Department of Neurology, The Third People's Hospital of Chengdu & The Affiliated Hospital of Southwest Jiaotong University, Chengdu, Sichuan, China.
Institute of Neuroscience, Kunming Medical University, Kunming, Yunnan, China.
PLoS One. 2022 Jun 2;17(6):e0263459. doi: 10.1371/journal.pone.0263459. eCollection 2022.
Ischemic stroke (IS) is a complex polygenic disease with a strong genetic background. The relationship between the ANRIL (antisense non-coding RNA in the INK4 locus) in chromosome 9p21 region and IS has been reported across populations worldwide; however, these studies have yielded inconsistent results. The aim of this study is to clarify the types of single-nucleotide polymorphisms on the ANRIL locus associated with susceptibility to IS using meta-analysis and comprehensively assess the strength of the association.
Relevant studies were identified by comprehensive and systematic literature searches. The quality of each study was assessed using the Newcastle-Ottawa Scale. Allele and genotype frequencies were extracted from each of the included studies. Odds ratios with corresponding 95% confidence intervals of combined analyses were calculated under three genetic models (allele frequency comparison, dominant model, and recessive model) using a random-effects or fixed-effects model. Heterogeneity was tested using the chi-square test based on the Cochran Q statistic and I2 metric, and subgroup analyses and a meta-regression model were used to explore sources of heterogeneity. The correction for multiple testing used the false discovery rate method proposed by Benjamini and Hochberg. The assessment of publication bias employed funnel plots and Egger's test.
We identified 25 studies (15 SNPs, involving a total of 11,527 cases and 12,216 controls maximum) and performed a meta-analysis. Eight SNPs (rs10757274, rs10757278, rs2383206, rs1333040, rs1333049, rs1537378, rs4977574, and rs1004638) in ANRIL were significantly associated with IS risk. Six of these SNPs (rs10757274, rs10757278, rs2383206, rs1333040, rs1537378, and rs4977574) had a significant relationship to the large artery atherosclerosis subtype of IS. Two SNPs (rs2383206 and rs4977574) were associated with IS mainly in Asians, and three SNPs (rs10757274, rs1333040, and rs1333049) were associated with susceptibility to IS mainly in Caucasians. Sensitivity analyses confirmed the reliability of the original results. Ethnicity and individual studies may be the main sources of heterogeneity in ANRIL.
Our results suggest that some single-nucleotide polymorphisms on the ANRIL locus may be associated with IS risk. Future studies with larger sample numbers are necessary to confirm this result. Additional functional analyses of causal effects of these polymorphisms on IS subtypes are also essential.
缺血性脑卒中（IS）是一种具有强烈遗传背景的复杂多基因疾病。9p21 染色体区域内的 ANRIL（INK4 基因座的反义非编码 RNA）与 IS 之间的关系已在全球范围内的人群中得到报道；然而，这些研究的结果并不一致。本研究旨在通过荟萃分析阐明与 IS 易感性相关的 ANRIL 基因座单核苷酸多态性的类型，并全面评估其关联的强度。
通过全面和系统的文献检索确定相关研究。使用纽卡斯尔-渥太华量表评估每个研究的质量。从每个纳入的研究中提取等位基因和基因型频率。使用随机效应或固定效应模型，在三种遗传模型（等位基因频率比较、显性模型和隐性模型）下计算合并分析的优势比及其相应的 95%置信区间。使用基于 Cochran Q 统计量和 I2 度量的卡方检验测试异质性，并使用亚组分析和荟萃回归模型来探索异质性的来源。使用 Benjamini 和 Hochberg 提出的错误发现率方法校正多重检验。使用漏斗图和 Egger 检验评估发表偏倚。
我们确定了 25 项研究（15 个 SNP，涉及最大的 11527 例病例和 12216 例对照），并进行了荟萃分析。ANRIL 中的 8 个 SNP（rs10757274、rs10757278、rs2383206、rs1333040、rs1333049、rs1537378、rs4977574 和 rs1004638）与 IS 风险显著相关。其中 6 个 SNP（rs10757274、rs10757278、rs2383206、rs1333040、rs1537378 和 rs4977574）与 IS 大动脉粥样硬化亚型显著相关。两个 SNP（rs2383206 和 rs4977574）与 IS 主要在亚洲人群中相关，三个 SNP（rs10757274、rs1333040 和 rs1333049）与 IS 易感性主要在高加索人群中相关。敏感性分析证实了原始结果的可靠性。种族和个体研究可能是 ANRIL 中异质性的主要来源。
我们的结果表明，ANRIL 基因座上的一些单核苷酸多态性可能与 IS 风险相关。需要更多的大样本量的研究来证实这一结果。此外，还需要对这些多态性对 IS 亚型的因果效应进行额外的功能分析。
