Use or Metabolomic Markers of Response to Fish Oil Supplementation to Identify Ef

描述(申请人提供)：我们最近完成了一项由NCCAM资助的R21临床试验，题为“ALOX5基因的变异和对omega-3脂肪酸补充剂的反应”(R21 AT003411，C.Stephensen，PI；ClinicalTrials.gov标识符，NCT00536185)。共有116名非洲血统的受试者在ALOX5启动子基因型中随机选择每天服用5g鱼油浓缩物或每天服用5g玉米/大豆安慰剂油的受试者进行为期6周的干预；98名受试者完成了试验。简而言之，补充鱼油对血脂和脂蛋白谱以及炎症标志物有显著的有益影响。然而，对这些变量的反应范围很广。我们假设，考虑到受试者对鱼油干预反应的可变性，将提高我们发现与慢性炎症性疾病发展相关的炎症标志物显著差异的能力。在本提案中，我们计划使用对补充反应的两个标记物来量化这种可变性。第一个标志是红细胞膜的脂肪酸组成因补充而发生变化，重点是花生四烯酸(AA)和鱼油中两种主要的omega-3脂肪酸，二十碳五烯酸(EPA)和二十二碳六烯酸(DHA)。这些数据来自父母的研究。第二个标记物集将根据一组18至20碳的omega-3和omega-6脂肪酸代谢物的血浆浓度开发，这些代谢物将与一系列白三烯(LT)、前列腺素(PG)和血栓烷(TX)一起进行测量，以用于这里提议的研究。我们将确定这些omega-3摄入量的红细胞或血浆生物标志物是否能比使用鱼油/安慰剂名称更可靠地预测特定的、高纯度细胞类型(单核细胞、粒细胞、淋巴细胞)炎症标志物的变化。单核细胞数据来自母体研究，而从母体研究保存的粒细胞和淋巴细胞样本将为这一建议进行分析。我们还将确定这些生物标志物是否可以预测全身炎症的血浆标志物的变化，包括为本研究测量的LT、PG和TX的血浆浓度，以及为本研究测量的46个炎症的血浆蛋白标志物的浓度，包括细胞因子、趋化因子、可溶性细胞黏附分子、急性时相蛋白、蛋白酶和抗蛋白酶以及补体成分。 公共卫生相关性：慢性炎症性疾病是美国民众的主要健康问题。饮食和其他补充和替代医学干预措施可以减轻这种炎症的严重程度，从而改善健康。评估这种干预措施对炎症的影响是困难的，因为由于行为、环境和遗传差异导致个人反应的多样性。在这项研究中，我们将开发和评估对摄入鱼油补充剂的反应的生物标志物，这将提高我们评估此类干预措施对炎症和慢性炎症性疾病风险的影响的能力。

DESCRIPTION (provided by applicant): We recently completed an NCCAM-funded R21 clinical trial entitled "Variation in the ALOX5 gene and response to omega-3 fatty acid supplements" (R21 AT003411, C. Stephensen, PI; ClinicalTrials.gov Identifier, NCT00536185). A total of 116 subjects of African ancestry were randomized within ALOX5 promoter genotypes to 5 g/day fish oil concentrate or 5 g/day corn/soy placebo oil for a six week intervention; 98 subjects completed the trial. In brief, there was a significant, beneficial effect of fish oil supplementation on plasma lipid and lipoprotein profiles and on markers of inflammation. However, there was a wide range of responses for these variables. We hypothesize that accounting for variability in subject responses to fish oil intervention will increase our ability to see significant differences in markers of inflammation linked to development of chronic inflammatory diseases. In the present proposal we plan to use two markers of response to supplementation to quantify this variability. The first marker is the change in fatty acid composition of erythrocyte cell membranes in response to supplementation, focusing on arachadonic acid (AA) and the two principal omega-3 fatty acids from fish oil, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). These data are available from the parent study. The second marker set will be developed from plasma concentrations of a panel of 18- to 20-carbon omega-3 and omega-6 fatty acid metabolites that will be measured along with an array of leukotrienes (LT), prostaglandins (PG) and thromboxanes (TX) for the study proposed here. We will determine if these erythrocyte or plasma biomarkers of omega-3 intake will predict changes in markers of inflammation by specific, highly purified cell types (monocyte, granulocyte, lymphocyte) more reliably than using the fish oil/placebo designation. Monocyte data are available from the parent study while granulocyte and lymphocyte samples saved from the parent study will be analyzed for this proposal. We will also determine if these biomarkers will predict changes in plasma markers of systemic inflammation, including plasma concentrations of LT, PG and TX measured for this study, and concentrations of 46 plasma protein markers of inflammation to be measured for this study, including cytokines, chemokines, soluble cell adhesion molecules, acute phase proteins, proteases and anti-proteases, and complement components. PUBLIC HEALTH RELEVANCE: Chronic inflammatory diseases are a major health concern for the US population. Dietary and other complementary and alternative medicine interventions can decrease the severity of such inflammation and thus improve health. Evaluating the impact of such interventions on inflammation is difficult because of the variability of response by individuals resulting from behavioral, environmental and genetic differences. In this study we will develop and evaluate biomarkers of response to intake of fish oil supplements that will improve our ability to evaluate the impact of such interventions on inflammation and risk of chronic inflammatory disease.