In the subgroup analysis, significantly increased risks were also found for Chinese (OR = 1.64, 95% CI, = 1.29–2.08; P < .001), PCR-RFLP genotyping (OR = 1.61, 95% CI, = 1.24–2.10; P < .001), ACS type (OR = 1.92, 95% CI, = 1.63–2.57 for 3 datasets; OR = 1.88, 95% CI, = 1.58–2.24.88 for 4 datasets; both P < .001), high quality (OR = 1.64, 95% CI, = 1.29–2.08; P < .001), and age/gender matching status (OR = 1.55, 95% CI, = 1.16–2.06; P = .003) under the dominant model. Furthermore, significant associations were similarly identified for ACS type under allelic (A vs T: OR = 1.32, 95% CI = 1.17–1.48 for 3 datasets; OR = 1.27, 95% CI = 1.13–1.42 for 4 datasets; both P < .001), homozygote (AA vs TT: OR = 1.64, 95% CI = 1.28–2.10, P < .001 for 3 datasets; OR = 1.50, 95% CI = 1.28–2.10, P = .001 for 4 datasets), heterozygote (AT vs TT: OR = 1.32, 95% CI = 1.10–1.58 for 3 datasets; OR = 1.30, 95% CI = 1.10–1.53 for 4 datasets; both P = .002) and recessive (AA vs AT + TT: OR = 1.40, 95% CI = 1.12–1.75, P = .047 for 3 datasets; OR = 1.28, 95% CI = 1.01–1.63, P = .040 for 4 datasets) models.
The evaluation of publication bias for AA + AT vs TT model using the Egger test indicated that the publication bias was nonsignificant (P = .370). Also, no obvious asymmetry was observed in the funnel plot (Fig. 3). These results revealed no evidence of publication bias.
The IL-8 gene, located on chromosome 4q12–21, is composed of 4 exons, 3 introns, and a proximal promoter region. Although several polymorphisms had been reported in these genomic structures of IL-8 gene, including +781C/T, −353A/T, +678T/C, +1633C/T, −251A/T, and +394 T/G,[23–25] only −251A/T[12–21] and +394 T/G polymorphisms were studied to investigate their associations with CAD. Also, −251A/T polymorphism in the promoter region was shown to be related to the expression alteration of IL-8, with AA genotype contributing to a significantly increased level of IL-8 compared with that of the AT or TT genotype.[12,26] Moreover, higher IL-8 mRNA levels were also reported in who presented the TA genotype compared with the TT genotype. Thus, −251A/T polymorphism may be a biomarker associated with a serial of inflammatory diseases, which had been demonstrated in cancer, Alzheimer's disease, and CAD.[12,13,19] In line with these studies, we also found AA + AT genotype was associated with an increased risk of overall CAD and all genetic models including mutant A-251 conferred susceptibility to ACS risk. This finding was also consistent with the fact that the cytokine related immune activity (exhibiting elevated level of IL-8, IL-18, IL-1β, IL-16, etc) was higher in the ACS patients compared with stable angina and normal controls.[30–32]
Although the mechanism remains unclear, it is supposed the higher IL-8 may contribute to the development and progression of CAD via the following potential mechanisms:
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