Prolylcarboxypeptidase is a Risk Factor for Cardiovascular Disease

描述(由申请人提供)：我们想要确定脯氨酸羧基肽酶(PRCP)是否是心血管疾病的危险因素。PRCP可降解血管紧张素II(AngII)和缓激肽1-8。我们发现丝氨酸蛋白酶PRCP是一种不依赖于XIIa因子的细胞表面血浆前激肽释放酶激活剂。PRCP已被预测为与原发性高血压相关的基因。在一项全基因组关联研究中，PRCP被确定为男性代谢综合征的风险因素。PRCP基因E112D多态与子痫前期有关，特别是在有慢性高血压病史的妇女中。此外，该基因在中国汉族人中的存在与高血压患者对血管紧张素转换酶抑制剂治疗的抵抗有关。此外，我们还发现PRCP将a-MSH1-13代谢成a-MSH1-12。在PRCP缺乏的小鼠中，这种活动导致下丘脑aMSH1-13代谢减少，从而过度刺激产生厌食冲动的瘦小鼠。瘦削的PRCP缺陷(PRCPgT/GT)小鼠是结构性高血压。此外，在光化学或三氯化铁诱导的颈动脉损伤后，它们是血栓前病变，动脉血栓闭塞时间较短。这项建议的目的是确定PRCP是否是高血压和/或心肌梗死(MI)/中风的危险因素，无论是否调整了身体类型，即身体质量指数。这项建议的总体假设是，PRCP是高血压和/或MI和中风的危险因素，而体重指数可能会减轻这些危险因素。这项建议的具体目标是：目标1：使用NIH/NHLBI PRCP和平和DASH-Na研究中个人的DNA，确定某些PRCP外显子和内含子SNP是否与高血压状态相关，并对体重指数(BMI)状态进行调整或不调整。这一目的的子假说是，与PRCP功能降低相关的PRCP SNPs预测高血压状态，这种影响被BMI状态缓解。我们还将探索PRCP SNPs与高血压状态之间关联的BMI分层分析。目的#2：利用NIH/NHLBI和平研究中个体的DNA，确定某些PRCP外显子和内含子SNPs是否与有或没有调整高血压和BMI状态的MI/卒中状态相关。这一目标的假设是，与功能降低相关的PRCP SNPs会增加MI和/或中风的风险，并且这些表型与一个人的体重指数有关。我们还将探索对PRCP SNPs和M/卒中状态之间的关联进行BMI分层分析，并调整高血压状态。这些研究将使用表明PRCP功能可预测减少的SNPs进行。选择外显子SNPs进行研究是基于它们在PRCP中的结构位置，这将具有可预测的成熟蛋白活性的变化。其他SNP之所以被选择，是因为它们在进化上是保守的，或者与功能SNP处于连锁不平衡状态。拟议的研究使用了NIH/NHLBI生物库样本，这些样本来自两项特点良好的心血管研究(见所附信件)；(1)PRACE研究，考察了在患有和不患有轻度高血压的患者中添加ACE抑制剂以改善心血管事件；以及(2)DASH-Na研究，研究了增加饮食盐对已知高血压患者和非高血压患者的高血压的影响。在他们的结论中，这些拟议的研究应该表明PRCP的某些基因多态与心血管疾病有关。PRCP的上调可能是保护个人免受心血管疾病的一个目标，这些疾病表现为高血压和动脉血栓形成，如中风和心肌梗塞。

DESCRIPTION (provided by applicant): We want to determine if prolylcarboxypeptidase (PRCP) is a risk factor for cardiovascular disease. PRCP degrades angiotensin II (AngII) and bradykinin 1-8. We identified that the serine protease PRCP as a cell- surface plasma prekallikrein activator independent of factor XIIa. PRCP has been predicted as a gene associated with essential hypertension. In a genome-wide association study, PRCP was identified as a risk factor for metabolic syndrome in males. A polymorphism in PRCP, E112D, was shown to be associated with preeclampsia, especially in women with a previous history of chronic hypertension. Also, the presence of this polymorphism in Han Chinese was shown to be associated with resistance to angiotensin converting enzyme inhibitor treatment for hypertension. Additionally, we showed that PRCP metabolizes a-MSH1-13 to a-MSH1-12. In mice deficient in PRCP, this activity results in reduced aMSH1-13 metabolism in the hypothalamus allowing for overstimulation of an anorexic impulse producing lean mice. Lean, PRCP-deficient (PRCPgt/gt) mice are constitutively hypertensive. Moreover, they are prothrombotic with shorter arterial thrombosis occlusion times after carotid artery photochemical- or ferric chloride-induced injury. The goal of this proposal is to determine if PRCP is a risk factor for hypertension and/or myocardial infarction (MI)/stroke with and without adjustment for body type, i.e. body mass index. The overall hypothesis of this proposal is that PRCP is a risk factor for hypertension and/or MI and stroke that are potentially mitigated by body mass index. The specific aims of this proposal are: Aim #1: To determine if certain PRCP exon and intron SNPs are associated with hypertension status with and without adjustment for body mass index (BMI) status using DNA from individuals in the NIH/NHLBI PEACE and DASH-sodium studies. The subhypothesis for this aim is that PRCP SNPs that are associated with reduced PRCP function predicts hypertension status and this effect is mitigated by BMI status. We will also explore BMI stratified analyses of the association between PRCP SNPs and hypertension status. Aim #2: To determine if certain PRCP exon and intron SNPs are associated with a history of MI/stroke status with and without adjustment for hypertension and BMI status using DNA from individuals in the NIH/NHLBI PEACE study. The subhypothesis for this aim is that PRCP SNPs that are associated with reduced function increases risk for MI and/or stroke and these phenotypes are related to one's body mass index. We will also explore BMI stratified analyses of the association between PRCP SNPs and M/stroke status, adjusting for hypertension status. These investigations will be performed using SNPs that suggest predictable reduction in PRCP function. The selection of the exon SNPs for studies is based upon their structural location in PRCP that would have predictable alterations in the activity of the mature protein. Other SNPs are chosen because they are evolutionary conserved or in linkage disequilibrium with a functional SNP. The proposed investigations use NIH/NHLBI biorepository samples from two well-characterized cardiovascular studies (see letter enclosed); (1) the PEACE study which examined the addition of an ACE inhibitor in individuals with and without mild hypertension to ameliorate cardiovascular events and (2) the DASH-Sodium study that examined the influence of increasing dietary salt on hypertension in subjects with and without known hypertension. At their conclusion, these proposed investigations should show that certain polymorphisms in PRCP are associated with cardiovascular disease. Up-regulation of PRCP may be a target to protect individuals from cardiovascular disease as manifested by hypertension and arterial thrombosis as seen in stroke and MI.