Background: 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.
Methods: 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.
Results: 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.
Conclusions: 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.