Epigenome-Wide Association Study of Abdominal Aortic Aneurysm Identifies Central Role for Inflammatory Pathways
Shuai Yuan, Michael G. Clark, Gabrielle Shakt, Michael G. Levin, Katherine Hartmann, Renae Judy, Tia Dinatale, Amy Voorhees, Julie A. Lynch, Saiju Pyarajan, Daniel Levy, Roby Joehanes, Kyong-Mi Chang, Jennifer A. Brody, Joshua C. Bis, Bruce M. Psaty, Benjamin F. Voight, Philip S. Tsao, Gregory T. Jones, Scott M. Damrauer, Sumitra Muralidhar, Jennifer Moser, Jennifer E. Deen, Sumitra Muralidhar, J. Michael Gaziano, Adriana Hung, Dave Oslin, Deepak Voora, J. Michael Gaziano, Jessica V. Brewer, Mary T. Brophy, Kelly Cho, Lori Churby, Jacob T. Kean, Robert Ringer, Luis E. Selva, Shahpoor (Alex) Shayan, Brady Stephens, Stacey B. WhitbourneBACKGROUND:
Epigenetic mechanisms underlying susceptibility to abdominal aortic aneurysm (AAA) remain poorly understood. Identifying causal DNA methylation markers for AAA can elucidate the regulatory processes that drive aneurysm formation and accelerate translational applications. We leveraged the Veterans Affairs (VA) Million Veteran Program to identify methylation biomarkers and delineate underlying pathways.
METHODS:
We first conducted an epigenome-wide association study of incident AAA (1324 cases and 42 065 noncases), performed stratified analyses by population group and smoking status, and conducted Mendelian randomization to facilitate causal inference of the CpG–AAA association. Chromatin state, island context, and transcription factor binding were implicated through functional annotation of identified CpGs. To identify genes impacted by change in methylation state, we aligned associations with transcriptional data obtained in blood, aorta, and liver. We performed expression quantitative trait methylation to capture CpG–gene-expression links across the genome. Network Mendelian randomization was used to test cardiometabolic and inflammatory mediation. Finally, we developed a methylation risk score for AAA using penalized regression and evaluated its performance against a clinical model in the Million Veteran Program and 2 external studies.
RESULTS:
Epigenome-wide association study identified 1253 CpGs associated with incident AAA, and Mendelian randomization supported a putative causal role for 143 of these associations. Functional annotation pointed to predominantly distal, enhancer-centered regulation and enrichment of inflammatory transcription factor programs (eg, activator protein-1 and nuclear factor κB). This distal architecture was consistent with expression quantitative trait methylation results, which showed a larger number of trans associations. Among 143 CpGs associated with AAA in Mendelian randomization analyses, we identified 213 CpG–gene expression pairs with strong colocalization support, including
CONCLUSIONS:
This study identified putative causal DNA methylation markers for AAA, and multi-omics analyses implicate activator protein-1–linked inflammatory transcriptional programs, blood lipids, and multiple inflammation-related proteins as key pathways underlying methylation-associated AAA risk.