Variation in the ALOX5 gene and response to omega-3 fatty acid supplements

描述（由申请人提供）：个体之间的遗传差异可能会影响营养需求和饮食干预的潜在健康益处。一些营养补充剂，如ω-3脂肪酸，在美国被广泛用作补充或替代医疗策略。特别是，建议从各种来源补充ω-3脂肪酸，以预防或缓解许多慢性炎症性疾病的症状，包括心血管疾病，高血压，关节炎和哮喘。这些疾病中有许多对美国黑人的影响比对白色美国人的影响更高或更严重。这种健康差异有多种原因，既有社会原因，也有生物原因，部分原因可能是不同的饮食习惯或遗传风险的差异。虽然ω-3补充剂对心血管疾病的益处被广泛认可，但最近的观察数据表明，具有花生四烯酸5-脂氧合酶基因（ALOX 5）的变异等位基因的受试者可能具有更大的心血管疾病风险，同时，与普通等位基因纯合子的受试者相比，可能从ω-3脂肪酸补充剂中获得更大的益处。感兴趣的变体等位基因在ALOX 5启动子中具有3或4个Sp1/Egr-1转录因子结合位点的重复，而共同等位基因具有5个重复。变异等位基因在白色人群中（18%）比在黑人人群中（52%）更不常见。流行病学数据表明，与具有两个常见等位基因的受试者相比，具有两个变体等位基因的受试者将具有更高的ALOX 5基因表达、更高的花生四烯酸衍生的白三烯产生和更“促炎”表型。这些数据还表明，具有变异等位基因的受试者将从omega-3补充剂中获得更大的健康益处。在这里提出的初步研究中，我们将招募具有（a）2种变异等位基因;（B）2种常见等位基因或（3）每种等位基因之一的黑人受试者，以确定基因型之间ALOX 5 mRNA、ALOX 5蛋白、白三烯产生和炎性细胞因子产生是否不同。然后，受试者将接受安慰剂或ω-3脂肪酸补充剂6周，以确定对于变体等位基因纯合或杂合的受试者中白三烯和细胞因子产生的预期降低是否更大。还将在干预前后评估心血管风险指标，包括血脂谱、血压、心率和血浆CRP、葡萄糖和胰岛素浓度。

DESCRIPTION (provided by applicant): Genetic differences among individuals may affect nutrient requirements and the potential health benefits from dietary interventions. Some nutritional supplements, such as omega-3 fatty acids, are widely used in the US as a complementary or alternative medical strategy. In particular, omega-3 supplements from a variety of sources are recommended for prevention of or symptomatic relief for many chronic inflammatory diseases, including cardiovascular disease, hypertension, arthritis and asthma. Many of these diseases affect black Americans at a higher rate or with greater severity than they do white Americans. Such health disparities have multiple causes, both social and biological, and may be partially due to different dietary practices or differences in genetic risk. While the benefit of omega-3 supplements for cardiovascular disease are widely recognized, recent observational data indicates that subjects with a variant allele for the arachidonate 5-lipoxygenase gene (ALOX5) may be at greater risk for cardiovascular disease and, at the same time, may derive a greater benefit from omega-3 fatty acid supplements than do subjects homozygous for the common allele. The variant alleles of interest have 3 or 4 repeats of the Sp1/Egr-1 transcription factor binding site in the ALOX5 promoter, while the common allele has 5 repeats. The variant alleles are less common in the white population (18%) than in the black population (52%). The epidemiologic data suggest that subjects with two variant alleles will have greater ALOX5 gene expression, greater production of arachidonic acid-derived leukotrienes and a more "proinflammatory" phenotype than subjects with two common alleles. These data also suggest that subjects with the variant alleles will derive greater health benefits from omega-3 supplementation. In the pilot study proposed here we will recruit black subjects who have (a) 2 variant alleles; (b) 2 common alleles or (3) one of each to determine if ALOX5 mRNA, ALOX5 protein, leukotriene production and inflammatory cytokine production differ among the genotypes. Subjects will then receive placebo or omega-3 fatty acid supplements for 6 wk to determine if the expected decreases in leukotriene and cytokine production are greater in subjects homozygous or heterozygous for the variant alleles. Indicators of cardiovascular risk will also be assessed before and after intervention, including blood lipid profile, blood pressure, heart rate, and plasma CRP, glucose and insulin concentrations.