Venkatesh L Murthy1,2, Rui Xia3, Abigail S Baldridge4, Mercedes R Carnethon5, Stephen Sidney5, Claude Bouchard6, Mark A Sarzynski7, João A C Lima8, Gregory D Lewis9, Sanjiv J Shah4,10,11, Myriam Fornage3, Ravi V Shah9. 1. Division of Cardiovascular Medicine, Department of Medicine, University of Michigan, Ann Arbor. 2. Frankel Cardiovascular Center, University of Michigan, Ann Arbor. 3. Brown Foundation Institute of Molecular Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston. 4. Department of Preventative Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois. 5. Kaiser Permanente Northern California Division of Research, Oakland. 6. Human Genomics Laboratory, Pennington Biomedical Research Center, Baton Rouge, Louisiana. 7. Department of Exercise Science, University of South Carolina, Columbia. 8. Department of Medicine, The Johns Hopkins School of Medicine, Baltimore, Maryland. 9. Cardiology Division, Department of Medicine, Massachusetts General Hospital, Boston. 10. Division of Cardiology, Department of Medicine, Northwestern University, Chicago, Illinois. 11. Associate Editor.
Abstract
Importance: Obesity is a major determinant of disease burden worldwide. Polygenic risk scores (PRSs) have been posited as key predictors of obesity. How a PRS can be translated to the clinical encounter (especially in the context of fitness, activity, and parental history of overweight) remains unclear. Objective: To quantify the relative importance of a PRS, fitness, activity, parental history of overweight, and body mass index (BMI) (calculated as weight in kilograms divided by height in meters squared) in young adulthood on BMI trends over 25 years. Design, Setting, and Participants: This population-based prospective cohort study at 4 US centers included white individuals and black individuals with assessments of polygenic risk of obesity, fitness, activity, and BMI in young adulthood (in their 20s) and up to 25 years of follow-up. Data collected between March 1985 and August 2011 were analyzed from April 25, 2019, to September 29, 2019. Main Outcomes and Measures: Body mass index at the initial visit and 25 years later. Results: This study evaluated an obesity PRS from a recently reported study of 1608 white individuals (848 women [52.7%]) and 909 black individuals (548 women [60.3%]) across the United States. At baseline (year 0), mean (SD) overall BMI was 24.2 (4.5), which increased to 29.6 (6.9) at year 25. Among white individuals, the PRS (combined with age, sex, self-reported parental history of overweight, and principal components of ancestry) explained 11.9% (at year 0) and 13.6% (at year 25) of variation in BMI. Although the addition of fitness increased the explanatory capability of the model (24.0% variance at baseline and up to 18.1% variance in BMI at year 25), baseline BMI in young adulthood was the strongest factor, explaining 52.3% of BMI in midlife in combination with age, sex, and self-reported parental history of overweight. Accordingly, models that included baseline BMI (especially BMI surveillance over time) were better in predicting BMI at year 25 compared with the PRS. In fully adjusted models, the effect sizes for fitness and the PRS on BMI were comparable in opposing directions. The added explanatory capacity of the PRS among black individuals was lower than among white individuals. Among white individuals, addition of baseline BMI and surveillance of BMI over time was associated with improved precision of predicted BMI at year 25 (mean error in predicted BMI 0 kg/m2 [95% CI, -11.4 to 11.4] to 0 kg/m2 [95% CI, -8.5 to 8.5] for baseline BMI and mean error 0 kg/m2 [95% CI, -5.3 to 5.3] for BMI surveillance). Conclusions and Relevance: Cardiorespiratory fitness in young adulthood and a PRS are modestly associated with midlife BMI, although future BMI is associated with BMI in young adulthood. Fitness has a comparable association with future BMI as does the PRS. Caution should be exercised in the widespread use of polygenic risk for obesity prevention in adults, and close clinical surveillance and fitness may have prime roles in limiting the adverse consequences of elevated BMI on health.
