Folate Pharmacogenomics and Risk of Atypical Antipsychtoic Metabolic Side Effects

描述(申请人提供)：在接受非典型抗精神病药物(AAPS)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)的发病率比普通人群高两到四倍。叶酸代谢异常与心血管疾病、糖尿病和内皮功能障碍的风险更高有关。具体地说，亚甲基四氢叶酸还原酶(MTHFR)677C/T变异与普通人群心血管疾病风险增加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饮食叶酸摄入量。这种变异还没有在精神分裂症中出现的代谢综合征和糖尿病中进行研究。我们的研究小组首次研究了精神分裂症患者MTHFR、代谢综合征和胰岛素抵抗之间的关系。这项应用的目的是更好地了解叶酸药物遗传学与饮食和生活方式因素在发生AAP相关代谢并发症、代谢综合征和胰岛素抵抗方面的相互作用。此外，我们将系统地测量这一人群的内皮功能，并确定补充叶酸在减轻这些代谢后果方面的作用。我们的主要假设是，MTHFR混淆了叶酸摄入不足，并增加了使用AAP导致的胰岛素抵抗的风险。这导致了代谢综合征、内皮功能障碍和心血管疾病。我们根据我们的试点数据(来自NIMH职业发展奖)提出了这一假设，该数据表明，在接受AAPS治疗的精神分裂症患者中，MTHFR T等位基因与代谢综合征和胰岛素抵抗的风险更高。我们的理论基础是，MTHFR T等位基因与饮食不足相结合，会增加使用AAP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，导致心血管疾病。因此，补充叶酸可能是减少AAP相关心血管并发症的一个现实的治疗选择。这项研究的成功完成将从根本上推进精神分裂症的治疗，因为我们对与AAP相关的代谢并发症相关的遗传、饮食和生活方式因素有了更多了解，并测量了这一人群中内皮功能障碍的发生率，并确定了潜在的改善因素，如补充叶酸，以努力减轻与AAP相关的总体心血管负担。公共卫生相关性：这项建议将帮助临床医生更好地了解遗传学、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的使用而面临代谢综合征、胰岛素抵抗和内皮功能障碍的风险增加。

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.