Genetic modification of PUFA biosynthesis and CHD

PUFA生物合成与CHD的基因改造

• 批准号: 7220061
• 负责人: ANA B BAYLIN
• 金额: $ 65.09万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-08 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7220061
• 关键词: Acids; Adipose tissue; Affect; Arachidonic Acids; Binding Proteins; Biochemical; Biological Markers; Blood Clot; Blood coagulation; Case-Control Studies; Condition; Coronary heart disease; Costa Rica; Cytochrome P450; DNA; Data; Development; Diet; Dietary Fatty Acid; Docosahexaenoic Acids; Eicosanoids; Eicosapentaenoic Acid; Enzymes; Essential Fatty Acids; Evaluation; Fatty Acid Desaturases; Fatty Acids; Feedback; Gene Expression Regulation; Genes; Genetic; Genetic Transcription; Genetic Variation; Goals; Haplotypes; Individual; Inflammation; Intake; Link; Linolenic Acids; Measurement; Membrane; Modification; Mutation; Myocardial Infarction; Numbers; Omega-3 Fatty Acids; PPAR alpha; Pathway interactions; Polyunsaturated Fatty Acids; Population; Prevention; Range; Regulation; Regulatory Element; Relative (related person); Research Personnel; Resolution; Risk; Role; Sampling; Signal Transduction; Sterols; Survivors; Testing; Trans Fatty Acids; Variant; alpha-Linolenic Acid; base; blood pressure regulation; desaturase; eicosanoid metabolism; experience; fatty acid biosynthesis; gene interaction; saturated fat; transcription factor

DESCRIPTION (provided by applicant): Polyunsaturated fatty acids (PUFA) exert vital functions on membrane structure, cell signaling, and regulation of gene expression. PUFA are the precursors of several different eicosanoids, which have multiple roles in inflammation, regulation of blood pressure, and blood clotting, among many other functions. Through these functions, PUFA are undoubtedly linked to the prevention of development of coronary heart disease (CHD). Linoleic (n-6) and alpha-linolenic acid (n-3) are essential fatty acids (FA) that can be converted into long- chain PUFA through elongation, desaturation, and strong feedback regulated by transcription factors, sterol desaturases enzymes involved in this biosynthetic pathway are regulated by transcription factors, sterol regulatory element-binding protein-1c (SREBP-1c) and peroxisome proliferators-activated receptor-alpha (PPAR-alpha). We hypothesize that mutations in these genes affect FA biosynthesis and risk of CHD. Our overall objective is to assess individual variability in the effect of dietary PUFA on Ml, by examining genes involved in their biosynthetic pathway. We will study 2,150 case survivors of Ml and 2,150 population-based controls from out ongoing study. Specific hypothesis will examine the genetic mechanisms that link intake of FA [1) n-3 FAs: alpha-linolenic acid, eicosapentaenoic acid (EPA), and docsahexaenoic acid, (DMA); 2) n-6 FAs: linoleic acid, and arachidonic acid, and 3) trans FA] to risk of Ml. The proposed genes include: fatty acid desaturase (FADS)2 (delta6-desaturase), FADS1 (delta5-desaturase), and FADS3, ELOVL-1,2,3,4,5,6,7 (7 elongase genes), PPAR-alpha, and SREBP-1c. Further hypothesis will be tested with other genes involved in the synthesis of eicosanoids from arachidonic acid and EPA: cycloxygenase(COX)-2, S-lypoxygenase(LOX), and cytochrome P450 2J2 (CYP2J2). FAs in adipose tissue will be used as biomarkers of intake. Biochemical measurements, dietary data, and general information are available for this population. The proposed study offers and unusual opportunity to expand our understanding of how genetic and environmental conditions can influence CHD. The diet of the population offers a wide range in variation of all the major types of FAs, particularly with low ranges of saturated fat and n-3 FAs represented. This strengthens evaluation of risk, and application to current dietary goals. The large number of SNPs proposed for final analysis will add to the resolution and power to identify the genes that underlie CHD.

描述（由申请人提供）：多不饱和脂肪酸（PUFA）对膜结构，细胞信号传导和基因表达的调节发挥重要作用。 PUFA是几种不同的类花生酸酯的前体，在炎症，血压调节和血液凝结中具有多个作用，以及许多其他功能。通过这些功能，PUFA无疑与预防冠心病（CHD）的发展有关。 Linoleic (n-6) and alpha-linolenic acid (n-3) are essential fatty acids (FA) that can be converted into long- chain PUFA through elongation, desaturation, and strong feedback regulated by transcription factors, sterol desaturases enzymes involved in this biosynthetic pathway are regulated by transcription factors, sterol regulatory element-binding protein-1c (SREBP-1c) and peroxisome扩散剂激活的受体-Alpha（PPAR-Alpha）。我们假设这些基因的突变会影响FA生物合成和CHD风险。我们的总体目标是通过检查与其生物合成途径有关的基因来评估饮食PUFA对ML的影响。我们将研究2,150名ML的病例幸存者和来自OUT持续研究的2,150个基于人群的对照。具体假设将检查连接FA摄入的遗传机制[1）N-3 FAS：α-烯醇酸，eicosapentaenoic（EPA）和Docsahecahexaenoic，（DMA）； 2）N-6 FAS：亚油酸和花生四烯酸，以及3）反式FA]。所提出的基因包括：脂肪酸去饱和酶（FADS）2（Delta6-决定酶），FADS1（delta5-脱发酶）和FADS3，Elovl-1,2,3,4,5,6,7（7个元负酶基因），PPAR-ALPHA和SREBPP-1C。进一步的假设将与涉及的其他基因一起测试来自花生四烯酸和EPA的eicosanoids：环氧酶（COX）-2，S-糖酶（LOX）和细胞色素P450 2J2（CYP2J2）。脂肪组织中的FAS将用作摄入量的生物标志物。生化测量，饮食数据和一般信息可用于该人群。拟议中的研究提供了不寻常的机会，以扩大我们对遗传和环境状况如何影响冠心病的理解。人群的饮食在所有主要类型的FAS的变化方面具有广泛的范围，尤其是代表饱和脂肪和N-3 FA的低范围。这加强了对风险的评估，并应用了当前饮食目标。提出的最终分析的大量SNP将增加分辨率和功率，以识别基因冠心基因。