸来改善（目的2）。该试验将针对接受重大非心脏手术的心脏事件高风险患者。K23提案的教学培训部分将是遗传流行病学科学硕士课程。总体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：术后心肌缺血是手术发病率和死亡率的最重要因素之一，每年有2-3百万美国人处于风险之中。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族维生素改善。因此，本研究可作为评估氧化亚氮在高危患者中安全性的重要依据。

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.