Cardiovascular Research Institute Dublin, Mater Private Network, Dublin, Ireland.
School of Pharmacy and Biomolecular Sciences, RCSI University of Medicine and Health Sciences, Dublin, Ireland.
Inflamm Res. 2021 Dec;70(10-12):1075-1087. doi: 10.1007/s00011-021-01505-7. Epub 2021 Sep 30.
Circulating IL-6 levels and at least one polymorphic form of IL6 gene (IL6 -174 G/C, rs1800795) have been shown to be independently associated with coronary artery disease (CAD) by several investigators. Despite more than 12 published meta-analyses on this subject, association of -174 G/C with CAD, especially amongst distinct ancestral population groups remain unclear. We, therefore, conducted a systematic review and an updated meta-analysis to comprehensively ascertain the association of IL6 -174 G/C with CAD and circulating IL-6 levels.
Relevant case-control/cohort studies investigating association of -174 G/C with CAD and circulating IL-6 levels were identified following a comprehensive online search. Association status for CAD was determined for the pooled sample, as well as separately for major ancestral subgroups. Association status for circulating IL-6 levels was assessed for the pooled sample, as well as separately for CAD cases and CAD free controls. Study-level odds ratios (OR) and 95% confidence intervals (CI) were pooled using random/fixed-effects model.
Quantitative synthesis for the CAD endpoint was performed using 55 separate qualifying studies with a collective sample size of 51,213 (19,160 cases/32,053 controls). Pooled association of -174 G/C with CAD was found to be statistically significant through dominant (OR 1.15; 95% CI 1.05-1.25, p = 0.002) as well as allelic genetic model comparisons (OR 1.13, 95% CI 1.06-1.21, p = 0.0003). This effect was largely driven by Asian and Asian Indian ancestral subgroups, which also showed significant association with CAD in both genetic model comparisons (OR range 1.29-1.53, p value range ≤ 0.02). Other ancestral subgroups failed to show any meaningful association. Circulating IL-6 levels were found to be significantly higher amongst the 'C' allele carriers in the pooled sample (Standard mean difference, SMD 0.11, 95% CI 0.01-0.22 pg/ml, p = 0.009) as well as in the CAD free control subgroup (SMD 0.10, 95% CI 0.02-0.17 pg/ml, p = 0.009), though not in the CAD case subgroup (SMD 0.17, 95% CI = - 0.02 to 0.37, p = 0.12).
The present systematic review and meta-analysis demonstrate an overall association between IL6 -174 G/C polymorphism and CAD, which seems to be mainly driven by Asian and Asian Indian ancestral subgroups. Upregulation of plasma IL-6 levels in the 'C' allele carriers seems to be at least partly responsible for this observed association. This warrants further investigations with large, structured case-control studies especially amongst Asian and Asian Indian ancestral groups.
多位研究人员已证实，循环中的白细胞介素-6（IL-6）水平和至少一种白细胞介素 6 基因（IL6-174G/C，rs1800795）的多态形式与冠状动脉疾病（CAD）独立相关。尽管针对该主题已经发表了超过 12 项荟萃分析，但 -174G/C 与 CAD 之间的关联，特别是在不同的祖先人群中仍然不清楚。因此，我们进行了系统评价和更新的荟萃分析，以全面确定 IL6-174G/C 与 CAD 和循环中的 IL-6 水平之间的关联。
通过全面的在线搜索，确定了调查 -174G/C 与 CAD 和循环 IL-6 水平之间关联的病例对照/队列研究。为汇总样本确定 CAD 的关联状态，以及为主要祖先亚组分别确定 CAD 的关联状态。为汇总样本评估循环 IL-6 水平的关联状态，以及为 CAD 病例和 CAD 无对照分别评估。使用随机/固定效应模型汇总研究水平的优势比（OR）和 95%置信区间（CI）。
使用 55 项符合条件的研究进行了针对 CAD 终点的定量综合，总样本量为 51,213 例（19,160 例病例/32,053 例对照）。发现 -174G/C 与 CAD 的总体关联具有统计学意义，通过显性（OR 1.15；95%CI 1.05-1.25，p=0.002）和等位基因遗传模型比较（OR 1.13，95%CI 1.06-1.21，p=0.0003）。这种影响主要是由亚洲和印度裔亚组驱动的，这两个亚组在两种遗传模型比较中均与 CAD 有显著关联（OR 范围 1.29-1.53，p 值范围≤0.02）。其他祖先亚组未能显示出任何有意义的关联。在汇总样本中，“C”等位基因携带者的循环 IL-6 水平明显升高（标准均差，SMD 0.11，95%CI 0.01-0.22pg/ml，p=0.009），以及在 CAD 无对照亚组（SMD 0.10，95%CI 0.02-0.17pg/ml，p=0.009），尽管在 CAD 病例亚组中没有（SMD 0.17，95%CI=-0.02 至 0.37，p=0.12）。
本系统评价和荟萃分析表明，IL6-174G/C 多态性与 CAD 之间存在总体关联，这似乎主要由亚洲和印度裔亚组驱动。“C”等位基因携带者血浆 IL-6 水平的上调至少部分解释了这种观察到的关联。这需要在亚洲和印度裔亚组中进行更大规模、结构化的病例对照研究来进一步证实。
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