MRC Biostatistics Unit, University of Cambridge, Cambridge, UK
Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
BMJ Open. 2024 May 15;14(5):e081399. doi: 10.1136/bmjopen-2023-081399.
To estimate the shape of the causal relationship between body mass index (BMI) and mortality risk in a Mendelian randomisation framework.
Mendelian randomisation analyses of two prospective population-based cohorts.
Individuals of European ancestries living in Norway or the UK.
56 150 participants from the Trøndelag Health Study (HUNT) in Norway and 366 385 participants from UK Biobank recruited by postal invitation.
All-cause mortality and cause-specific mortality (cardiovascular, cancer, non-cardiovascular non-cancer).
A previously published non-linear Mendelian randomisation analysis of these data using the residual stratification method suggested a J-shaped association between genetically predicted BMI and mortality outcomes with the lowest mortality risk at a BMI of around 25 kg/m. However, the 'constant genetic effect' assumption required by this method is violated. The reanalysis of these data using the more reliable doubly-ranked stratification method provided some indication of a J-shaped relationship, but with much less certainty as there was less precision in estimates at the lower end of the BMI distribution. Evidence for a harmful effect of reducing BMI at low BMI levels was only present in some analyses, and where present, only below 20 kg/m. A harmful effect of increasing BMI for all-cause mortality was evident above 25 kg/m, for cardiovascular mortality above 24 kg/m, for cancer mortality above 30 kg/m and for non-cardiovascular non-cancer mortality above 26 kg/m. In UK Biobank, the association between genetically predicted BMI and mortality at high BMI levels was stronger in women than in men.
This research challenges findings from previous conventional observational epidemiology and Mendelian randomisation investigations that the lowest level of mortality risk is at a BMI level of around 25 kg/m. Our results provide some evidence that reductions in BMI will increase mortality risk for a small proportion of the population, and clear evidence that increases in BMI will increase mortality risk for those with BMI above 25 kg/m.
在孟德尔随机化框架中估计体重指数（BMI）与死亡风险之间因果关系的形状。
对两个前瞻性基于人群的队列进行孟德尔随机化分析。
生活在挪威或英国的欧洲血统个体。
来自挪威特隆赫姆健康研究（HUNT）的 56150 名参与者和通过邮寄邀请招募的英国生物库的 366385 名参与者。
全因死亡率和死因特异性死亡率（心血管疾病、癌症、非心血管非癌症）。
使用残差分层方法对这些数据进行的先前发表的非线性孟德尔随机化分析表明，遗传预测 BMI 与死亡率结果之间呈 J 形关联，在 BMI 约为 25kg/m 时死亡风险最低。然而，该方法所需的“恒定遗传效应”假设是违反的。使用更可靠的双重分层方法对这些数据进行的重新分析提供了 J 形关系的一些迹象，但由于 BMI 分布低端的估计精度较低，确定性要低得多。在低 BMI 水平降低 BMI 会产生有害影响的证据仅在某些分析中存在，并且仅在 BMI 低于 20kg/m 时存在。对于全因死亡率，BMI 增加的有害影响在 BMI 超过 25kg/m 时明显，对于心血管死亡率，在 BMI 超过 24kg/m 时明显，对于癌症死亡率，在 BMI 超过 30kg/m 时明显，对于非心血管非癌症死亡率，在 BMI 超过 26kg/m 时明显。在英国生物库中，遗传预测 BMI 与高 BMI 水平下的死亡率之间的关联在女性中强于男性。
这项研究对先前传统观察性流行病学和孟德尔随机化研究的发现提出了挑战，即最低死亡率风险出现在 BMI 水平约为 25kg/m 时。我们的研究结果提供了一些证据表明，对于一小部分人群，降低 BMI 会增加死亡率风险，并且明确表明，对于 BMI 超过 25kg/m 的人群，增加 BMI 会增加死亡率风险。