Importance: Obesity is a major determinant of disease burden worldwide. Polygenic risk scores (PRSs) have been posited as key predictors of obesity. How a PRS can be translated to the clinical encounter (especially in the context of fitness, activity, and parental history of overweight) remains unclear. Objective: To quantify the relative importance of a PRS, fitness, activity, parental history of overweight, and body mass index (BMI) (calculated as weight in kilograms divided by height in meters squared) in young adulthood on BMI trends over 25 years. Design, Setting, and Participants: This population-based prospective cohort study at 4 US centers included white individuals and black individuals with assessments of polygenic risk of obesity, fitness, activity, and BMI in young adulthood (in their 20s) and up to 25 years of follow-up. Data collected between March 1985 and August 2011 were analyzed from April 25, 2019, to September 29, 2019. Main Outcomes and Measures: Body mass index at the initial visit and 25 years later. Results: This study evaluated an obesity PRS from a recently reported study of 1608 white individuals (848 women [52.7%]) and 909 black individuals (548 women [60.3%]) across the United States. At baseline (year 0), mean (SD) overall BMI was 24.2 (4.5), which increased to 29.6 (6.9) at year 25. Among white individuals, the PRS (combined with age, sex, self-reported parental history of overweight, and principal components of ancestry) explained 11.9% (at year 0) and 13.6% (at year 25) of variation in BMI. Although the addition of fitness increased the explanatory capability of the model (24.0% variance at baseline and up to 18.1% variance in BMI at year 25), baseline BMI in young adulthood was the strongest factor, explaining 52.3% of BMI in midlife in combination with age, sex, and self-reported parental history of overweight. Accordingly, models that included baseline BMI (especially BMI surveillance over time) were better in predicting BMI at year 25 compared with the PRS. In fully adjusted models, the effect sizes for fitness and the PRS on BMI were comparable in opposing directions. The added explanatory capacity of the PRS among black individuals was lower than among white individuals. Among white individuals, addition of baseline BMI and surveillance of BMI over time was associated with improved precision of predicted BMI at year 25 (mean error in predicted BMI 0 kg/m2 [95% CI, -11.4 to 11.4] to 0 kg/m2 [95% CI, -8.5 to 8.5] for baseline BMI and mean error 0 kg/m2 [95% CI, -5.3 to 5.3] for BMI surveillance). Conclusions and Relevance: Cardiorespiratory fitness in young adulthood and a PRS are modestly associated with midlife BMI, although future BMI is associated with BMI in young adulthood. Fitness has a comparable association with future BMI as does the PRS. Caution should be exercised in the widespread use of polygenic risk for obesity prevention in adults, and close clinical surveillance and fitness may have prime roles in limiting the adverse consequences of elevated BMI on health.
Authors: Zhe Wang; Shing Wan Choi; Nathalie Chami; Eric Boerwinkle; Myriam Fornage; Susan Redline; Joshua C Bis; Jennifer A Brody; Bruce M Psaty; Wonji Kim; Merry-Lynn N McDonald; Elizabeth A Regan; Edwin K Silverman; Ching-Ti Liu; Ramachandran S Vasan; Rita R Kalyani; Rasika A Mathias; Lisa R Yanek; Donna K Arnett; Anne E Justice; Kari E North; Robert Kaplan; Susan R Heckbert; Mariza de Andrade; Xiuqing Guo; Leslie A Lange; Stephen S Rich; Jerome I Rotter; Patrick T Ellinor; Steven A Lubitz; John Blangero; M Benjamin Shoemaker; Dawood Darbar; Mark T Gladwin; Christine M Albert; Daniel I Chasman; Rebecca D Jackson; Charles Kooperberg; Alexander P Reiner; Paul F O'Reilly; Ruth J F Loos Journal: Front Endocrinol (Lausanne) Date: 2022-05-03 Impact factor: 6.055
Authors: Donald M Lloyd-Jones; Cora E Lewis; Pamela J Schreiner; James M Shikany; Stephen Sidney; Jared P Reis Journal: J Am Coll Cardiol Date: 2021-07-20 Impact factor: 27.203