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Abstract：
BACKGROUND: Associations between metabolic status and metabolic changes with the risk of cardiovascular outcomes have been reported. However, the role of genetic susceptibility underlying these associations remains unexplored. We aimed to examine how metabolic status, metabolic transitions, and genetic susceptibility collectively impact cardiovascular outcomes and all-cause mortality across diverse body mass index (BMI) categories.
METHODS: In our analysis of the UK Biobank, we included a total of 481,576 participants (mean age: 56.55; male: 45.9%) at baseline. Metabolically healthy (MH) status was defined by the presence of < 3 abnormal components (waist circumstance, blood pressure, blood glucose, triglycerides, and high-density lipoprotein cholesterol). Normal weight, overweight, and obesity were defined as 18.5 ≤ BMI < 25 kg/m2, 25 ≤ BMI < 30 kg/m2, and BMI ≥ 30 kg/m2, respectively. Genetic predisposition was estimated using the polygenic risk score (PRS). Cox regressions were performed to evaluate the associations of metabolic status, metabolic transitions, and PRS with cardiovascular outcomes and all-cause mortality across BMI categories.
RESULTS: During a median follow-up of 14.38 years, 31,883 (7.3%) all-cause deaths, 8133 (1.8%) cardiovascular disease (CVD) deaths, and 67,260 (14.8%) CVD cases were documented. Among those with a high PRS, individuals classified as metabolically healthy overweight had the lowest risk of all-cause mortality (hazard ratios [HR] 0.70; 95% confidence interval [CI] 0.65, 0.76) and CVD mortality (HR 0.57; 95% CI 0.50, 0.64) compared to those who were metabolically unhealthy obesity, with the beneficial associations appearing to be greater in the moderate and low PRS groups. Individuals who were metabolically healthy normal weight had the lowest risk of CVD morbidity (HR 0.54; 95% CI 0.51, 0.57). Furthermore, the inverse associations of metabolic status and PRS with cardiovascular outcomes and all-cause mortality across BMI categories were more pronounced among individuals younger than 65 years (Pinteraction < 0.05). Additionally, the combined protective effects of metabolic transitions and PRS on these outcomes among BMI categories were observed.
CONCLUSIONS: MH status and a low PRS are associated with a lower risk of adverse cardiovascular outcomes and all-cause mortality across all BMI categories. This protective effect is particularly pronounced in individuals younger than 65 years. Further research is required to confirm these findings in diverse populations and to investigate the underlying mechanisms involved.
METHODS: In our analysis of the UK Biobank, we included a total of 481,576 participants (mean age: 56.55; male: 45.9%) at baseline. Metabolically healthy (MH) status was defined by the presence of < 3 abnormal components (waist circumstance, blood pressure, blood glucose, triglycerides, and high-density lipoprotein cholesterol). Normal weight, overweight, and obesity were defined as 18.5 ≤ BMI < 25 kg/m2, 25 ≤ BMI < 30 kg/m2, and BMI ≥ 30 kg/m2, respectively. Genetic predisposition was estimated using the polygenic risk score (PRS). Cox regressions were performed to evaluate the associations of metabolic status, metabolic transitions, and PRS with cardiovascular outcomes and all-cause mortality across BMI categories.
RESULTS: During a median follow-up of 14.38 years, 31,883 (7.3%) all-cause deaths, 8133 (1.8%) cardiovascular disease (CVD) deaths, and 67,260 (14.8%) CVD cases were documented. Among those with a high PRS, individuals classified as metabolically healthy overweight had the lowest risk of all-cause mortality (hazard ratios [HR] 0.70; 95% confidence interval [CI] 0.65, 0.76) and CVD mortality (HR 0.57; 95% CI 0.50, 0.64) compared to those who were metabolically unhealthy obesity, with the beneficial associations appearing to be greater in the moderate and low PRS groups. Individuals who were metabolically healthy normal weight had the lowest risk of CVD morbidity (HR 0.54; 95% CI 0.51, 0.57). Furthermore, the inverse associations of metabolic status and PRS with cardiovascular outcomes and all-cause mortality across BMI categories were more pronounced among individuals younger than 65 years (Pinteraction < 0.05). Additionally, the combined protective effects of metabolic transitions and PRS on these outcomes among BMI categories were observed.
