- •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.
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.
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.
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).
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.
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)
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- The global syndemic of obesity, undernutrition, and climate change: the lancet commission report.Lancet (London, England). 2019; 393: 791-846
- Overweight, obesity, and mortality in a large prospective cohort of persons 50 to 71 years old.N Engl J Med. 2006; 355: 763-778
- Body-mass index and mortality among 1.46 million white adults.N Engl J Med. 2010; 363: 2211-2219
- Body-mass index and all-cause mortality: Individual-participant-data meta-analysis of 239 prospective studies in four continents.Lancet (London, England). 2016; 388: 776-786
- Association of all-cause mortality with overweight and obesity using standard body mass index categories: a systematic review and meta-analysis.JAMA. 2013; 309: 71-82
- Association of weight status with mortality in adults with incident diabetes.JAMA. 2012; 308: 581-590
- Inverse relationship between body mass index and mortality in older nursing home residents: a meta-analysis of 19,538 elderly subjects.Obes Rev. 2015; 16: 1001-1015
- The obesity paradox in type 2 diabetes mellitus: relationship of body mass index to prognosis: a cohort study.Ann Intern Med. 2015; 162: 610-618
- Predicted lean body mass, fat mass, and all cause and cause specific mortality in men: prospective US cohort study.BMJ (Clin Res Ed). 2018; 362k2575
- Levels and changes in body mass index decomposed into fat and fat-free mass index: relation to long-term all-cause mortality in the general population.Int J Obes (Lond). 2005; 2020: 2092-2100
- Relation of body fat mass and fat-free mass to total mortality: results from 7 prospective cohort studies.Am J Clin Nutr. 2021; 113: 639-646
- Associations of skeletal muscle mass and fat mass with incident cardiovascular disease and all-cause mortality: a prospective cohort study of UK biobank participants.J Am Heart Assoc. 2021; 10e019337
- Predicted fat mass and lean mass in relation to all-cause and cause-specific mortality.J Cachexia Sarcopenia Muscle. 2022; 13: 1064-1075
- Genome-wide association study of body fat distribution identifies adiposity loci and sex-specific genetic effects.Nat Commun. 2019; 10: 339
- Body mass index and body composition in relation to 14 cardiovascular conditions in UK biobank: a Mendelian randomization study.Eur Heart J. 2020; 41: 221-226
- Fat mass and fat-free mass in relation to cardiometabolic diseases: a two-sample Mendelian randomization study.J Intern Med. 2020; 288: 260-262
- Use of genetic variation to separate the effects of early and later life adiposity on disease risk: Mendelian randomisation study.BMJ. 2020; 369m1203
- Body mass index and all cause mortality in HUNT and UK biobank studies: linear and non-linear mendelian randomisation analyses.BMJ. 2019; 364l1042
- Interaction of recommended levels of physical activity and protein intake is associated with greater physical function and lower fat mass in older women: Kuopio osteoporosis risk factor- (OSTPRE) and fracture-prevention study.Br J Nutr. 2020; 123: 826-839
- Diet high in protein-rich foods with structured sport activity may be useless to lose fat mass and maintain fat-free mass.Minerva Gastroenterol Dietol. 2020; 66: 321-327
- Impact of physical activity and weight loss on fat mass, glucose metabolism, and inflammation in older African Americans with osteoarthritis.Nutrients. 2020; 12
- Healthy lifestyle and life expectancy free of cancer, cardiovascular disease, and type 2 diabetes: prospective cohort study.BMJ. 2020; 368l6669
- Body-mass index and mortality among adults with incident type 2 diabetes.N Engl J Med. 2014; 370: 233-244
- Strategies for promotion of a healthy lifestyle in clinical settings: pillars of ideal cardiovascular health: a science advisory from the American Heart Association.Circulation. 2021; 144: e495-e514
- Estimating dose-response relationships for vitamin D with coronary heart disease, stroke, and all-cause mortality: observational and Mendelian randomisation analyses.Lancet Diabetes Endocrinolog. 2021; 9: 837-846
- Avoiding collider bias in Mendelian randomization when performing stratified analyses.Eur J Epidemiol. 2022; 37: 671-682
- Dual energy X-ray absorptiometry body composition reference values from NHANES.PLoS One. 2009; 4e7038
- Healthy obese versus unhealthy lean: the obesity paradox.Nat Rev Endocrinol. 2015; 11: 55-62
- The obesity paradox in cancer: epidemiologic insights and perspectives.Curr Nutr Rep. 2019; 8: 175-181
- Strengthening the reporting of observational studies in epidemiology using mendelian randomization: the STROBE-MR statement.JAMA. 2021; 326: 1614-1621
- The association between healthy lifestyle score with cardiorespiratory fitness and muscle strength.Int J Clin Pract. 2020; 74e13640
- Cardiorespiratory fitness and dietary intake in european adolescents: the healthy lifestyle in Europe by nutrition in adolescence study.Br J Nutr. 2012; 107: 1850-1859
- Impact of unhealthy lifestyle on cardiorespiratory fitness and heart rate recovery of medical science students.BMC Public Health. 2020; 20: 1012
Published online: September 01, 2022
Accepted: August 28, 2022
Received: June 3, 2022
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