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Lifestyle for the prevention of type 2 diabetes: what is the role of genetic risk information?

Guo-Chong Chen,Q. Qi

Published 2020 in American Journal of Clinical Nutrition

ABSTRACT

The prevalence of diabetes has been continuously increasing over the past 3 decades, globally but particularly in low-income and middle-income regions (1). There are 463 million adults (aged 20–79 y) estimated to be living with diabetes in 2019, with the largest number found in developing countries in Asia, such as China (116.4 million) and India (2). In the context of globalization, large proportions of populations in these less developed regions are undergoing urbanization and a host of environmental and nutritional transitions. The drastic shifts in lifestyle characterized by sedentary-style behaviors and Westernpattern diets are recognized as a major driver of the growing epidemic of diabetes (3). Most (>90%) cases of adult diabetes are type 2 diabetes (T2D), which is a complex disease concordantly determined by environmental and genetic factors. Being facilitated by the extension of the inventory of T2D-risk variants by largescale genome-wide association studies, a body of research, conducted predominantly in populations of European ancestry, has assessed the potential role of gene–environment interactions in the development of T2D (4). Currently, however, interpretation of these findings is complicated and their application in public health practice remains limited because relevant studies 1) have mostly evaluated potential interplays between individual lifestyle factors (e.g., obesity, physical activity, or individual foods or nutrients) prone to confounding by each other and individual genetic variants; 2) are often underpowered owing to relatively small sample sizes; 3) have potential concerns of multiple testing leading to false positive findings as well as selective reporting bias because of only reporting selective findings; and 4) have few cases of replications (4). In this issue of the Journal, Li et al. (5) examined independent and joint associations of combined lifestyle, genetic susceptibility to T2D, and incident T2D in the China Kadoorie Biobank (CKB) and the Singapore Chinese Health Study (SCHS), 2 prospective studies of (ethnic) Chinese participants. Genetic risk scores (GRSs) were computed by summing 49 (for the CKB) or 37 (for the SCHS) single nucleotide polymorphisms which have been associated with T2D in Chinese. Scores of unhealthy lifestyle were derived based on BMI (plus waist-to-hip ratio in the CKB) in addition to 4 behavioral factors (i.e., physical activity, diet quality, smoking, and drinking habits). Pooling data from the 2 cohorts, the results of Li et al.’s analysis expectedly showed that participants with the bottom quintile of the unhealthy lifestyle scores had 70% lower risk of T2D than those in the top quintile. With respect to genetic susceptibility, participants in the top quintile of the GRSs were estimated to have 90% higher risk of T2D than those in the bottom quintile. Perhaps more importantly, Li et al. further highlighted that a combination of healthy lifestyles was similarly associated with lower risk of T2D across all categories of genetic risk. The lack of gene– environment interaction observed by Li et al. is not surprising given the limited evidence that these T2D-associated genetic variants might be involved in the relation between lifestyle factors and risk of T2D or risk factors [with the exception of the fat mass and obesity–associated (FTO) genotype, which has been shown to interact with diet/lifestyle intervention on regulating weight loss (6)]. Li et al.’s analyses are notable for the inclusion of 2 nationwide cohorts with ethnically comparable participants, the utilization of broadly consistent (albeit slightly variable) definitions for lifestyle and genetic susceptibility, and the adjustment for similar potential confounders. The large population sample size also provided adequate statistical power to detect potential gene– lifestyle interactions had these been present. These factors are all helpful for addressing the aforementioned limitations of most previous analyses on gene–environment interactions in relation to risk of T2D. In line with the results of Li et al.’s analyses, recent findings from a large prospective study of a UK population also suggest that lifestyle combination and genetic predisposition were associated with risk of T2D independently of each other (7). Of note, in both analyses, adiposity was assigned a weight almost equal to those of other individual lifestyles in deriving the lifestyle score. Because excess adiposity is the

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