Interpreting Clinical Trials With Omega-3 Supplements in the Context of Ancestry and FADS Genetic Variation.
Interpreting Clinical Trials With Omega-3 Supplements in the Context of Ancestry and FADS Genetic Variation.
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DOI：
10.3389/fnut.2021.808054
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发表时间：
2021
影响因子：
5
通讯作者：
Hallmark B
中科院分区：
文献类型：
--
作者：
Chilton FH;Manichaikul A;Yang C;O'Connor TD;Johnstone LM;Blomquist S;Schembre SM;Sergeant S;Zec M;Tsai MY;Rich SS;Bridgewater SJ;Mathias RA;Hallmark B
在过去的75年里，美国等发达国家的人类饮食发生了巨大变化，导致肥胖、炎症和心脏代谢功能障碍的增加。过去十年的证据表明，遗传变异与18碳必需膳食欧米茄-6（n-6）和欧米茄-3（n-3）多不饱和脂肪酸（PUFA）、亚油酸（LA）和α-亚麻酸（ALA）摄入量变化的相互作用分别影响了许多分子和临床表型。相互作用与FADS 1和FADS 2基因特别相关，FADS 1和FADS 2基因编码将LA和ALA转化为其长链（≥20个碳）高度不饱和脂肪酸（HUFA）对应物的途径中的关键脂肪酸去饱和酶。这些基因与营养素的相互作用影响n-6和n-3 HUFA的水平和平衡，这些HUFA又转化为具有信号传导作用的广泛的脂质，包括类花生酸、二十二烷酸、其他氧化脂质和内源性大麻素。除了少数例外，n-6 HUFA是促炎/促血栓形成信号脂质的前体，n-3 HUFA通常具有抗炎/抗血栓形成作用。我们和其他人已经证明，非洲血统人群具有更高频率的FADS“衍生”单倍型（与欧洲，亚洲或美洲土著血统人群相比），该单倍型与高水平的饮食n-6 PUFA向促炎n-6 HUFA的有效转化有关。相比之下，一个“祖先”的单倍型，携带等位基因与有限的能力，合成HUFA，这可能会导致n-3 HUFA缺乏症，被发现在某些西班牙裔人群中的高频率，几乎是固定的几个土著人口从美洲。基于这些观察结果，VITAL n-3 HUFA补充试验的重点次要亚组分析基于自我报告的血统对数据进行了分层，结果显示，非洲裔美国人可能从n-3 HUFA补充中受益，未来的临床试验设计应考虑血统和FADS变异性。
Human diets in developed countries such as the US have changed dramatically over the past 75 years, leading to increased obesity, inflammation, and cardiometabolic dysfunction. Evidence over the past decade indicates that the interaction of genetic variation with changes in the intake of 18-carbon essential dietary omega-6 (n-6) and omega-3 (n-3) polyunsaturated fatty acids (PUFA), linoleic acid (LA) and α-linolenic acid (ALA), respectively, has impacted numerous molecular and clinical phenotypes. Interactions are particularly relevant with the FADS1 and FADS2 genes, which encode key fatty acid desaturases in the pathway that converts LA and ALA to their long chain (≥20 carbons), highly unsaturated fatty acid (HUFA) counterparts. These gene by nutrient interactions affect the levels and balance of n-6 and n-3 HUFA that in turn are converted to a wide array of lipids with signaling roles, including eicosanoids, docosanoids, other oxylipins and endocannabinoids. With few exceptions, n-6 HUFA are precursors of pro-inflammatory/pro-thrombotic signaling lipids, and n-3 HUFA are generally anti-inflammatory/anti-thrombotic. We and others have demonstrated that African ancestry populations have much higher frequencies (vs. European-, Asian- or indigenous Americas-ancestry populations) of a FADS “derived” haplotype that is associated with the efficient conversion of high levels of dietary n-6 PUFA to pro-inflammatory n-6 HUFA. By contrast, an “ancestral” haplotype, carrying alleles associated with a limited capacity to synthesize HUFA, which can lead to n-3 HUFA deficiency, is found at high frequency in certain Hispanic populations and is nearly fixed in several indigenous populations from the Americas. Based on these observations, a focused secondary subgroup analysis of the VITAL n-3 HUFA supplementation trial stratifying the data based on self-reported ancestry revealed that African Americans may benefit from n-3 HUFA supplementation, and both ancestry and FADS variability should be factored into future clinical trials design.
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