Louisa Gnatiuc Friedrichs, Pablo Kuri-Morales, Eirini Trichia, Natalie Staplin, Jason Torres, Jesus Alegre-Díaz, Paulina Baca, Adrián Garcilazo-Ávila, Carlos González-Carballo, Raul Ramirez-Reyes, Fernando Rivas, Diego Aguilar-Ramirez, Fiona Bragg, Robert Clarke, William G Herrington, Michael Hill, Tianshu Liu, Alejandra Vergara-Lope, Rachel Wade, Rory Collins, Richard Peto, Jaime Berumen, Roberto Tapia-Conyer, Jonathan R Emberson
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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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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. 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引用次数: 0
摘要
背景：糖尿病患者持续高血糖可导致体重减轻，扭曲了肥胖与死亡率的关系。我们在125003名墨西哥成年人中估计了遗传预测的体重指数（BMI）与52种死亡原因的终生相关性，其中糖尿病患者持续高血糖很常见。方法：使用单样本孟德尔随机化（MR）方法，对BMI的跨祖先遗传工具（从724个BMI相关的单核苷酸多态性中）估计BMI与75岁前死亡率的因果关系，按性别分层，并根据年龄和潜在的祖先结构进行调整。还进行了双样本MR和其他敏感性分析。结果：遗传仪器解释了3%的BMI变异，并预测了男性和女性的BMI相似。基因预测BMI每升高5 kg/m2, 35-74岁人群全因死亡风险几乎增加一倍[13 066例死亡；风险比（HR） 1.80, 95%可信区间（CI） 1.63-2.00]。血管代谢的风险比更大(n = 7111；HR 2.15, 95% CI 1.87-2.48)比非血管代谢原因(n = 5955；HR 1.47, 95% CI 1.27-1.71)，尤其严重(n = 2034；HR 3.59, 95% CI 2.76-4.67)，急性糖尿病危象(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)。对于全因死亡率，hr在年轻时略高于老年，而在美洲原住民血统比例较高的人群中略高。在对糖尿病的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。结论：在墨西哥人群中，遗传预测终身BMI与死亡率密切相关，并通过糖尿病介导。
A Mendelian randomization study of the effect of body mass index on 52 causes of death among 125 000 Mexican adults with admixed ancestry.
Background: 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.
Methods: 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.
Results: 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.
Conclusion: In this Mexican population, genetically predicted lifelong BMI was strongly related to mortality and mediated substantially through diabetes.
期刊介绍：
The International Journal of Epidemiology is a vital resource for individuals seeking to stay updated on the latest advancements and emerging trends in the field of epidemiology worldwide.
The journal fosters communication among researchers, educators, and practitioners involved in the study, teaching, and application of epidemiology pertaining to both communicable and non-communicable diseases. It also includes research on health services and medical care.
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Overall, this journal is an indispensable tool for staying informed and connected within the dynamic realm of epidemiology.
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