Abstract
Understanding of the genetic basis of type 2 diabetes (T2D) has progressed rapidly, but the interactions between common genetic variants and lifestyle risk factors have not been systematically investigated in studies with adequate statistical power. Therefore, we aimed to quantify the combined effects of genetic and lifestyle factors on risk of T2D in order to inform strategies for prevention. The InterAct study includes 12,403 incident T2D cases and a representative sub-cohort of 16,154 individuals from a cohort of 340,234 European participants with 3.99 million person-years of follow-up. We studied the combined effects of an additive genetic T2D risk score and modifiable and non-modifiable risk factors using Prentice-weighted Cox regression and random effects meta-analysis methods. The effect of the genetic score was significantly greater in younger individuals (p for interaction = 1.20×10-4). Relative genetic risk (per standard deviation [4.4 risk alleles]) was also larger in participants who were leaner, both in terms of body mass index (p for interaction = 1.50×10-3) and waist circumference (p for interaction = 7.49×10-9). Examination of absolute risks by strata showed the importance of obesity for T2D risk. The 10-y cumulative incidence of T2D rose from 0.25% to 0.89% across extreme quartiles of the genetic score in normal weight individuals, compared to 4.22% to 7.99% in obese individuals. We detected no significant interactions between the genetic score and sex, diabetes family history, physical activity, or dietary habits assessed by a Mediterranean diet score. The relative effect of a T2D genetic risk score is greater in younger and leaner participants. However, this sub-group is at low absolute risk and would not be a logical target for preventive interventions. The high absolute risk associated with obesity at any level of genetic risk highlights the importance of universal rather than targeted approaches to lifestyle intervention.
Highlights
Diabetes is currently estimated to affect 382 million people worldwide [1], with severe consequences for the health and economy of developed and developing nations alike
The high absolute risk associated with obesity at any level of genetic risk highlights the importance of universal rather than targeted approaches to lifestyle intervention
We found no significant interactions of the genetic risk score with sex, diabetes family history, physical activity, or dietary habits as assessed by a Mediterranean diet score
Summary
Diabetes is currently estimated to affect 382 million people worldwide [1], with severe consequences for the health and economy of developed and developing nations alike. This study included only high-risk individuals and may have been underpowered because of the small number of people in each subgroup (947 in the placebo group, 955 in the lifestyle intervention group, and the 941 metformin group), even in this relatively large intervention trial. A complementary approach to the analysis of lifestyle trials is the investigation of interactions between genetic and lifestyle factors in observational cohort studies. Such interactions have not been systematically investigated in prospective cohorts with standardised assessment of lifestyle factors at baseline and adequate statistical power. Understanding of the genetic basis of type 2 diabetes (T2D) has progressed rapidly, but the interactions between common genetic variants and lifestyle risk factors have not been systematically investigated in studies with adequate statistical power. Long-term complications of diabetes, which include an increased risk of heart disease and stroke, reduce the life expectancy of people with diabetes by about ten years compared to people without diabetes
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