Highlights
- •Mendelian randomization analyses indicated a causal association between genetically determined fat mass and mortality.
- •The association between anthropometric fat mass and all-cause mortality was manifested as J-shaped.
- •The elevated risk of mortality observed in people with low fat mass was modified by a high-risk lifestyle.
Abstract
Background
The association between fat mass and mortality has been equivocally shown to be linear,
J-shaped, and U-shaped. We aimed to clarify this relationship based on Mendelian randomization
(MR) analysis and lifestyle modification.
Methods
This prospective analysis included 449,831 participants from UK Biobank. Linear MR
analysis was used to estimate the linear relationship between fat mass and mortality.
We assessed whole body fat mass by bioimpedance analysis at baseline and categorized
subjects into five equal groups based on fat mass index (FMI). The association between
FMI and mortality were investigated among whole population and in subgroups stratified
by individual lifestyle factors, including diet, physical activity, smoking, alcohol,
sleep and psychological health.
Findings
Linear MR analyses indicated a positive association between genetically predicted
fat mass and all-cause mortality (HR 1.10, 95 % CI 1.08–1.12, P < 0.001). The association between FMI and all-cause mortality was manifested as J-shaped
(HRs across FMI categories: 1.04, 1.00, 1.07, 1.21, 1.54), which was significantly
modified by the number of low-risk lifestyle factors (P for interaction<0.001). When evaluating individual lifestyle factors, we observed
a nonlinear relationship between FMI and all-cause mortality among participants who
had high-risk lifestyle factors, while a linear relationship was observed among participants
who had low-risk lifestyle factors, especially for those with adequate physical activity
(HRs across FMI categories: 0.95, 1.00, 1.05, 1.17, 1.44) and who never smoked (0.96,
1.00, 1.03, 1.14, 1.51).
Interpretation
Genetically determined fat mass is causally and linearly associated with mortality.
The J-shape association between anthropometric FMI and mortality is caused by high-risk
lifestyle factors.
Graphical abstract
Graphical Abstract
Abbreviations:
BIA (bioimpedance analysis), BMI (body mass index), CVD (cardiovascular disease), CI (confidence interval), DXA (dual-energy X-ray absorptiometry), FMI (fat mass index), GWAS (genome-wide association studies), HR (hazard ratio), MR (mendelian randomization), PRS (polygenic risk score), SNPs (single nucleotide polymorphisms)Keywords
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Article info
Publication history
Published online: September 01, 2022
Accepted:
August 28,
2022
Received:
June 3,
2022
Identification
Copyright
© 2022 Elsevier Inc. All rights reserved.
