Objectives: Smoking is a well-established risk factor for abdominal aortic aneurysm (AAA) development and progression. Many metrics to evaluate smoking exposure are limited, with commonly assessed self-reported smoking status being subjective and categorizing heterogenous smoking patterns into the three groups of current smoker, former smoker, or never smoker. Currently, clinicians lack precise tools to quantify individual patient risk based on their unique smoking exposure. DNA methylation (DNAm) of CpG site cg05575921 within the AHRR gene has recently been shown as a highly accurate epigenetic marker of smoking status and cessation duration. Given this, we aimed to assess the utility of DNAm in AAA patients and the association of this marker with AAA annual growth.
Methods: Whole blood cg05575921 (AHRR gene) DNAm was quantified using a validated restriction enzyme digestion-based ddPCR assay. Using previously defined DNAm thresholds for smoking status and time of cessation, each AAA patient’s imputed smoking status was determined. Association of DNAm imputed smoking status and AAA annual growth were analyzed using random effects generalized linear models.
Results: DNAm data was obtained from 164 AAA patients (88% male). There was substantial heterogeneity in DNAm levels and imputed smoking exposure within the self-reported former smoker cohort. Among these patients, 37% had DNAm levels consistent with current smokers, 25% consistent with cessation of < 21 years duration, 18% consistent with cessation > 21 years duration, and 20% had DNAm levels similar to never smokers. AAA annual growth was significantly associated with DNAm levels. In age- and sex-adjusted models, patients classified as imputed current smoker exhibited mean AAA annual growth of 0.20 cm/year, compared with 0.18 cm/year for imputed former smoker with < 21 years cessation, 0.14 cm/year for imputed former smoker with >21 years cessation, and 0.17 cm/year in imputed never smoker (P = 0.005).
Conclusions: AHRR DNA methylation is a robust epigenic marker of smoking status and provides a more detailed assessment of AAA patients smoking exposure, especially among self-reported former smokers where cessation duration and pack year use is highly variable. Given that DNAm is also significantly associated with AAA growth, incorporating the DNAm biomarker in the care of these patients may have significant clinical utility and enable more precision medicine approaches into the care and risk prediction of AAA patients.
