Folate Pharmacogenomics and Risk of Atypical Antipsychtoic Metabolic Side Effects

描述（由申请方提供）：在接受非典型抗精神病药（AAP）治疗的精神分裂症患者中，代谢综合征和胰岛素抵抗/糖尿病（DM）的发生率比一般人群高2 - 4倍。叶酸代谢异常与CVD、DM和内皮功能障碍的风险增加有关。特别是亚甲基四氢叶酸还原酶（MTHFR）677 C/T变异与一般人群CVD风险增加14%和精神分裂症风险增加36%相关，尽管这些关系高度依赖于膳食叶酸摄入量。尚未对精神分裂症中出现的代谢综合征和DM进行研究。本课题组首次对精神分裂症患者MTHFR、代谢综合征和胰岛素抵抗的关系进行了研究。本申请的目的是更好地了解叶酸药物遗传学和饮食和生活方式因素对AAP相关代谢并发症、代谢综合征和胰岛素抵抗的相互作用。此外，我们还将系统地测量这一人群的内皮功能，并确定补充叶酸对减轻这些代谢后果的作用。我们的主要假设是，MTHFR混淆叶酸摄入不足，并赋予AAP使用胰岛素抵抗的风险更大。这导致了该人群中的代谢综合征、内皮功能障碍和CVD。我们已经制定了这一假设的基础上，我们的试点数据（从NIMH职业发展奖）显示MTHFR T等位基因和接受AAP的精神分裂症患者的代谢综合征和胰岛素抵抗的风险更大之间的关系。我们的理论依据是MTHFR T等位基因与饮食不足相结合，增加了AAP使用的胰岛素抵抗风险，导致代谢综合征，从而促进内皮功能障碍，导致CVD。因此，补充叶酸可能是一个现实的治疗选择，以减少AAP相关的心血管并发症。这项研究的成功完成将从根本上推进精神分裂症的治疗，因为我们了解更多与AAP相关代谢并发症相关的遗传，饮食和生活方式因素，以及测量该人群中内皮功能障碍的发生率，并确定潜在的改善因素，如补充叶酸，以减轻与AAP使用相关的总体心血管负担。公共卫生相关性：这一建议将有助于临床医生更好地了解遗传、饮食和生活方式因素如何相互作用，使精神分裂症患者因非典型抗精神病药物使用而增加代谢综合征、胰岛素抵抗和内皮功能障碍的风险。

DESCRIPTION (provided by applicant): In schizophrenia patients treated with atypical antipsychotics (AAPs), metabolic syndrome and insulin resistance/diabetes mellitus (DM) incidence is two to four fold higher than the general population. Aberrant folate metabolism is linked to a greater risk for CVD, DM, and endothelial dysfunction. Specifically the methylenetetrahydrofolate reductase (MTHFR) 677C/T variant has been associated with a 14% increase in CVD risk in the general population and a 36% greater risk for schizophrenia, although these relationships are highly dependent on dietary folate intake. This variant has not been investigated with metabolic syndrome and DM seen in schizophrenia. Our research group is the first to investigate the relationship between MTHFR, metabolic syndrome, and insulin resistance in schizophrenia. The objective of this application is to better understand the interplay of folate pharmacogenetics and diet and lifestyle factors on developing AAP-associated metabolic complications; metabolic syndrome, and insulin resistance. Additionally we will systematically measure endothelial functioning in this population and determine the role of supplemental folate administration on attenuation of these metabolic consequences. Our primary hypothesis is that MTHFR confounds inadequate folate intake and confers a greater risk for insulin resistance from AAP use. This contributes to the metabolic syndrome, endothelial dysfunction, and CVD in this population. We have formulated this hypothesis based on our pilot data (from a NIMH Career Development Award) showing a relationship between the MTHFR T allele and a greater risk for metabolic syndrome and insulin resistance in schizophrenia patients receiving AAPs. Our rationale is that the MTHFR T allele combined with inadequate diet, increases insulin resistance risk with AAP use, contributing to the metabolic syndrome, which facilitates endothelial dysfunction, leading to CVD. Thus, supplemental folate may be a realistic treatment option to reduce AAP-associated cardiovascular complications. Successful completion of this study would fundamentally advance schizophrenia treatment as we learn more about genetic, dietary, and lifestyle factors that relate to AAP-associated metabolic complications, as well as measuring the incidence of endothelial dysfunction in this population, and identifying potential ameliorating factors such as supplemental folate in an effort to attenuate the overall cardiovascular burden associated with AAP use. PUBLIC HEALTH RELEVANCE: This proposal will help clinicians gain a better understanding of how genetics, dietary and lifestyle factors interact to place patients with schizophrenia at increased risk for metabolic syndrome, insulin resistance, and endothelial dysfunction from atypical antipsychotic use.