MYOCARDIAL FA METABOLISM GENE-GENE INTERACTIONS IN HYPERTENSIVE HEART DISEASE

描述(申请人提供)：高血压性心脏病(HHD)由长期的高血压(HTN)引起，早期表现为左室肥厚(LVH)和/或左室舒张功能不全(LVDD)。虽然最初是一种适应性反应，但随着时间的推移，LVH和LVDD变得适应性不良，导致心室增大、收缩功能障碍(LVSD)和/或扩张型心肌病/心力衰竭。我们和其他研究小组已经证明，在动物模型和人类中，心肌脂肪酸(FA)代谢的改变是LVH、LVDD和LVSD存在和发展的重要决定因素。长链脂肪酸(LCFA)是心脏的重要能量来源。虽然一些LCFA被动地扩散到肌膜上，这是一种蛋白质促进的转运蛋白，但脂肪酸转位酶(脂肪或CD36)提供组织特异性表达，从而获得底物的可获得性。CD36-PPAR1/3-PGC11 FA代谢调节通路在心血管疾病尤其是左心室肥厚和心肌病的发病机制中起重要作用。因此，该方案的假设是FA代谢途径基因的遗传变异调节了人类HHD的表型表达。这一假说将被检验如下：特定目的1)利用控制潜在混杂因素的传统回归分析在高加索人和非裔美国人队列中识别与高血压病个体特征(即左心室重量、左室大小、左心室收缩和舒张期功能指数)的存在和严重程度相关的CD36标签SNPs；以及特定目的2)通过使用包括因子分析和基于贝叶斯网络的可分解图形模型在内的创新数据简化方法来探索潜在的高血压病相关表型的修饰因素。CD36和参与FA代谢的3个调控通路基因(即PPAR1、PPAR3和PGC11)之间的基因-基因交互作用将被测试。这项研究的结果将产生稳健的数据，支持这位新的调查者随后提交的R01提案，以执行高危单倍型的深度重测序，改进分析技术，并进一步验证R21试点研究的结果。这项研究旨在了解心肌肥厚反应的基因调控与相关的心肌代谢表型变化之间的关系。允许更好地阐明导致HTN向HHD转化的机制及其相关的发病率，可能有助于识别心血管发病率和死亡率的高危个体，并可能促进未来在预防和/或治疗HHD方面寻找新的治疗策略的努力。高血压心脏病是由长期存在的高血压引起的，早期表现为左室肥厚和/或左室舒张功能不全(LVDD)，是导致心血管疾病发病率和死亡率的重要原因，包括进展为心力衰竭。这项研究的目的是通过使用能够分析复杂遗传和表型数据的复杂技术，探索心肌代谢基因变异在调节双族人群高血压心脏病特征方面的潜在作用。

DESCRIPTION (provided by applicant): Hypertensive heart disease (HHD) results from long-standing hypertension (HTN) and manifests early as left ventricular hypertrophy (LVH) and/or left ventricular diastolic dysfunction (LVDD). Although initially an adaptive response, over-time LVH and LVDD become maladaptive leading to ventricular enlargement, systolic dysfunction (LVSD), and/or dilated cardiomyopathy/heart failure. Our group and others have shown that alterations in myocardial fatty acid (FA) metabolism are important determinants of the presence and development of LVH, LVDD, and LVSD in animal models and in humans. Long-chain fatty acids (LCFA) are an essential source of energy for the heart. Although some LCFAs diffuse passively across the sarcolemma, a protein-facilitated transporter, the fatty acid translocase (FAT or CD36) confers tissue-specific expression entrained to substrate availability. The CD36-PPAR1/3-PGC11 FA metabolism regulatory pathway plays an important role in the etiology of cardiovascular diseases, especially LVH and cardiomyopathy. Thus, the hypothesis of the proposal is that genetic variations of FA metabolism pathway genes modulate the phenotypic expression of HHD in humans. This hypothesis will be tested as follows: Specific Aim 1) Identify CD36 tagSNPs associated with the presence and severity of individual HHD traits (i.e. LV mass, LV size, and indices of LV systolic and diastolic function) in a Caucasian and an African-American cohort using conventional regression analyses controlling for potential confounders; and Specific Aim 2) Investigate modifying factors of latent HHD-related phenotypes by exploring gene-gene and gene-environment interactions using innovative data-reduction methods including factor analysis and Bayesian network-based decomposable graphical models. Gene-gene interactions will be tested between CD36 and 3 regulatory pathway genes involved in FA metabolism (i.e., PPAR1, PPAR3, and PGC11). The results of this research will generate robust data in support of a subsequent submission by this new investigator of an R01 proposal to perform deep resequencing of high-risk haplotypes, to refine the analytic techniques, and to further validate the findings of the R21 pilot study. This research is designed to provide an understanding of the association between gene regulation of the cardiac hypertrophic response and the associated phenotypic changes in myocardial metabolism. Allowing better elucidation of the mechanisms that lead to the transition from HTN to HHD phenotypes and their associated morbidity may allow identification of individuals at high risk of cardiovascular morbidity and mortality and may facilitate future efforts at identifying novel therapeutic strategies in the prevention and/or treatment of HHD. PUBLIC HEALTH RELEVANCE Hypertensive heart disease, which results from long-standing hypertension and manifests early as left ventricular hypertrophy and/or left ventricular diastolic dysfunction (LVDD), is responsible for significant cardiovascular morbidity and mortality including progression to heart failure. The purpose of this research is to explore the potential role of variants in myocardial metabolism genes to modulate hypertensive heart disease traits in a biracial population by use of sophisticated techniques capable of analyzing complex genetic and phenotype data.