Comparative Analysis of Surrogate Adiposity Markers and Their Relationship With Mortality

ImportanceBody mass index (BMI) is an easily obtainable surrogate for adiposity. However, there is substantial variability in body composition and adipose tissue distribution between individuals with the same BMI. Furthermore, previous literature is conflicting regarding the optimal BMI linked with the lowest mortality risk. ObjectiveTo determine which of BMI, fat mass index (FMI), and waist-to-hip (WHR) is the strongest and most consistent causal predictor for mortality. DesignWe created a case-control cohort using all incident deaths from the UK Biobank (UKB; 2006 to 2022). Setting22 Clinical assessment centres across the United Kingdom. ParticipantsWe partitioned UKB British participants (N= 387,672) into a discovery (N = 337,078) and validation cohort (N = 50,594), the latter consisting of 25,297 deaths and 25,297 randomly selected age- and sex-matched controls. The discovery cohort was used to derive genetically-determined adiposity measures while the validation cohort was used for all other analyses. Relationships between exposures and outcomes were analyzed through both observational and Mendelian randomization (MR) analyses to infer causality. ExposuresBMI, FMI and WHR. Main Outcomes and MeasuresAll-cause mortality; Cause-specific mortality (cancer, cardiovascular disease (CVD), respiratory disease, or other causes). ResultsObservational relationships between measured BMI and FMI with all-cause mortality were J-shaped, whereas the relationship with WHR was linear. Genetically-determined WHR had a stronger association with all-cause mortality compared to BMI or FMI (OR per SD increase of WHR (95% CI): 1.51 (1.32 - 1.72); 1.29 (1.20 - 1.38) for BMI, and 1.45 (1.36 - 1.54) for FMI, heterogeneity P<0.05), and exhibited a stronger effect in males than females (males: 1.89 [1.54 - 2.52], females: 1.20 [1.06-1.30], heterogeneity P<0.05). Unlike BMI or FMI, the relationship between genetically-determined WHR and all-cause mortality was consistent irrespective of observed BMI (heterogeneity P > 0.05). Conclusions and RelevanceWHR has the strongest and most consistent causal association with risk of mortality irrespective of BMI, with the effect being stronger in males than females. Clinical recommendations and interventions should prioritize adiposity distribution rather than mass. Key PointsO_ST_ABSQuestionC_ST_ABSAmong body mass index (BMI), fat mass index (FMI), or waist-to-hip (WHR) ratio, what is the optimal adiposity measure for predicting mortality outcomes in adults? FindingsIn this Mendelian randomization study consisting of 387,672 British adult participants from the UK Biobank (UKB), WHR was found to have the strongest and most consistent causal relationship with all-cause and cause-specific mortality. MeaningWHR was the most robust predictor of mortality risk and may serve as a more appropriate target for health care intervention.