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Background: Genetic variants of the SLC39A8 gene are associated with several cardiovascular disease risk factors, including body mass index, systolic blood pressure (SBP), diastolic blood pressure (DBP), N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-density lipoprotein cholesterol (HDL-C) levels. The present study aimed to investigate the association between the SLC39A8 SNPs rs13107325 and rs74650330 and CAD in the Han population in Jiangsu (China). Methods: Genotyping of these SNPs was performed in 258 patients with CAD and 170 healthy controls using the base-quenched probe technique. The association between the alleles of the rs74650330 locus and blood lipid and glucose profiles was investigated. Receiver operating characteristic (ROC) curve analysis was used to quantify the optimal thresholds for lipid and FBG levels and the risk factors for CAD were estimated by logistic regression analysis. Results: The rs13107325 polymorphism was not found in the 428 Chinese individuals enrolled in the current study. For rs74650330, individuals harboring the C allele had significantly higher HDL levels than those without this allele in the control group (p = 0.039), while the opposite was true for low-density lipoprotein cholesterol (LDL-C) levels (p = 0.046). Further analysis indicated that when LDL-C levels were lower than 2.365 mmol/L, subjects with C/del and del/del had a 7.293-fold increased risk of CAD compared with that of controls without the mutation (odds ratio: 7.293; 95% confidence interval: 0.953–55.79). Conclusions: The susceptibility of SLC39A8 polymorphisms to CAD were studied and revealed a possible role for the deletion variant of rs74650330 in increasing the risk of CAD among the Chinese Han population. [ABSTRACT FROM AUTHOR]