Genetic Susceptibility to Diabetes Subtypes and Risk of Developing Coronary Artery Disease

Diabetes significantly increases the risk for atherosclerotic complications, including coronary artery disease (CAD). Previous studies have suggested that adult-onset diabetes can be classified into five different clinical subtypes, including moderate obesity-related diabetes (MOD). The aim of this study was to investigate the genetic associations between the five diabetes subtypes and the risk of developing CAD and diabetes in the general population.

The Malmö Diet and Cancer cohort (N = 24,025) was used to assess whether polygenic risk scores (PRSs) for the five diabetes subtypes could predict future diabetes and CAD. Genetic correlations and causal effects of the MOD subtype on CAD were investigated using data from large genome-wide association studies of the MOD subtype (N = 4,116) and CAD (N = 296,525).

During follow-up, 4,105 participants (17.1%) developed diabetes (median follow-up 24.0 years) and 3,841 (16.0%) developed CAD (median follow-up 24.6 years). PRS for MOD (PRSMOD) was associated with incident diabetes and CAD. In addition, participants in the third tertile of PRSMOD had a 1.10-fold higher risk of developing CAD compared with those in the first tertile. A positive genetic correlation between MOD and CAD was observed, and Mendelian randomization analyses suggested a causal effect of MOD on CAD.

The current study showed that the genetic susceptibilities for all five diabetes subtypes were associated with incident diabetes. However, only the MOD subtype was associated with incident CAD. These findings underscore the significance of a high genetic risk for MOD as an early marker for CAD.