Background: 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.
Methods and Findings: 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 Prenticeweighted
Cox regression and random effects meta-analysis methods. The effect of the genetic score was significantly
greater in younger individuals (p for interaction = 1.2061024
). 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 = 1.5061023
) and waist
circumference (p for interaction = 7.4961029
). 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.
Conclusions: The relative effect of a T2D genetic risk score is greater in younger and leaner participants. However, this subgroup
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