Abstract
Metabolic syndrome is a group of heritable metabolic traits that are highly associated with type 2 diabetes (T2DM). Classical interventions to T2DM include individual self-management of environmental risk factors, such as improving diet quality, increasing physical activity, and reducing smoking and alcohol consumption, which decreases the risk of developing metabolic syndrome. However, it is poorly understood how the phenotypes of diabetes-related metabolic traits change with respect to lifestyle modifications at the individual level. In the analysis, we used 12 diabetes-related metabolic traits and eight lifestyle covariates from the UK Biobank comprising 288,837 white British participants genotyped for 1,133,273 genome-wide single nucleotide polymorphisms. We found 16 GxE interactions. Modulation of genetic effects by physical activity was seen for four traits (glucose, HbA1c, C-reactive protein, systolic blood pressure) and by alcohol and smoking for three (BMI, glucose, waist–hip ratio and BMI and diastolic and systolic blood pressure, respectively). We also found a number of significant phenotypic modulations by the lifestyle covariates, which were not attributed to the genetic effects in the model. Overall, modulation in the metabolic risk in response to the level of lifestyle covariates was clearly observed, and its direction and magnitude were varied depending on individual differences. We also showed that the metabolic risk inferred by our model was notably higher in T2DM prospective cases than controls. Our findings highlight the importance of individual genetic differences in the prevention and management of diabetes and suggest that the one-size-fits-all approach may not benefit all.
Highlights
Diabetes mellitus is a metabolic disease normally caused by high blood glucose levels, which can lead to complications in kidneys, eyes, and the nervous system (Rolo and Palmeira, 2006)
We show that the direction and magnitude of metabolic risk in response to the level of lifestyle covariates vary depending on individual genetic differences, i.e., phenotypic plasticity of the risk
There was no evidence of orthogonal interaction between physical activity and body mass index (BMI), other lifestyle factors significantly modulated the genetic effects of BMI (e.g., p-value = 1.86E-10 for alcohol intake frequency (ALC)-BMI) (Figure 1)
Summary
Diabetes mellitus is a metabolic disease normally caused by high blood glucose levels, which can lead to complications in kidneys, eyes, and the nervous system (Rolo and Palmeira, 2006). It is one of the top 10 leading causes of death in the world (Heron, 2018), highlighting the importance of improved strategies on prevention and management. Type 2 diabetes mellitus (T2DM), which accounts for more than 90% of all cases of diabetes (Chatterjee et al, 2017), is known to be more polygenic than other types of diabetes (Kramer et al, 2003; Jiang et al, 2019). Metabolic syndrome is a group of traits that causes metabolic diseases, such as diabetes. Diabetes-related metabolic traits can include glucose, hemoglobin A1c (HbA1c), C-reactive protein (CRP), body mass index (BMI), cholesterols, and blood pressure (BP) (Sabatti et al, 2009)
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