Practice Update: Diabetes

OBESITY 20

Physical Activity Alters Genetic Susceptibility to Long-TermWeight Gain Diabetes Take-home message • To determine whether physical activity alters genetic susceptibility to long-term weight gain, this study evaluated 9390 women and 5291 men every 5 years from 1986 to 2006. Each participant was assigned a genetic risk score (GRS) based on 77 sin- gle-nucleotide polymorphisms (SNPs) for body mass index (BMI) and a GRS for body fat percentage (BF%) based on 12 SNPs. Multivariate analysis showed that long-term increases in BMI were associated with GRS for BMI and %BF. There was a significant interaction between change in physical activity and BF%-GRS on BMI change, with a 10-risk allele increment of −0.02 vs 0.24 kg/m2 4-year change in BMI among participants with greatest increase versus greatest decrease in physical activity. There was a similar trend for the BMI-GRS. • This study shows that increasing physical activity may decrease genetic susceptibility to weight gain.

weight change within five 4-year intervals from 1986 to 2006 using multivariable generalized linear models with repeated-measures analyses. Both the BMI-GRS and the BF%-GRS were asso- ciated with long-term increases in BMI/weight, and change in physical activity consistently inter- acted with the BF%-GRS on BMI change in the NHS (P[interaction]=0.025) and HPFS (P[inter- action]=0.001). In the combined cohorts, 4-year BMI change per 10-risk allele increment was -0.02 kg/m(2) among participants with greatest increase in physical activity and 0.24 kg/m(2) among those with greatest decrease in physical over each interval, their GRSs had very lit- tle impact on actual change in BMI during each period; in contrast, in those individu- als with the greatest decrease in physical activity during each interval, their GRSs had the largest impact on increased BMI. Although a strength of this study is the rel- atively large number of genetic variants included in the BMI GRS, there are likely 1000s of variants not yet identified that also contribute to the heritability of both BMI and %BF. Nevertheless, the current body of evidence supports a critical role of physical activity in weight management, no matter a person’s genetic predisposi- tion for obesity. Providers can therefore offer an optimistic view to their patients, that having an increased genetic risk for obesity is likely not fatalistic, and can be mitigated by increased physical activity.

activity (P[interaction]<0.001), corresponding to 0.01 kg versus 0.63 kg weight changes every 4 years (P[interaction]=0.001). Similar but marginal interactions were observed for the BMI-GRS (P[interaction]=0.045). Our data indicate that the genetic susceptibility to weight gain may be diminished by increasing physical activity. Genetic susceptibility, change in physical activ- ity, and long-term weight gain. Diabetes 2017 Jul 12;[EPub Ahead of Print], T Wang, T Huang, Y Heianza,et al. www.practiceupdate.com/c/56629 References 1. Rampersaud E, Mitchell BD, Pollin TI, et al. Physical activity and the association of common FTO gene variants with body mass index and obesity. Arch Intern Med. 2008;168(16):1791- 1797. https://www.ncbi.nlm.nih.gov/pmc/articles/ PMC3635949/ 2. Vimaleswaran KS, Li S, Zhao JH, et al. Physical activity attenuates the body mass index- increasing influence of genetic variation in the FTO gene. Am J Clin Nutr. 2009;90(2):425-428. http://ajcn.nutrition.org/content/90/2/425.long 3. Li S, Zhao JH, Luan J, et al. Physical activity attenuates the genetic predisposition to obesity in 20,000 men and women from EPIC-Norfolk prospective population study. PLoS Med. 2010;7(8). pii: e1000332. https://www.ncbi.nlm. nih.gov/pmc/articles/PMC2930873/ 4. Kilpelainen TO, Qi L, Brage S, et al. Physical activity attenuates the influence of FTO variants on obesity risk: a meta-analysis of 218,166 adults and 19,268 children. PLoS Med. 2011;8(11):e1001116. https://www.ncbi.nlm.nih.gov/ pmc/articles/PMC3206047/ 5. Andreasen CH, Stender-Petersen KL, Mogensen MS, et al. Low physical activity accentuates the effect of the FTO rs9939609 polymorphism on body fat accumulation. Diabetes. 2008;57(1):95-101. http://diabetes. diabetesjournals.org/content/57/1/95.long 6. Zhu J, Loos RJ, Lu L, et al. Associations of genetic risk score with obesity and related traits and the modifying effect of physical activity in a Chinese Han population. PLoS One. 2014;9(3):e91442. https://www.ncbi.nlm.nih.gov/ pmc/articles/PMC4683059/

Abstract Whether change in physical activity over time modifies the genetic susceptibility to long-term weight gain is unknown. We calculated a body mass index (BMI)-genetic risk score (GRS) based on 77 BMI-associated single-nucleotide poly- morphisms (SNPs) and a body fat percentage (BF%)-GRS based on 12 BF%-associated SNPs, respectively, in 9,390 women from the Nurses’ Health Study (NHS) and 5,291 men from the Health Professionals Follow-up Study (HPFS). We analyzed the interactions between each GRS and change in physical activity on BMI/body COMMENT By Miriam S Udler MD, PhD T his study by Wang et al. adds to the growing body of literature showing that inherited genetic risk of obesity can be mitigated by increased physical activity.1-6 Their analysis involved two well-established cohorts, both with long- term follow-up: 9390 women from the Nurses’ Health Study and 5291 men from the Health Professionals Follow-up Study. In contrast to previous studies which have generally defined levels of physical activ- ity based on a single time point, Wang et al. were able to assess changes in levels of physical activity over five 4-year inter- vals. Additionally, they evaluated genetic risk of increased body mass index (BMI) using 77 genetic variants, together defin- ing a genetic risk score (GRS). They also utilized a GRS of 12 variants impacting body-fat percentage (BF%), which has been less well studied than the BMI GRS. In each cohort, and in the cohorts com- bined, the authors found a significant interaction between physical activity and BMI change over time per number of genetic alleles, using either the BMI of BF% GRS. Put simply, in individuals who had the greatest increase in physical activity

Dr Miriam S. Udler is Assistant in Medicine, Massachusetts General Hospital, Instructor in Medicine, Harvard Medical School, Post-doctoral fellow, Broad Institute, Boston, MA.

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