Genetic modification of PUFA biosynthesis and CHD

PUFA生物合成与CHD的基因改造

• 批准号: 7103946
• 负责人: ANA B BAYLIN
• 金额: $ 61.31万
• 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/7103946
• 关键词: Central American; adipose tissue; atherosclerosis; biomarker; biotechnology; cardiovascular disorder epidemiology; cardiovascular disorder risk; dietary lipid; enzyme activity; fatty acid biosynthesis; fatty acid metabolism; gene environment interaction; gene interaction; genetic markers; genetic screening; genetic susceptibility; human genetic material tag; human subject; myocardial infarction; nutrition related tag; nutritional epidemiology; oxidoreductase; single nucleotide polymorphism; unsaturated fatty acids

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调控发挥重要作用。PUFA是几种不同的类花生酸的前体，类花生酸在炎症、血压调节和血液凝固等许多功能中具有多种作用。通过这些功能，PUFA无疑与预防冠心病（CHD）的发展有关。亚油酸（n-6）和α-亚麻酸（n-3）是必需脂肪酸（FA），其可以通过转录因子调节的延伸、去饱和和强反馈转化为长链PUFA，参与该生物合成途径的甾醇去饱和酶受转录因子调节，固醇调节元件结合蛋白-1c（SREBP-1c）和过氧化物酶体增殖物激活受体-α（PPAR-alpha）。我们假设这些基因的突变影响FA的生物合成和CHD的风险。我们的总体目标是通过检查参与其生物合成途径的基因来评估膳食PUFA对MI的影响的个体变异性。我们将研究来自我们正在进行的研究的2,150例MI幸存者和2,150例基于人群的对照。具体假设将检查将FA [1）n-3 FA：α-亚麻酸、二十碳五烯酸（EPA）和二十二碳六烯酸（DMA）; 2）n-6 FA：亚油酸和花生四烯酸，和3）反式FA]的摄入与MI风险联系起来的遗传机制。拟议的基因包括：脂肪酸去饱和酶（FADS）2（δ 6-去饱和酶）、FADS 1（δ 5-去饱和酶）和FADS 3、FADVL-1、2、3、4、5、6、7（7种延伸酶基因）、PPAR-alpha和SREBP-1c。进一步的假设将用参与花生四烯酸和EPA合成类花生酸的其他基因进行检验：环氧化酶（考克斯）-2，S-脂氧合酶（LOX）和细胞色素P450 2 J2（CYP 2 J2）。脂肪组织中的脂肪酸将用作摄入量的生物标志物。可获得该人群的生化测量、饮食数据和一般信息。这项拟议中的研究提供了一个不同寻常的机会，以扩大我们对遗传和环境条件如何影响CHD的理解。人群的饮食提供了所有主要类型的脂肪酸的广泛变化，特别是低范围的饱和脂肪和n-3脂肪酸。这加强了对风险的评估，并将其应用于当前的饮食目标。提出用于最终分析的大量SNP将增加识别CHD基础基因的分辨率和能力。