COMT Genotype and Executive Function in HIV Infection and Methamphetamine Use

描述（由申请人提供）：我们建议研究儿茶酚-o-甲基转移酶（COMT）的遗传基因型与HIV相关的执行功能受损之间的关系，当受影响的个体使用甲基苯丙胺（METH）时，执行功能会丧失。我们将重点研究一种常见的功能多态性，即改变血液中可溶性COMT （S-COMT）中第108位（Val108Met）或大脑中膜结合COMT （MB-COMT）中第158位（Val158Met）氨基酸密码子的基因外显子4上缬氨酸（Val）到蛋氨酸（Met）的替换。当Val等位基因不存在时，这种多态性导致降解多巴胺的酶活性发生显著变化。我们对270名受试者（包括健康对照）进行了COMT基因Val/Met等位基因的基因分型；感染艾滋病毒/甲基苯丙胺阴性；甲基苯丙胺阳性/未感染艾滋病毒；以及艾滋病毒感染者/甲基苯丙胺阳性个体。我们注意到携带met等位基因的健康对照组的损伤水平明显较低，即使在HIV感染的受试者中，该等位基因也继续赋予更好的执行功能。然而，无论COMT基因型如何，在甲基安非他明依赖组和HIV感染/甲基安非他明依赖组中，执行功能的损害更高，因为met等位基因的保护作用已经丢失。第二个发现是，在55岁以上的HIV感染者中，与对照组相比，1-突触核蛋白沉积的频率显著增加。我们的首要假设是，具有COMT-met等位基因的个体可以保护自己免受HIV介导的额叶认知功能障碍，而这在冰毒的背景下是缺失的。我们打算通过人脑组织和体外人脑组织培养的神经变性和炎症的神经病理标记来评估遗传COMT基因型与记录的冰毒使用和生活中的执行功能之间的关系。具体来说，我们将评估氧化蛋白、硝基酪氨酸、脂质过氧化、氧化DNA损伤和1-突触核蛋白沉积的积累，因为这些与冰毒使用有关，我们最近证明了HIV感染者中1-突触核蛋白沉积的显著增加。我们将进一步评估甲基苯丙胺的分子效应，以阐明甲基苯丙胺在假设其可能与氧化应激有关的情况下，取消met/met COMT的保护作用的过程。这种认识将在未来的应用中促进靶向治疗的发展，以防止甲基苯丙胺相关的分子功能障碍。公共卫生相关性：甲基苯丙胺使用者是美国艾滋病毒感染增长最快的人群。此外，感染艾滋病毒的甲基苯丙胺使用者遭受最严重的认知障碍。在这项研究中，我们建议研究甲基转移酶（COMT）基因的遗传变异与甲基苯丙胺使用者的HIV相关神经认知障碍（HAND）之间的关系。

DESCRIPTION (provided by applicant): We propose to investigate the relationship between the inherited genotype of catechol-o-methyl transferase (COMT) and the protection against the development of HIV related impaired executive function, which is lost when methamphetamine (METH) is used by the affected individuals. We intend to focus on a common functional polymorphism, a Valine (Val) to Methionine (Met) substitution in exon 4 of the gene that alters the amino acid codon at position 108 (Val108Met) in the soluble-COMT (S-COMT) which is found in blood or position 158 (Val158Met) in the membrane-bound COMT (MB-COMT) located in the brain. This polymorphism results in a significant change in the enzymatic activity to degrade dopamine when the Val allele is not present. We have performed genotyping for the Val/Met alleles of the COMT gene in 270 subjects that include healthy controls; HIV infected/METH negative; METH positive/HIV uninfected; and HIV infected/METH positive individuals. We noted significantly lower levels of impairment in the healthy controls carrying a met allele and this allele continued to confer better executive functioning even in the HIV infected subjects. However, impairment of executive functioning was higher in the METH dependent and HIV infected/METH dependent groups regardless of COMT genotype with the protective effects of the met allele having been lost. The second finding is that in HIV infected individuals over 55 years that is a significant increase in the frequency of 1- synuclein deposition compared to controls. Our overarching hypothesis is that individuals with COMT-met allele conferred protection against HIV mediated frontal cognitive dysfunction, which is lost in the context of METH. We intend to assess the relationship between the inherited COMT genotype and documented meth use and executive function in life with neuropathological markers of neurodegeneration and inflammation in human brain tissue and in vitro human brain tissue cultures. Specifically we will assess the accumulation oxidative proteins, nitrotyrosine, lipid peroxidation, oxidative DNA damage and 1-synuclein deposition as these are associated with meth use and we have recently demonstrated a significant increase in 1-synuclein deposition in HIV infected individuals. We will further assess the molecular effects of methamphetamine to elucidate the process by which methamphetamine abrogates the protective effect of met/met COMT with the presumption that it may be related to oxidative stress. Such an understanding will in a future application facilitate the development of targeted therapies to prevent the methamphetamine related molecular dysfunction. PUBLIC HEALTH RELEVANCE: Methamphetamine users are the fastest growing population in the United States to acquire HIV infection. Furthermore, HIV infected methamphetamine users suffer the most severe cognitive impairment. In this investigation we are proposing to investigate the relationship between the inherited variant of the catechol-o-methyl-transferase (COMT) gene and HIV associated neurocognitive disorder (HAND) in methamphetamine users.