Epigenome-wide association of myocardial infarction with DNA methylation sites at loci related to cardiovascular disease.

BACKGROUND: Development of cardiovascular disease (CVD), including coronary artery disease, arrhythmia, and ischemic stroke, depends on environmental and genetic factors. To investigate the epigenetic basis of myocardial infarction (MI), we performed an epigenome-wide association study for this condition in elderly Japanese subjects. A total of 192 case subjects with MI and 192 control subjects were recruited from hospital attendees and the general population, respectively. Genome-wide DNA methylation (DNAm) profiles for DNA isolated from whole blood were obtained by analysis with an Infinium HumanMethylation450 BeadChip. The relation of DNAm sites found to be significantly associated with MI to nearby single nucleotide polymorphisms (SNPs) previously shown to be associated with CVD was assessed in the control group. FINDINGS: Three DNAm sites (cg06642177, cg07786668, cg17218495) showed genome-wide significant associations with MI (p = 4.33 × 10-8, 3.96 × 10-10, and 3.77 × 10-8, respectively). Two of these sites (cg07786668, cg17218495) still showed such associations after adjustment for classical risk factors of MI (p = 1.04 × 10-7 and 6.60 × 10-8, respectively). The DNAm sites cg07786668 and cg17218495 are located in ZFHX3 (zinc finger homeobox 3) and SMARCA4 (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a, member 4) genes, respectively. SNPs in ZFHX3 or SMARCA4 that were previously found to be associated with CVD were not significantly associated with these DNAm sites in our control subjects. CONCLUSIONS: We identified two DNAm sites-cg07786668 in ZFHX3 and cg17218495 in SMARCA4- that are independently and significantly associated with MI. Our results suggest that the development of MI might be influenced by changes in DNAm at these sites via a pathway that differs from that affected by CVD-associated SNPs in these genes. The Kita-Nagoya Genomic Epidemiology (KING) study, which was the source of control samples in the present study, was registered in ClinicalTrials.gov (NCT00262691) on 6 December 2005.

Epigenome-wide association study suggests that SNPs in the promoter region of RETN influence plasma resistin level via effects on DNA methylation at neighbouring sites.

AIMS/HYPOTHESIS: To investigate epigenetic regulation of the plasma concentration of resistin, we performed an epigenome-wide association study for this variable and DNA methylation (DNAm) in an elderly Japanese cohort and then assessed the relation of single nucleotide polymorphisms (SNPs) associated with the plasma resistin concentration to DNAm level at identified sites. METHODS: The association of plasma resistin level with DNAm status was examined in 191 nondiabetic elderly men with the Illumina Infinium HumanMethylation450 BeadChip array. The association between DNAm status at specific sites in the flanking region of the resistin gene (RETN) and RETN mRNA abundance was then evaluated with a public data set for 1202 monocyte samples from a multi-ethnic cohort. Finally, the association of DNAm status and SNPs in the promoter region of RETN was assessed in two cohorts comprising a total of 478 Japanese individuals. RESULTS: DNAm status at cg02346997 located in the RETN promoter region showed a negative genome-wide significant association with the plasma resistin level (p = 6.02 × 10(-10)). Four DNAm sites in the RETN promoter region including cg02346997 (p = 4.23 × 10(-70)) showed a negative genome-wide significant association with RETN mRNA abundance in monocytes. Furthermore, the number of minor alleles of the RETN promoter SNPs rs34861192 and rs3219175 was negatively associated with DNAm level at cg02346997 (p = 4.43 × 10(-17)). CONCLUSIONS/INTERPRETATION: Our results suggest that RETN promoter SNPs might influence the circulating resistin level through an effect on DNAm at cg02346997 and on RETN mRNA abundance in monocytes.

Relationship between severity of renal impairment and 2-year outcomes after sirolimus-eluting stent implantation.

BACKGROUND: The presence of chronic kidney disease (CKD) is associated with an increased risk of restenosis and major adverse cardiac events (MACEs) after coronary interventions, especially in patients on hemodialysis (HD). The aim of this study was to assess the impact of varying degrees of renal impairment on angiographic and 2-year clinical outcomes after treatment with sirolimus-eluting stents (SESs). METHODS: A total of 675 lesions of 593 patients treated with SES were analyzed. Patients were classified into 3 groups: 34 patients on HD; 337 patients with estimated glomerular filtration rate > or =60 mL min(-1) 1.73 m(-2) (non-CKD group); and 222 patients who had lower estimated glomerular filtration rate <60 mL min(-1) 1.73 m(-2) without HD dependency (CKD group). RESULTS: At angiographic follow-up (201 +/- 73 days), in-segment late loss was markedly higher in the HD group versus the non-CKD and CKD groups (0.68 +/- 1.06 vs 0.11 +/- 0.45 and 0.15 +/- 0.50 mm, respectively, P < .001), resulting in a significantly higher in-segment restenosis rate (40.0% vs 10.4% and 11.5%, respectively, P < .001). At 2 years, HD vs non-CKD and CKD was associated with a significantly higher MACE rate (35.3% vs 10.4% and 12.6%, respectively, P < .001), mainly driven by significantly higher mortality (11.8% vs 0.6% and 2.3%, respectively, P < .001) and target-lesion revascularization (23.5% vs 9.2% and 8.1%, respectively, P = .016) rates. Multivariable analysis revealed that HD was the independent predictor of 2-year MACE (hazard ratio 4.70, 95% CI 2.40-9.20, P < .001). CONCLUSIONS: Although angiographic and clinical outcomes after SES implantation were similarly favorable in non-HD-dependent CKD patients, regardless of renal function, in patients with end-stage CKD requiring HD, frequencies of restenosis and 2-year MACE were markedly higher than in non-HD-dependent patients.