Abstract 2319: Genetic Variations Of Mrf-2/Arid5b Confer Risk Of Coronary Artery Disease And Diabetes Mellitus In The Japanese Population
Mrf-2/Arid5b, a member of AT-rich interaction domain family of transcription factors, is highly expressed in the cardiovascular system and is believed to play essential roles in the phenotypic change through its regulation of smooth muscle cell differentiation. In addition, recent studies on gene-engineered mice suggested that this transcriptional factor is involved in obesity and adipogenesis, which are critical aspects of metabolic syndrome and diabetes mellitus. Thus, we hypothesized that genetic variations of the Mrf-2 gene may be associated with susceptibility to coronary artery disease (CAD) and diabetes mellitus (DM). To examine the association between Mrf-2 polymorphisms and CAD, we investigated 17 common SNPs of Mrf-2 in 475 CAD subjects and 310 control subjects. Four nearby SNPs (rs2893880, rs10740055, rs7087507 and rs10761600) showed almost complete linkage disequilibrium, and disease associations were revealed not only for individual SNPs (P =0.0002, rs2893880; P =0.0067, rs7087507, respectively) but also for their haplotype combination (P =0.04, G-C-G-A (rs2893880-rs10740055-rs7087507-rs10761600)). Furthermore, these positive disease associations still existed after logistic regression analysis was performed to eliminate confounding conventional coronary risk factors. Subsequent analysis revealed that the aforementioned SNPs also statistically conferred risk of DM. To confirm these findings, we recruited another 500 DM subjects and 500 control subjects, and assessed the same haplotype block for their disease associations. Consistent significant associations were observed (P =0.0238, rs2893880; P =0.0014, rs10740055; P=0.0067, rs7087507; P =0.0022, rs10761600; P =0.0031 and P =0.04, C-A-A-T and G-C-G-A (rs2893880-rs10740055-rs7087507- rs10761600), respectively). Moreover, the disease-associated genotypes were also revealed to be correlated with the level of serum adiponectin, which is known as an anti-diabetic adipocytokine. . In conclusion, our study implicates genetic variations of Mrf-2 as previously unknown genetic risk factors for CAD and DM. We believe that the associations of Mrf-2 with CAD may be mediated at least partly via its associations with DM.