However, despite this potential problem, the locus may have potential as a candidate clinical biomarker for heart disease. Follow-up studies by Breitling, Zhang and colleagues [45,57,58,59], using bisulfite conversion and spectrometry and DNA from European samples have shown that methylation is strongly associated with mortality from all causes, cardiovascular disease, and cancer [45,57,58,59]. The studies establish dose-effect relationships between methylation and current intensity of smoking, pack-years smoked, and years since quitting, and a dose-effect relationship between methylation level and mortality risk. This relationship also appeared to mediate the relationship between smoking intensity and risk of mortality.
