Polymorphisms and Gene-Gene Interaction in AGER/IL6 Pathway Might Be Associated with Diabetic Ischemic Heart Disease

Background: Although the genetic susceptibility to diabetes and ischemic heart disease (IHD) has been well demonstrated, studies aimed at exploring gene variations associated with diabetic IHD are still limited; Methods: Our study included 204 IHD cases who had been diagnosed with diabetes before the diagnosis of IHD and 882 healthy controls. Logistic regression was used to find the association of candidate SNPs and polygenic risk score (PRS) with diabetic IHD. The diagnostic accuracy was represented with AUC. Generalized multifactor dimensionality reduction (GMDR) was used to illustrate gene-gene interactions; Results: For IL6R rs4845625, the CT and TT genotypes were associated with a lower risk of diabetic IHD than the CC genotype (OR = 0.619, p = 0.033; OR = 0.542, p = 0.025, respectively). Haplotypes in the AGER gene (rs184003-rs1035798-rs2070600-rs1800624) and IL6R gene (rs7529229-rs4845625-rs4129267-rs7514452-rs4072391) were both significantly associated with diabetic IHD. PRS was associated with the disease (OR = 1.100, p = 0.005) after adjusting for covariates, and the AUC were 0.763 (p < 0.001). The GMDR analysis suggested that rs184003 and rs4845625 were the best interaction model after permutation testing (p = 0.001) with a cross-validation consistency of 10/10; Conclusions: SNPs and haplotypes in the AGER and IL6R genes and the interaction of rs184003 and rs4845625 were significantly associated with diabetic IHD.