TRIB3 R84 variant affects glucose homeostasis by altering the interplay between insulin sensitivity and secretion

The results of studies on the genetics of complex traits need to be replicated and to reach robust statistical significance before they can be considered as established. We here tried to replicate the previously reported association between the TRIB3 Q84R polymorphism (rs2295490) and glucose homeostasis. Three samples of Europeans with fasting glucose < 7.0 mmol/l were studied. In sample 1 (n = 791), the association between TRIB3 Q84R and impaired glucose regulation (IGR; defined as impaired fasting glucose and/or impaired glucose tolerance and/or type 2 diabetes by OGTT) and insulin sensitivity (ISI), and its interplay with early-phase insulin secretion (i.e. disposition index [DI]) were analysed. Sample 2 (n = 374) and sample 3 (n = 394) were used to replicate the association with IGR and insulin sensitivity (by glucose clamp), respectively. Genotyping was performed by TaqMan allele discrimination. R84 carriers were at higher risk of IGR: OR for the additive model 1.54, p = 0.004, and 1.63, p = 0.027, in samples 1 and 2, respectively. In sample 1, both ISI (p = 0.005) and DI (p = 0.043) were progressively lower from QQ to QR and RR individuals. A 'triangulation approach' indicated that the association with IGR was mostly mediated by DI rather than by ISI changes (i.e. being the expected ORs 1.51 and 1.25, respectively). In sample 3, glucose disposal was 38.8 +/- 17.7, 33.8 +/- 14.4, and 31.6 +/- 13.3 mu mol min(-1) kg(-1), p = 0.022, in QQ, QR and RR individuals, respectively. Our data confirm that the TRIB3 R84 variant affects glucose homeostasis and suggest this effect is due to an alteration of the interplay between insulin sensitivity and secretion.