OBJECTIVE Whether genetic susceptibility to disease and dietary cholesterol (DC) absorption contribute to inconsistent associations of DC consumption with diabetes and cardiovascular disease (CVD) remains unclear. RESEARCH DESIGN AND METHODS DC consumption was assessed by repeated 24-h dietary recalls in the UK Biobank. A polygenetic risk score (PRS) for DC absorption was constructed using genetic variants in the Niemann-Pick C1-Like 1 and ATP Binding Cassettes G5 and G8 genes. PRSs for diabetes, coronary artery disease, and stroke were also created. The associations of DC consumption with incident diabetes (n = 96,826) and CVD (n = 94,536) in the overall sample and by PRS subgroups were evaluated using adjusted Cox models. RESULTS Each additional 300 mg/day of DC consumption was associated with incident diabetes (hazard ratio [HR], 1.17 [95% CI, 1.07–1.27]) and CVD (HR, 1.09 [95% CI, 1.03–1.17]), but further adjusting for BMI nullified these associations (HR for diabetes, 0.99 [95% CI, 0.90–1.09]; HR for CVD, 1.04 [95% CI, 0.98–1.12]). Genetic susceptibility to the diseases did not modify these associations (P for interaction ≥0.06). The DC-CVD association appeared to be stronger in people with greater genetic susceptibility to cholesterol absorption assessed by the non-high-density lipoprotein cholesterol-related PRS (P for interaction = 0.04), but the stratum-level association estimates were not statistically significant. CONCLUSIONS DC consumption was not associated with incident diabetes and CVD, after adjusting for BMI, in the overall sample and in subgroups stratified by genetic predisposition to cholesterol absorption and the diseases. Nevertheless, whether genetic predisposition to cholesterol absorption modifies the DC-CVD association requires further investigation.

中文翻译：

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膳食胆固醇消耗与糖尿病和心血管疾病的关联：遗传变异在胆固醇吸收和疾病易感性中的作用

目的 目前尚不清楚疾病的遗传易感性和膳食胆固醇 (DC) 吸收是否会导致 DC 消耗与糖尿病和心血管疾病 (CVD) 之间不一致的关联。研究设计和方法 通过英国生物银行重复的 24 小时饮食召回来评估 DC 消耗量。使用 Niemann-Pick C1-Like 1 和 ATP 结合盒 G5 和 G8 基因中的遗传变异构建了 DC 吸收的多遗传风险评分 (PRS)。还创建了针对糖尿病、冠状动脉疾病和中风的 PRS。使用调整后的 Cox 模型评估了总体样本和 PRS 亚组中 DC 消耗与糖尿病 (n = 96,826) 和 CVD (n = 94,536) 事件的关联。结果 每增加 300 毫克/天的 DC 摄入量，与糖尿病发生率（风险比 [HR]，1.17 [95% CI，1.07–1.27]）和 CVD（HR，1.09 [95% CI，1.03–1.17]）相关。但进一步调整 BMI 消除了这些关联（糖尿病的 HR，0.99 [95% CI，0.90–1.09]；CVD 的 HR，1.04 [95% CI，0.98–1.12]）。对疾病的遗传易感性并没有改变这些关联（交互作用 P ≥0.06）。通过非高密度脂蛋白胆固醇相关 PRS 评估，在对​​胆固醇吸收具有较高遗传易感性的人群中，DC-CVD 关联似乎更强（交互作用 P = 0.04），但分层关联估计值并不具有统计显着性。结论 在调整 BMI 后，在总体样本以及按胆固醇吸收和疾病的遗传易感性分层的亚组中，DC 消耗与糖尿病和 CVD 事件无关。然而，胆固醇吸收的遗传倾向是否会改变 DC-CVD 的关联性还需要进一步研究。