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Role of PUFA-Gene Interactions in Health Disparities

PUFA-基因相互作用在健康差异中的作用

基本信息

批准号：
9889900
负责人：
FLOYD H CHILTON
金额：
$ 55.43万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-01-16 至 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9889900
关键词：
11q12 Accounting Address Admixture African African American Alleles American Anabolism Arachidonic Acids Atherosclerosis Attention Biological Biological Markers Canola Oil Cardiovascular system Chinese American Cholesterol Chronic Disease Clinical Collaborations Complex Consumption Corn Oil Coronary Arteriosclerosis Data Diet Dietary Component Dietary Fats Dietary Intervention Disease Eicosanoids Environment Enzymes Equilibrium Ethnic Origin Ethnic group European Evaluation Exhibits Fatty Acid Desaturases Fatty acid glycerol esters Food Frequencies Gene Cluster Genes Genetic Genetic Determinism Genome Genotype Goals Health High Density Lipoproteins Hispanic Americans Hispanics Human Incidence Individual Inflammation Inflammatory Ingestion Intervention Studies Intervention Trial Investigation Laboratories Linoleic Acids Lipoxygenase Literature Malignant Neoplasms Margarine Measures Medical center Metabolism Modernization Multi-Ethnic Study of Atherosclerosis N-3 polyunsaturated fatty acid Non-Insulin-Dependent Diabetes Mellitus Not Hispanic or Latino Nutrient Nutritional Nutritional Study Oils Omega-6 Fatty Acids Outcome Phospholipids Plasma Play Polyunsaturated Fatty Acids Population Population Heterogeneity Process Production Prostaglandin-Endoperoxide Synthase Publishing Race Randomized Recommendation Research Research Personnel Risk Factors Role Severities Signal Transduction Soybean Oil Talents Testing Variant Vegetable Oils Vegetables Whole Blood admixture mapping base burden of illness cohort cooking desaturase ethnic minority population fatty acid biosynthesis fatty acid metabolism gene interaction genetic variant genome wide association study health disparity improved inflammatory marker insight low density lipoprotein triglyceride nutrition related genetics nutritional genomics palm oil population based public health relevance racial and ethnic racial minority response risk variant social trait urinary western diet

项目摘要

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.

在过去的50年里，西方饮食中n-6必需多不饱和脂肪酸(PUFA)、亚油酸(LA)和添加植物油产品(大豆、玉米、棕榈油和菜籽油，以及人造黄油和起酥油)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，以及一项特定的饮食PUFA建议(消耗5-10%的能量，主要是LA)是对美国等西方国家的人们有利还是有害的问题，存在着激烈的辩论。LA通过三个步骤(2个去饱和和1个延伸)转化为长链(LC-)PUFA花生四烯酸(ARA，20：4N-6)，然后ARA可以通过脂氧合酶、环氧合酶和P450酶转化为促炎二十烷酸。由FADS簇(11q12.2-q13.1)中相邻的两个脂肪酸去饱和酶基因(FADS1和FADS2)编码，两个关键的去饱和酶的活性是ARA生物合成的限速步骤。来自文献的关键观察和我们自己的初步数据显示，FADS簇中的基因变异与产生LC-PUFAs的能力增加、与心血管生物标记物(包括低密度脂蛋白、甘油三酯、高密度脂蛋白、总胆固醇、C反应蛋白、酶和非酶产生的二十烷类化合物)的产生以及临床心血管疾病有关。重要的是，非裔美国人群体有更高频率的FADS风险等位基因，产生更多包括ARA在内的LC-PUFA，并表现出更高水平的心血管疾病和冠状动脉疾病生物标志物。综上所述，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，未被研究的人群同时创造了一个挑战和机会，以了解饮食中LA急剧增加对人类健康的影响。因此，根据RFA《营养遗传学和营养基因组学研究方法》(PAR-13-375)修订的R01申请的目标是：i.首次全面研究FADS基因决定因素对多不饱和脂肪酸生物合成和代谢的作用，以及在两种(低LA和高LA)平行饮食的受控饮食环境中炎症标志物的水平；大大提高我们对基因*饮食相互作用的理解(S)，在受控饮食环境的设置中，通过直接比较由rs174537上三种不同基因之一分层的欧美个体；在动脉粥样硬化多民族研究(MESA)队列中，通过检查FADS基因簇变异与血浆磷脂中多不饱和脂肪酸水平和心血管疾病/风险因素之间的关联是否因种族/民族而不同，从而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先前存在的合作的专业知识来回答基本问题，并弥合我们在理解膳食LA增加对不同人群健康的影响方面的差距，以及当前的饮食建议是否有助于观察到的健康差距。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Temporal Associations of Plasma Levels of the Secreted Phospholipase A 2 Family and Mortality in Severe COVID-19.

分泌型磷脂酶 A 2 家族血浆水平与严重 COVID-19 死亡率的时间关联。

DOI：
10.1101/2022.11.21.22282595
发表时间：
2022
期刊：
medRxiv : the preprint server for health sciences
影响因子：
0
作者：
Lu,Eric;Hara,Aki;Sun,Shudong;Hallmark,Brian;Snider,JustinM;Seeds,MichaelC;Watkins,JosephC;McCall,CharlesE;Zhang,HaoHelen;Yao,Guang;Chilton,FloydH
通讯作者：
Chilton,FloydH

Impact of FADS gene variation and dietary fatty acid exposure on biochemical and anthropomorphic phenotypes in a Hispanic/Latino cohort.

DOI：
10.3389/fnut.2023.1111624
发表时间：
2023
期刊：
FRONTIERS IN NUTRITION
影响因子：
5
作者：
Sergeant, Susan;Keith, Brian A.;Seeds, Michael C.;Legins, Jimaree A.;Young, Caroline B.;Vitolins, Mara Z.;Chilton, Floyd H.
通讯作者：
Chilton, Floyd H.

FADS genetic and metabolomic analyses identify the ∆5 desaturase (FADS1) step as a critical control point in the formation of biologically important lipids.

DOI：
10.1038/s41598-020-71948-1
发表时间：
2020-09-28
期刊：
Scientific reports
影响因子：
4.6
作者：
Reynolds LM;Dutta R;Seeds MC;Lake KN;Hallmark B;Mathias RA;Howard TD;Chilton FH
通讯作者：
Chilton FH

Tissue-specific impact of FADS cluster variants on FADS1 and FADS2 gene expression.