In two prospective cohorts of U.S. women and men, we found that greater consumption of sugar-sweetened beverages was associated with a more pronounced genetic predisposition to an elevated BMI and an increased risk of obesity. The findings were further replicated in an independent large cohort of U.S. women. In all three cohorts, the combined genetic effects on BMI and obesity risk among persons consuming one or more servings of sugar-sweetened beverages per day were approximately twice as large as those among persons consuming less than one serving per month. These data suggest that persons with greater consumption of sugar-sweetened beverages may be more susceptible to genetic effects on adiposity. Viewed differently, persons with a greater genetic predisposition to obesity appeared to be more susceptible to the deleterious effects of sugar-sweetened beverages on BMI. Our findings further underscore the need to test interventions that reduce the intake of sugary drinks as a means of reducing the risk of obesity and related diseases.
Our study shows a significant interaction between an important dietary factor, the intake of sugar-sweetened beverages, and a genetic-predisposition score in relation to BMI and obesity risk. Most studies that have investigated gene–environment interactions in relation to obesity have focused on a single locus, FTO
, and physical activity; and they have yielded inconsistent results.28,30–34
Major reasons for the inconsistent results include small samples in previous studies and the small effect of a single genetic variant. Recently, a meta-analysis with a large sample (218,166 persons) validated a modest interaction between physical activity and FTO
variants in relation to obesity risk.35
In the current analysis, we calculated a genetic-predisposition score that was composed of multiple genetic variants, which has become the preferred method in analyses of gene–environment interactions.36
As expected, owing to the modest effect of each individual SNP on BMI, most of the individual SNPs did not show significant interactions with intake of sugar-sweetened beverages in relation to BMI (Table S2 in the Supplementary Appendix
). Furthermore, our prospective analysis minimized the potential reverse causality that is more likely to occur in cross-sectional studies,37
and the repeated-measures analysis with the use of longitudinally collected data represented long-term dietary habits, reduced random measurement error, and enhanced the robustness of our findings. The highly consistent results were replicated in a large independent cohort, further verifying the reliability of our findings.
Numerous studies have shown a positive association between the intake of sugar-sweetened beverages, obesity, and related cardiometabolic diseases.6–11
As reported elsewhere in this issue of the Journal
, two randomized intervention studies show that a reduction in the consumption of sugar-sweetened beverages and a replacement of sugar-sweetened beverages with noncaloric sweetened beverages reduced weight gain in children.38,39
Although further evidence is warranted, these data support a causal relationship among the consumption of sugar-sweetened beverages, weight gain, and the risk of obesity. The current finding that the genetic effects on adiposity are stronger in persons with higher intake than in those with lower intake provides useful information on the role of sugar-sweetened beverages in triggering obesity; increased consumption might contribute to the obesity epidemic by interacting with a genetic predisposition to elevated BMI. From another perspective, persons with a greater genetic predisposition may be more susceptible to obesity-inducing effects of sugar-sweetened beverages.
The intake of sugar-sweetened beverages contributes to obesity through several potential mechanisms, including a high caloric content with low satiety and incomplete compensation for these liquid calories, resulting in an increased total energy intake.40,41
In addition, because of the large amounts of rapidly absorbable carbohydrates in sugar-sweetened beverages, greater consumption may increase the risks of insulin resistance, beta-cell dysfunction, inflammation, visceral adiposity, and other metabolic disorders.42,43
However, it is unclear whether these factors linking the intake of sugar-sweetened beverages to obesity modify the genetic effect, accounting for the observed interactions. Because the biologic functions of most established BMI-associated loci are largely unknown,5
the underlying mechanisms of the interaction between the intake of sugar-sweetened beverages and a genetic predisposition to elevated adiposity or obesity need to be clarified in future studies.
The major strengths of this study include the prospective design, the large sample, use of repeated measures of sugar-sweetened beverage intake and BMI, comprehensive coverage of the established BMI-associated genetic factors, and replication of the results across three cohorts. Several limitations need to be acknowledged. Measurement errors in the intake of sugar-sweetened beverages and other dietary factors are inevitable, but the food-frequency questionnaires have been extensively validated.21–23
In addition, the self-reported weight and height in our cohorts were found to be highly reliable.24
Although we adjusted for several major lifestyle and dietary factors in the analysis, the potential for confounding by unmeasured or unknown factors could not be fully eliminated. The proportion of the total energy intake derived from sugar-sweetened beverages was not evaluated. Our genetic-predisposition score captured the combined information from all the established BMI-associated loci that have been identified to date, but it accounts for only a small amount of variation in BMI.5
Our study cohorts were restricted to persons of European ancestry, and it is unknown whether our results can be generalized to other ethnic groups.
In conclusion, our data provide consistent evidence from three separate cohorts that greater consumption of sugar-sweetened beverages was associated with a more pronounced genetic predisposition to elevated BMI and obesity risk among women and men.