Diet Composition and Genetics: Effects on Weight, Inflammation and Biomarkers

过度肥胖是绝经后乳腺癌的危险因素，也是绝经前后乳腺癌复发的主要危险因素，其生物学机制尚不完全清楚。 肥胖与内源性循环雌激素升高以及免疫系统激活有关，免疫系统是胰岛素抵抗和高胰岛素血症的关键致病因素。减肥饮食的最佳常量营养素分配尚未确定。癌症控制指南历来鼓励低脂饮食，但目前的证据表明，这一策略并没有特别有益。新出现的证据表明，基于新陈代谢，减肥的最佳饮食结构可能会因个体而异 身份和遗传因素。在减肥干预中，饮食结构对荷尔蒙和其他将肥胖与乳腺癌联系在一起的因素的影响尚未进行比较或检查。这项研究的具体目的是：(1)检验在健康肥胖女性的减肥干预中，是否存在对不同膳食常量营养素成分的不同减肥反应，这取决于胰岛素抵抗状况； (2)。通过对可能将肥胖与乳腺癌死亡率联系起来的激素因素和炎症标记物(胰岛素、SHBG、雌激素、C反应蛋白、白介素6、肿瘤坏死因子a)以及作为基因表达标记物的IL-6和肿瘤坏死因子-a进行减肥干预，研究是否对不同饮食中的常量营养素成分有不同的反应(取决于胰岛素抵抗状态)。 基因甲基化)；以及(3)确定营养-基因相互作用，这些相互作用有助于细胞因子对减肥的不同反应，以及与IL-6和TNF-α基因多态相关的饮食结构。 这些目标将在一项随机对照研究中得到解决，156名肥胖女性随机分配到高碳水化合物(65%能量)、低脂肪(20%能量)或低碳水化合物(45%能量)、高单不饱和脂肪(35%能量)饮食中，进行为期12个月的行为减肥计划。我们假设，分配到低碳水化合物、高脂肪饮食的胰岛素抵抗女性会出现更大的体重减轻和生物标记物的减少。我们还假设，减肥和改变饮食以降低IL-6和TNF-α浓度的能力将受到这些基因多态的影响。这项研究的结果将有助于完善和个性化饮食指导，以实现最佳体重控制和乳腺癌预防，并将有助于了解将胰岛素抵抗、炎症和肥胖与乳腺癌风险和进展联系起来的机制。

Excess adiposity is a risk factor for postmenopausal breast cancer and a major risk factor for recurrence in both pre- and postmenopausal breast cancer, and the biological mechanisms are not fully understood. Obesity is associated with elevated endogenous circulating estrogen as well as activation of the immune system, a key causative factor in insulin resistance and hyperinsulinemia. Optimal macronutrient distribution of weight loss diets has not been established. Cancer control guidelines have historically encouraged a lowfat diet, but current evidence does not suggest this strategy to be of particular benefit. Emerging evidence suggests that the optimal diet composition for weight loss may differ across individuals based on metabolic status and genetic factors. Effects of diet composition on hormonal and other factors linking obesity to breast cancer in weight loss interventions have not been compared or examined. The specific aims ofthis study are: (1) To examine whether there is a differential weight loss response to different dietary macronutrient composition in a weight loss intervention in healthy obese women, depending on insulin resistance status; (2). To examine whether there is a differential response (depending on insulin resistance status) to different dietary macronutrient composition in a weight loss intervention in the hormonal factors and markers of inflammation that may link obesity to breast cancer mortality (insulin, SHBG, estrogens, C-reactive protein, interleukin-6 [IL-6], tumor necrosis factor a [TNF-a], and as a marker for gene expression, IL-6 and TNF-a gene methylation); and (3) To identify nutrient-gene interactions that contribute to differential response of cytokines to weight loss and diet composition associated with polymorphisms in IL-6 and TNF-a genes. These aims will be addressed in a randomized controlled study involving 156 obese women randomly assigned to a high-carbohydrate (65% energy) low-fat (20% energy) or low-carbohydrate (45% energy) highmonounsaturated fat (35% energy) diet in a 12-month behavioral weight loss program. We hypothesize that greater weight loss and reduction in biomarkers will occur in insulin resistant women assigned to the lower carbohydrate, higher fat diet. We also hypothesize that the ability of weight loss and diet modification to decrease IL-6 and TNF-a concentrations will be influenced by polymorphisms in these genes. Results of this study will help to refine and individualize dietary guidance for optimal weight control and breast cancer prevention and will contribute to knowledge of mechanisms that link insulin resistance, inflammation and obesity to risk and progression of breast cancer.