Gnatiuc Friedrichs Louisa, Kuri-Morales Pablo, Trichia Eirini, Staplin Natalie, Torres Jason, Alegre-Díaz Jesus, Baca Paulina, Garcilazo-Ávila Adrián, González-Carballo Carlos, Ramirez-Reyes Raul, Rivas Fernando, Aguilar-Ramirez Diego, Bragg Fiona, Clarke Robert, Herrington William G, Hill Michael, Liu Tianshu, Vergara-Lope Alejandra, Wade Rachel, Collins Rory, Peto Richard, Berumen Jaime, Tapia-Conyer Roberto, Emberson Jonathan R
Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom.
School of Medicine, National Autonomous University of Mexico, Mexico City, Mexico.
Int J Epidemiol. 2025 Jun 11;54(4). doi: 10.1093/ije/dyaf110.
Persistent hyperglycaemia in diabetes can cause weight loss, distorting the association of adiposity with mortality. We estimated the lifelong associations of genetically predicted body mass index (BMI) with 52 causes of death among 125 003 Mexican adults, in whom persistent hyperglycaemia in diabetes was common.
A trans-ancestry genetic instrument for BMI (from 724 BMI-associated single-nucleotide polymorphisms) estimated the causal relevance of BMI to mortality before age 75 years, stratified by sex and adjusted for age and underlying ancestry structure, using a one-sample Mendelian randomization (MR) approach. Two-sample MR and other sensitivity analyses were also performed.
The genetic instrument explained 3% of the BMI variation and predicted BMI similarly in men and women. Each 5-kg/m2 higher genetically predicted BMI was associated with nearly a doubling in the risk of all-cause mortality at ages 35-74 years [13 066 deaths; hazard ratio (HR) 1.80, 95% confidence interval (CI) 1.63-2.00]. Hazard ratios were greater for vascular-metabolic (n = 7111; HR 2.15, 95% CI 1.87-2.48) than for non-vascular-metabolic causes (n = 5955; HR 1.47, 95% CI 1.27-1.71) and particularly strong for renal (n = 2034; HR 3.59, 95% CI 2.76-4.67), acute diabetic crises (n = 557; HR 2.70, 95% CI 1.64-4.44), and infective deaths (n = 811; HR 2.61, 95% CI 1.73-3.92). For all-cause mortality, HRs were somewhat greater at younger ages compared with older ages, and slightly larger in those with a higher proportion of Indigenous American ancestry. The strength of the association with mortality was reduced by more than half after simple adjustment for genetic predisposition to diabetes. Sensitivity analyses supported the main conclusions.
In this Mexican population, genetically predicted lifelong BMI was strongly related to mortality and mediated substantially through diabetes.
糖尿病患者持续性高血糖会导致体重减轻，从而扭曲肥胖与死亡率之间的关联。我们估计了在125003名墨西哥成年人中，基因预测的体重指数（BMI）与52种死因之间的终生关联，这些成年人中糖尿病患者持续性高血糖很常见。
使用单样本孟德尔随机化（MR）方法，通过一种用于BMI的跨血统基因工具（来自724个与BMI相关的单核苷酸多态性），估计BMI与75岁之前死亡率的因果相关性，按性别分层，并对年龄和潜在血统结构进行调整。还进行了两样本MR和其他敏感性分析。
该基因工具解释了3%的BMI变异，在男性和女性中对BMI的预测相似。在35 - 74岁年龄段，基因预测的BMI每升高5kg/m²，全因死亡率风险几乎翻倍[13066例死亡；风险比（HR）1.80，95%置信区间（CI）1.63 - 2.00]。血管 - 代谢性死因（n = 7111；HR 2.15，95% CI 1.87 - 2.48）的风险比高于非血管 - 代谢性死因（n = 5955；HR 1.47，95% CI 1.27 - 1.71），尤其在肾脏疾病（n = 2034；HR 3.59，95% CI 2.76 - 4.67）、急性糖尿病危机（n = 557；HR 2.70，95% CI 1.64 - 4.44）和感染性死亡（n = 811；HR 2.61，95% CI 1.73 - 3.92）方面风险比很强。对于全因死亡率，较年轻年龄段的HRs相比年长年龄段略高，在美洲原住民血统比例较高的人群中略大。在对糖尿病遗传易感性进行简单调整后，与死亡率的关联强度降低了一半以上。敏感性分析支持主要结论。
在这个墨西哥人群中，基因预测的终生BMI与死亡率密切相关，且很大程度上通过糖尿病介导。
