Abstract
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.
Highlights
The inclusion criteria for the cases were as follows: (1) Self-reported or physiciandiagnosed diabetes according to the American Diabetes Association Criteria [20]; (2) Ischemic heart disease defined by clinical history, including acute myocardial infarction, angina pectoris, non-ST-elevation acute coronary syndromes, and/or ischemic electrocardiographic alterations; (3) type 2 diabetes mellitus (T2DM) was diagnosed earlier than ischemic heart disease for at least one year; and (4) Medical records or copies should be provided to verify the diagnosis of diseases
The levels of Advanced glycation end products (AGEs), TG, Fasting plasma glucose (FPG), and diastolic blood pressure (DBP) were significantly higher in the ischemic heart disease cases than in the controls (p < 0.001)
According to the recommendation of the “2017 Guidelines for the prevention and treatment of type 2 diabetes in China”, the percentages of systolic blood pressure (SBP), DBP, high-density lipoprotein cholesterol (HDLC), low-density lipoprotein cholesterol (LDLC), TG, and total cholesterol (TC) in the ideal range were significantly higher in the control group than in the case group (p < 0.001), see Supplementary Materials Table S2
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Ischemic heart disease (IHD) remains the leading global cause of death and lost life years in adults, and it is the leading cause of mortality in people with type 2 diabetes mellitus (T2DM). 68% of deaths in type 2 diabetic patients are caused by cardiac complications [1,2]. It has been demonstrated that the advanced glycation end products (AGER)/interleukin-6 (IL-6) pathway plays an important role in the physiological mechanism of diabetic cardiovascular complications [3–5]; whether gene polymorphisms in this pathway can influence the disease susceptibility are still unknown
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