CONCLUSIONS: MH status and a low PRS are associated with a lower risk of adverse cardiovascular outcomes and all-cause mortality across all BMI categories. This protective effect is particularly pronounced in individuals younger than 65 years. Further research is required to confirm these findings in diverse populations and to investigate the underlying mechanisms involved.
摘要：
背景：已经报道了代谢状态和代谢变化与心血管结局风险之间的关联。然而,遗传易感性在这些关联背后的作用仍未被探索.我们的目的是检查代谢状态，代谢转变，和遗传易感性共同影响不同体重指数(BMI)类别的心血管结局和全因死亡率.
方法：在我们对英国生物库的分析中，基线时,我们共纳入481,576名参与者(平均年龄:56.55岁;男性:45.9%).代谢健康(MH)状态定义为存在<3个异常成分(腰部情况、血压,血糖，甘油三酯，和高密度脂蛋白胆固醇）。正常体重,超重,肥胖定义为18.5≤BMI<25kg/m2,25≤BMI<30kg/m2,BMI≥30kg/m2。使用多基因风险评分（PRS）估计遗传易感性。进行Cox回归以评估代谢状态的关联，代谢转变，和PRS与不同BMI类别的心血管结局和全因死亡率。
结果：在14.38年的中位随访中，31,883（7.3％）全因死亡，8133例（1.8%）心血管疾病（CVD）死亡，记录了67,260例（14.8%）CVD病例。在那些具有高PRS的人中，与代谢不健康的肥胖人群相比，代谢健康超重人群的全因死亡率(风险比[HR]0.70;95%置信区间[CI]0.65,0.76)和CVD死亡率(HR0.57;95%CI0.50,0.64)风险最低。在中度和低度PRS组中，有益的关联似乎更大。代谢健康正常体重的个体患CVD的风险最低(HR0.54;95%CI0.51,0.57)。此外，不同BMI类别的代谢状态和PRS与心血管结局和全因死亡率的负相关在65岁以下的个体中更为显著(P交互作用<0.05).此外,在BMI类别中,观察到代谢转变和PRS对这些结局的综合保护作用.
结论：MH状态和低PRS与所有BMI类别的不良心血管结局和全因死亡率的较低风险相关。这种保护作用在65岁以下的个体中尤其明显。需要进一步的研究来确认不同人群的这些发现，并调查所涉及的潜在机制。
方法：在我们对英国生物库的分析中，基线时,我们共纳入481,576名参与者(平均年龄:56.55岁;男性:45.9%).代谢健康(MH)状态定义为存在<3个异常成分(腰部情况、血压,血糖，甘油三酯，和高密度脂蛋白胆固醇）。正常体重,超重,肥胖定义为18.5≤BMI<25kg/m2,25≤BMI<30kg/m2,BMI≥30kg/m2。使用多基因风险评分（PRS）估计遗传易感性。进行Cox回归以评估代谢状态的关联，代谢转变，和PRS与不同BMI类别的心血管结局和全因死亡率。
结果：在14.38年的中位随访中，31,883（7.3％）全因死亡，8133例（1.8%）心血管疾病（CVD）死亡，记录了67,260例（14.8%）CVD病例。在那些具有高PRS的人中，与代谢不健康的肥胖人群相比，代谢健康超重人群的全因死亡率(风险比[HR]0.70;95%置信区间[CI]0.65,0.76)和CVD死亡率(HR0.57;95%CI0.50,0.64)风险最低。在中度和低度PRS组中，有益的关联似乎更大。代谢健康正常体重的个体患CVD的风险最低(HR0.54;95%CI0.51,0.57)。此外，不同BMI类别的代谢状态和PRS与心血管结局和全因死亡率的负相关在65岁以下的个体中更为显著(P交互作用<0.05).此外,在BMI类别中,观察到代谢转变和PRS对这些结局的综合保护作用.
结论：MH状态和低PRS与所有BMI类别的不良心血管结局和全因死亡率的较低风险相关。这种保护作用在65岁以下的个体中尤其明显。需要进一步的研究来确认不同人群的这些发现，并调查所涉及的潜在机制。
