Table 2.
Top-ranked paired differentially methylated probes (DMPs).
| Probe ID | P-value | Δβ* | Chromosome position | Gene | Feature | UCSC (hg19) island name | Biological function and/or association with heart disease |
|---|---|---|---|---|---|---|---|
| CpG probes hypermethylated in cases compared to controls | |||||||
| cg15417294 | 1.52E−04 | 0.09 | chr10:119019957 | SLC18A2/VMAT2 | Body | Neurotransmitter transport. Murine knockout models and polymorphisms in humans are associated with cardiac arrhythmias and human cardiac sudden death syndromes62 | |
| cg19815989 | 1.25E−04 | 0.08 | chr21:45161359 | PDXK | Body | Pyridoxal kinase is in the critical region on chromosome 21 for congenital heart disease and has increased expression in the developing human Down syndrome heart63 | |
| cg13848826 | 2.45E−05 | 0.07 | chr10:15476870 | – | IGR | NA | |
| cg18772399 | 6.24E−05 | 0.06 | chr8:89478349 | – | IGR | CpG and SNP rs1012116 associated with blood lipid levels64,65 | |
| cg27461310 | 2.71E−04 | 0.06 | chr19:41037348 | SPTBN4 | 5'UTR | chr19:41035100–41035440 | Actin-binding and cardiac conduction. Primarily found at the cardiomyocyte intercalated disc. Loss results in increased fibrosis and decreased heart function66 |
| cg18637832 | 2.99E−04 | 0.06 | chr4:119890132 | SYNPO2 | Body | Actin binding muscle protein. Localized at the Z-disc of skeletal muscle cells and cardiomyocytes49,50,67 | |
| cg04297105 | 2.82E−05 | 0.06 | chr2:103235258 | SLC9A2 /NHE2 | TSS1500 | chr2:103235376–103236554 | Na+ -H+ exchange (NHE) is a major mechanism by which the heart adapts to intracellular acidosis during ischemia and recovers from the acidosis after reperfusion68 |
| cg06802630 | 1.30E−04 | 0.06 | chr5:322735 | AHRR | Body | chr5:320788–323010 | DNA methylation of the aryl hydrocarbon receptor repressor is associated with subclinical atherosclerosis69 |
| cg08053904 | 5.36E−05 | 0.06 | chr16:20085897 | GPR139 | TSS1500 | chr16:20084707–20085305 | G-protein coupled receptors play a central physiological role in the regulation of cardiac function and are targeted for the treatment of hypertension and heart failure70 |
| cg04369835 | 3.26E−04 | 0.06 | chr5:322705 | AHRR | Body | chr5:320788–323010 | As above69 |
| cg25752677 | 1.33E−04 | 0.05 | chr16:56309206 | GNAO1 | Body | In animal models, increased expression of Gαo1, induced by attenuation of NRSF-mediated repression, plays a pivotal role in the progression of heart failure by evoking Ca2+ handling abnormality71 | |
| cg25325322 | 1.06E−05 | 0.05 | chr2:85073715 | C2orf89 /TRABD2A/TIKI1 | Body | SNPs in the loci show significant associations with either Troponin I or T in GWAS72 | |
| cg24512097 | 1.16E−04 | 0.05 | chr4:156298332 | MAP9 | TSS1500 | chr4:156297601–156298094 | Cell division, mitosis |
| cg23058405 | 1.95E−04 | 0.05 | chr3:105072537 | – | IGR | chr3:105072529–105072962 | NA |
| cg00840433 | 1.34E−04 | 0.05 | chr1:180182658 | – | IGR | NA | |
| CpG probes hyomethylated in cases compared to controls | |||||||
| cg17241353 | 2.45E−04 | −0.05 | chr20:53868015 | – | IGR | NA | |
| cg21125179 | 1.21E−04 | −0.05 | chr2:72858044 | EXOC6B | Body | Circular EXOC6B is a key biomarker for the diagnosis of HF43 | |
| cg07714001 | 4.37E−05 | −0.05 | chr14:42880359 | – | IGR | NA | |
| cg25742326 | 1.88E−04 | −0.05 | chr1:901449 | PLEKHN1 | TSS1500 | chr1:894313–902654 | Binds to cardiolipin (CL) in mitochondria. Protein downregulated in hearts of rodent model of T1DM73 |
| cg05679760 | 7.45E−05 | −0.05 | chr11:72711174 | FCHSD2 | Body | Variants associated with cardiovascular events74 | |
| cg02683668 | 4.54E−06 | −0.05 | chr5:130844625 | RAPGEF6 | Body | Guanine-nucleotide releasing factor | |
| cg11830489 | 3.47E−04 | −0.05 | chr7:39045208 | POU6F2 | 5'UTR | Transcription regulation | |
| cg02909936 | 1.05E−04 | −0.05 | chr7:18939140 | HDAC9 | Body | Epigenetic repression and transcriptional regulation. Variants associated with ischemic stroke and increased risk via promoting carotid atherosclerosis. HDAC inhibitors as antifibrotic drugs in cardiac and pulmonary fibrosis. Governs responsiveness of the Heart to stress signals and plays a role in Heart Development75–77 | |
| cg02828505 | 1.96E−05 | −0.05 | chr3:57875202 | SLMAP | TSS1500 | Regulator of cardiac function at the sarcoplasmic reticulum. Associated with human dilated cardiomyopathy. Emerging regulator of normal and abnormal cardiac excitation–contraction coupling78–81 | |
| cg05558609 | 1.93E−05 | −0.05 | chr15:56726855 | TEX9 | 3'UTR | Differentially expressed and methylated in mice developing heart82 | |
| cg24017056 | 2.83E−04 | −0.05 | chr15:80366893 | ZFAND6 | 5'UTR | Loci significantly associated with MetS-related components in T2D83 and role in insulin secretion84 | |
| cg15185986 | 1.16E−04 | −0.05 | chr13:98919378 | FARP1/PLEKHC2 | Body | Developmental protein, guanine-nucleotide releasing factor | |
| cg14119788 | 2.43E−05 | −0.05 | chr11:59243571 | OR4D10 | TSS1500 | Olfactory receptor | |
| cg02737747 | 7.59E−05 | −0.06 | chr8:99264018 | NIPAL2/SLC57A4 | Body | Magnesium ion transport | |
| cg15288329 | 5.60E−05 | −0.06 | chr6:170268691 | – | IGR | NA | |
| cg08993331 | 3.52E−04 | −0.06 | chr2:45310530 | – | IGR | NA | |
| cg23280506 | 1.24E−04 | −0.08 | chr17:14201938 | – | IGR | chr17:14201726–14202052 | NA |
IGR intergenic region, TSS1500: 200–1500 bases upstream of the transcriptional start site, 3'UTR 3′ untranslated region, 5'UTR 5′ untranslated region.
*Ranked on methylation difference (Δβ) between cases vs. controls.