Comparative Analysis of Surrogate Adiposity Markers and Their Relationship With Mortality

Abstract

Importance: Body 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. Objective: To determine which of BMI, fat mass index (FMI), and waist-to-hip (WHR) is the strongest and most consistent causal predictor for mortality. Design: We created a case-control cohort using all incident deaths from the UK Biobank (UKB; 2006 to 2022). Setting: 22 Clinical assessment centres across the United Kingdom. Participants: We 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. Exposures: BMI, FMI and WHR. Main Outcomes and Measures: All-cause mortality; Cause-specific mortality (cancer, cardiovascular disease (CVD), respiratory disease, or other causes). Results: Observational 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 Relevance: WHR 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.

Competing Interest Statement

The authors have declared no competing interest.

Funding Statement

Ontario Graduate Scholarship (IK)

Author Declarations

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Ethics Statement: Approval was received to use UKBiobank study data in this work under application ID # 15255 ("Identification of the shared biological and sociodemographic factors underlying cardiovascular disease and dementia risk"). The UKBiobank study obtained ethics approval from the North West Multi-centre Research Ethics Committee which encompasses the UK (REC reference: 11/NW/0382). All research participants provided informed consent.

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I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

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Data Availability

Individual-level UKBiobank genotypes and phenotypes can be acquired upon successful application (https://bbams.ndph.ox.ac.uk/ams/). All individual-level UKBiobank data was accessed as part of application # 15255. GIANT summary statistics are freely available to download (https://portals.broadinstitute.org/collaboration/giant/index.php/GIANT_consortium). All data products generated as part of this study will be made publicly accessible. All remaining data are available in the main text or supplementary materials.

https://portals.broadinstitute.org/collaboration/giant/index.php/GIANT_consortium

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