Humans

DNA methylation links inflammation to abdominal aortic aneurysm

In an analysis of 1,324 cases and 42,065 noncases, 143 DNA methylation sites showed putative causal links to incident abdominal aortic aneurysm.

Circulation4 Oct 2026, 08:14 BST

In human participants from the Veterans Affairs Million Veteran Program, researchers conducted an epigenome-wide association study of incident abdominal aortic aneurysm, comparing 1,324 cases with 42,065 noncases. They identified 1,253 CpG sites associated with the condition. Mendelian randomization supported a putative causal role for 143 of these DNA methylation sites.

Functional annotation revealed enrichment for inflammatory transcription factor programs, including activator protein-1 and nuclear factor kappa B. The team identified 213 CpG-gene expression pairs with colocalization support, including AGER, C2, and DDR1. Network Mendelian randomization identified 135 putative mediation pathways, with 58 involving cardiometabolic traits and 77 involving inflammatory markers such as MMP9 and IL1RN. Blood lipids mediated over 40% of the risk at CpGs near LDLR and TRIB1. A derived methylation risk score predicted aneurysm risk across discovery and two external cohorts.

Why it matters

Abdominal aortic aneurysm is a serious vascular disease with risk that increases with age. Mapping putative causal epigenetic marks clarifies how chronic inflammation and lipid metabolism drive age-associated arterial deterioration.

Caveats

The primary findings rely on observational data and genetic modeling within the Veterans Affairs Million Veteran Program, which predominantly samples military veterans. Experimental validation is necessary to confirm the biological function of the identified causal pathways.