PRKCZ might be the functional gene for rs10797416, the most significant SNP of this locus reported in CAD-GWAS. Rs10797416 has a cis-eQTL effect on PRKCZ. PRKCZ is involved in proliferation, differentiation and secretion of almost all cell types including cardiac myocytes and has been associated with cardiomyopathy in chromosome 1p36 deletions [16, 17]. We found that tobacco smoking is associated with decreased methylation of cg05603985, which is in turn associated with decreased expression of PRKCZ. We propose that demethylation of cg05603985 might be involved in development of CAD through PRKCZ expression, although the causality and mechanism through which this might occur are unclear. Cg05603985 is located in the binding site of transcriptional repressor CTCF [ENCODE:GSM1022677, UW, HCM] [18]. Demethylation of this CTCF binding site facilitates binding of CTCF, resulting in decreased expression of PRKCZ. This is due to the fact that CTCF prevents the binding of enhancers to the promoter of PRKCZ [19].
