The existing case-control studies used to identify the genetic loci associated with type 2 diabetes are not optimally designed to investigate gene-environment or lifestyle interaction (GEI) since they do not have standardised assessment of key lifestyle, behavioural factors and do not have a prospective design in which those factors are assessed in an unbiased manner before the onset of disease. An optimal study design for investigating GEI is a case-cohort study nested within a large prospective cohort, as this combines the efficiency of the case-control design with the advantages of the longitudinal cohort approach with extensive prospective assessment of key exposures that are not subject to recall bias. Selecting a random subcohort (nested case-cohort study) rather than matched controls (nested case-control study) has the additional advantage that it facilitates the design and conduct of future case-cohort studies for other diseases occurring in the same background population or cohort.
