Aryl hydrocarbon receptor repressor (AHRR) methylation predicts risk of vascular disease: A cohort study of the general population

AIMS: Smoking is a risk factor for cardiovascular disease, but there is currently no clinically established biomarker for its cardiovascular damage. We aimed to investigate the hypothesis that aryl hydrocarbon receptor repressor ( AHRR ) methylation at CpG site cg05575921, a biomarker of smoking behavior, is associated with the risk of peripheral artery disease (PAD) and aortic aneurysm (AA) in the general population. METHODS AND RESULTS: In this prospective cohort study of the general population, we measured AHRR methylation in individuals from three visits to the Copenhagen City Heart Study. Information on risk factors was collected at visits with 10 years intervals; visit 1 (1991-1994), visit 2 (2001-2003), and visit 3 (2011-2015). Individuals were followed up in the Danish National Patient Register for PAD and AA until December 2018. Subhazard ratios were calculated using Fine and Gray competing risk regression. In 11 332 individuals from visit 1 ( n =9234), visit 2 ( n =5384), and visit 3 ( n =4387), there were 613 and 219 events of PAD and AA during up to 26.5 years of follow-up. AHRR hypomethylation was associated with a higher risk of PAD and AA with multivariable-adjusted subhazard ratios of 2.82 (1.91; 4.15) for PAD and 2.88 (1.42; 5.88) for AA in individuals within the lowest versus highest methylation quintile. CONCLUSIONS: We found that AHRR methylation, a strong biomarker for smoking, was associated with the risk of PAD and AA. AHRR methylation could be a useful tool in more personalized risk prediction of PAD and AA.