Infrequent TRIB3 coding variants and coronary artery disease in type 2 diabetes

•Infrequent variants in TRIB3 have been searched by re-sequencing of coding exons in patients with T2D ascertained for CAD.•Eight variants have been genotyped and analyzed in three case-control studies for CAD from Italy and US.•Infrequent variants, as a whole, were significantly associated with CAD in samples from Italy, but not from the US.•The association in the Italian sets was especially strong among individuals who also carried the common TRIB3 R84 variant.

ObjectiveGenes that modulate insulin sensitivity may also be involved in shaping the risk of coronary artery disease (CAD). The relatively common TRIB3 Q84R polymorphism (rs2295490) has been associated with abnormal insulin signaling, endothelial dysfunction, insulin resistance, and pro-atherogenic phenotypes. The aim of our study was to investigate the association between low-frequency TRIB3 coding variants and CAD in patients with type 2 diabetes (T2D).MethodsThree case-control studies for CAD from Italy and US were analyzed, for a total of 1565 individuals, all with type 2 diabetes. Infrequent variants were identified by re-sequencing TRIB3 exons in 140 “extreme cases” and 140 “super-controls” and then genotyped in all study subjects.ResultsTRIB3 infrequent variants (n = 8), considered according to a collapsing rare variants framework, were significantly associated with CAD in diabetic patients from Italy (n = 700, OR = 0.43, 95% CI 0.20-0.91; p = 0.027), but not from the US (n = 865, OR = 1.22, 95% CI 0.69-2.18; p = 0.49). In the Italian sets, the association was especially strong among individuals who also carried the common R84 variant.ConclusionAlthough preliminary, our finding suggests a role of TRIB3 low-frequency variants on CAD among Italian patients with T2D. Further studies are needed to address the role of TRIB3 infrequent variants in other populations of both European and non-European ancestries.