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omega-3脂肪酸，在美国被广泛用作补充或替代医疗策略。特别是，各种来源的omega-3补充剂被推荐用于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。与美国白人相比，许多这些疾病对美国黑人的影响更高或更严重。这种健康差异有多种原因，包括社会和生物原因，部分原因可能是不同的饮食习惯或遗传风险的差异。虽然omega-3脂肪酸补充剂对心血管疾病的益处已得到广泛认可，但最近的观察数据表明，花生四烯酸5-脂氧合酶基因（ALOX5）变异等位基因的受试者患心血管疾病的风险可能更高，同时，与普通等位基因纯合的受试者相比，omega-3脂肪酸补充剂可能获得更大的益处。感兴趣的变异等位基因在ALOX5启动子中的Sp1/Egr-1转录因子结合位点有3或4个重复，而普通等位基因有5个重复。变异等位基因在白人人群中（18%）比在黑人人群中（52%）更少见。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，具有两个变异等位基因的受试者ALOX5基因的表达量更高，花生四烯酸衍生白三烯的产量更高，并且具有更强的“促炎”表型。这些数据还表明，携带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个变异等位基因的黑人受试者；(b) 2个共同等位基因或(3)各一个等位基因，以确定ALOX5 mRNA、ALOX5蛋白、白三烯的产生和炎症细胞因子的产生在基因型之间是否存在差异。然后，受试者将接受安慰剂或omega-3脂肪酸补充剂6周，以确定变异等位基因纯合或杂合的受试者白三烯和细胞因子产生的预期减少量是否更大。干预前后还将评估心血管风险指标，包括血脂、血压、心率、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.