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Background  Both DNA genotype and methylation of antisense non-coding RNA in the INK4 locus ( ANRIL ) have been robustly associated with coronary artery disease (CAD), but the interdependent mechanisms of genotype and methylation remain unclear.    Methods  Eighteen tag single nucleotide polymorphisms (SNPs) of  ANRIL  were genotyped in a matched case–control study (cases 503 and controls 503). DNA methylation of  ANRIL  and the INK4/ARF locus ( p14   ARF  ,  p15   INK4b   and  p16   INK4a  ) was measured using pyrosequencing in the same set of samples (cases 100 and controls 100).    Results  Polymorphisms of  ANRIL  (rs1004638, rs1333048 and rs1333050) were significantly associated with CAD ( p  < 0.05). The incidence of CAD, multi-vessel disease, and modified Gensini scores demonstrated a strong, direct association with  ANRIL  gene dosage ( p  < 0.05). There was no significant association between  ANRIL  polymorphisms and myocardial infarction/acute coronary syndrome (MI/ACS) ( p  > 0.05). Methylation levels of  ANRIL  were similar between the two studied groups ( p  > 0.05), but were different in the rs1004638 genotype, with AA and AT genotype having a higher level of  ANRIL  methylation (pos4,  p  = 0.006; pos8,  p  = 0.019). Further Spearman analyses indicated that methylation levels of  ANRIL  were positively associated with systolic blood pressure (pos6,  r  = 0.248,  p  = 0.013), diastolic blood pressure (pos3,  r  = 0.213,  p  = 0.034; pos6,  r  = 0.220,  p  = 0.028), and triglyceride (pos4,  r  = 0.253,  p  = 0.013), and negatively associated with high-density lipoprotein cholesterol (pos2,  r  = − 0.243,  p  = 0.017). Additionally, we identified 12 transcription factor binding sites (TFBS) within the methylated  ANRIL  region, and functional annotation indicated these TFBS were associated with basal transcription. Methylation at the INK4/ARF locus was not associated with  ANRIL  genotype.    Conclusions  These results indicate that  ANRIL  genotype (tag SNPs rs1004638, rs1333048 and rs1333050) mainly affects coronary atherosclerosis, but not MI/ACS. There may be allele-related DNA methylation and allele-related binding of transcription factors within the  ANRIL  promoter.    Supplementary Information  The online version contains supplementary material available at 10.1186/s12920-021-01094-8.

Genetic and epigenetic associations of ANRIL with coronary artery disease and risk factors