Will Diet and Exercise Save Us All?

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Will Diet and Exercise Save Us All?

How many times have you been to the doctor and was told that a balanced lifestyle is key for a healthy, disease-free, long life? How many times did genetics take the blame? But do we really know whether genetic risk associated with complex diseases can be offset by behavioral changes? A recent study at the New England Journal of Medicine now brings us some answers. The idea that most human diseases are the result of a

complex interplay between genes and environment is not new. Complex genetic disorders, those in which the effects of multiple genes are at play and clear-cut patterns of inheritance are difficult to pinpoint, are particularly influenced by lifestyle and environmental factors. Take heart disease as an example. While one’s own risk of cardiovascular disease increases by 3- to 5-fold if a person’s parent is diseased, fac- tors such as diet, physical activity, tobacco use, environ- mental stress, and host factors such as age and sex also play a significant role in the risk of developing disease. The problem is that quantifying the contribution of each of these factors is tricky. Khera et al. (2016) set up to try to answer the billion dollar question: can a healthy lifestyle compensate for a strong genetic risk of developing disease? Genetic risk in complex diseases results from the combina-

tion of incremental effects of a large number of DNA seq- uence polymorphisms. In the case of coronary artery disease and myocardial infarct—a common and severe complication of cardiac disease—over 50 independent loci have been associated with risk of disease in genome-wide analyses. The aggregate of these risk genes provides has proved useful in defining genetic susceptibility to cardiovascular events. Khera et al. make use of this strategy to stratify the �60,000 subjects in their prospective study into three genetic risk categories: low, intermediate, and high. Then they ask whether baseline heathy lifestyle choices impact the risk of developing coronary events and atherosclerosis. The defini- tion of healthy lifestyle was drawn from the strategic goals of the American Heart Association (AHA) to reduce the risk of cardiovascular in the general population and include no current smoking, no obesity, physical activity at least once

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weekly, and a healthy diet pattern. Importantly, the subjects in the study were previously enrolled in independent studies and represent three completely independent cohorts, what helps to power their analyses. As one would expect, subjects with high polygenic risk

score were atmuch higher risk of developing coronary events than those at low genetic risk. What may come as a surprise is that further dividing subjects of different genetic risk groups according to their lifestyle choices shows that those who make healthy lifestyle choices present �45%–47% lower relative risk of developing coronary events. Even sub- jects at high genetic risk have their risk reduced when they make healthy lifestyle choices. The association also seems to hold true in men and women, and it does not seem to be under strong influence of ancestry. Moreover, not only the risk of adverse coronary events is reduced by adherence to healthy lifestyle but also coronary artery calcification, which is a prelude to more severe disease. Does that mean that going to the gym and eating fresh fruit,

vegetables, grains, nuts and fish (while avoiding saturated fat, red meat and sugar-sweetened beverages) can coun- teract completely the effect of genetic inheritance? Certainly not. The new study clearly shows that high genetic risk is a strong and independent risk factor that increases the risk of coronary events and atherosclerosis. What perhaps is unex- pected is that genetics and healthy lifestyle choices seem to be independently contributing to the susceptibility of heart disease. While it is true that people with high genetic risk benefit the most from healthy choices, the positive effect is also seen in those with intermediate and low genetic risk. In other words, healthy lifestyle benefits everyone, and high ge- netic risk is not necessarily deterministic of disease outcome. What do these findingsmean fromabasic biology perspec-

tive? Will we be able to get passed associations and begin to understand relationships of causality between healthy habits, genetics and disease? Will we be able to move beyond generic prescriptions of diet and exercise and tailor one’s choices to his or her genetics? Recent data have already showed that the response to food, for instance, is highly indi- vidualized when it comes to metabolism and glucose response (Zeevi et al., 2015), speaking to the need a person- alized approaches for nutrition andmedicine. Further, can the risk to other complex diseases be modified by behavioral changes?While we eagerly wait for answers to some of these questions, perhaps it would be wise to stick with carrots.


Khera, A.V., Emdin, C.A., Drake, I., Natarajan, P., Bick, A.G., Cook, N.R.,

Chasman, D.I., Baber, U., Mehran, R., Rader, D.J., et al. (2016). N. Engl. J.

Med. Published online November 13, 2016. http://dx.doi.org/10.1056/


Zeevi, D., Korem, T., Zmora, N., Israeli, D., Rothschild, D.,Weinberger, A., Ben-

Yacov, O., Lador, D., Avnit-Sagi, T., Lotan-Pompan,M., et al. (2015). Personal-

ized Nutrition by Prediction of Glycemic Responses. Cell 163, 1079–1094.

João Monteiro

ell 167, December 1, 2016 ª 2016 Published by Elsevier Inc. 1431

Will Diet and Exercise Save Us All?
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