Role of PUFA-Gene Interactions in Health Disparities

在过去的50年里，随着西方饮食中植物油产品（大豆、玉米、棕榈和菜籽油，以及人造黄油和起酥油）的加入，n-6必需多不饱和脂肪酸（PUFA）、亚油酸（LA）的摄入量急剧增加（3-4倍）。最近，关于这种增加对健康的影响以及特定的膳食PUFA建议（消耗5-10%的能量，主要是LA）是否有益于或损害西方国家（如美国）的人们，一直存在激烈的争论。利用三个（2个去饱和和1个延伸）酶促步骤将LA转化为长链（LC-）PUFA花生四烯酸（ARA，20：4 n-6），然后ARA可以通过脂氧合酶、环氧合酶和p450酶转化为促炎性类花生酸。由位于FADS簇（11q12.2-q13.1）中彼此相邻的两个脂肪酸去饱和酶基因（FADS 1和FADS 2）编码，两个关键去饱和酶的活性是ARA生物合成中的限速步骤。来自文献和我们自己的初步数据的关键观察结果表明，FADS簇中的基因变异与产生LC-PUFA的能力增加和CVD生物标志物（包括LDL，甘油三酯，HDL，总胆固醇，CRP，酶促和非酶促生成的类花生酸）的产生以及临床CVD相关。重要的是，非洲裔美国人群体具有更高频率的FADS风险等位基因，产生更多的LC-PUFA，包括ARA，并表现出更高水平的CVD和冠状动脉疾病生物标志物。总之，这些研究表明迫切需要在许多种族/民族群体中进行研究，并强调研究不足的人群同时创造了挑战和机会，以了解饮食LA急剧增加对人类健康的影响。因此，响应RFA题为“营养遗传学和营养基因组学方法用于营养研究”（PAR-13-375）的修订R 01申请的目标是：提供在使用两种（低LA和高LA）平行饮食的受控饮食环境中FADS遗传决定因素对PUFA生物合成和代谢以及炎症标志物水平的作用的第一次全面调查; ii.通过在受控饮食环境的设置中直接比较由rsl 74537处的三种单独基因型之一分层的欧洲裔美国人个体，实质上提高了我们对基因 * 饮食相互作用的理解;以及iii.在多种族动脉粥样硬化研究（梅萨）队列中，通过检查FADS基因簇变异与血浆磷脂中PUFA水平和CVD/风险因素之间的关联是否因种族/种族而异，提高我们对健康结果的理解。我们将利用六个主要医疗中心之间现有合作的专业知识来回答基本问题，并缩小我们对饮食LA增加对不同人群健康影响的理解的差距，以及目前的饮食建议是否有助于观察到的健康差异。

There has been a dramatic (3-4 fold) increase over the past 50 years in the ingestion of the n-6 essential polyunsaturated fatty acid (PUFA), linoleic acid (LA) with the addition of vegetable oil products (soybean, corn, palm, and canola oils, as well as margarine and shortenings) to the Western diet. More recently, there has been an intense debate regarding the health impact of this increase and whether a particular dietary PUFA recommendation (to consume 5-10% of energy as predominantly LA) is benefiting or harming people in Western nations such as the US. LA is converted to the long chain (LC-) PUFA arachidonic acid (ARA, 20:4n-6) utilizing three (2 desaturation and 1 elongation) enzymatic steps, and ARA then can be converted to pro-inflammatory eicosanoids by lipoxygenase, cyclooxygenase and p450 enzymes. Encoded for by two fatty acid desaturase genes (FADS1 and FADS2) that sit next to each other in the FADS cluster (11q12.2-q13.1), the activity of two key desaturases are the rate limiting steps in ARA biosynthesis. Key observations from the literature and our own preliminary data reveal that gene variants in the FADS cluster are associated with an increased capacity to produce LC-PUFAs and with the production of CVD biomarkers (including LDL, triglycerides, HDL, total cholesterol, CRP, enzymatically- and nonenzymatically-generated eicosanoids) and with clinical CVD. Importantly, African American populations have much higher frequencies of FADS risk alleles, produce more LC-PUFAs including ARA, and exhibit higher levels of both CVD and coronary artery disease biomarkers. Taken together, these studies demonstrate a desperate need to conduct studies across many racial/ethnic groups and emphasize that understudied populations create a simultaneous challenge and opportunity to understand the impact of the dramatic increase in dietary LA on human health. Consequently, the goals of this revised R01 application in response to the RFA titled ‘Nutrigenetics and Nutrigenomics Approaches for Nutrition Research’ (PAR-13-375) are to: i. provide the first comprehensive investigation of the role of FADS genetic determinants on PUFA biosynthesis and metabolism as well as levels of inflammatory markers in a controlled dietary environment using two (low LA and high LA) parallel diets; ii. substantially improve our understanding of gene*diet interaction(s) with a direct comparison of European American individuals stratified by one of three separate genotypes at rs174537 in the setting of a controlled dietary environment; and iii. improve our understanding of health outcomes by examining whether the association between variants in the FADS gene cluster with levels of PUFAs in plasma phospholipids and CVD/risk factors differs by race/ethnicity in the Multi-Ethnic Study of Atherosclerosis (MESA) cohort. We will leverage the expertise of pre-existing collaborations among six major medical centers to answer essential questions and close the gap in our understanding of the influence of the increase in dietary LA on the health of diverse populations, and whether current dietary recommendations are contributing to observed health disparities.