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Abdominal Aortic Aneurysm Genetic Study Finds Lipid Metabolism Loci, Potential Drug Target

NEW YORK – A team led by investigators at the University of Michigan, Ann Arbor, the Corporal Michael Crescenz VA Medical Center, and the University of Pennsylvania has unearthed genes and pathways contributing to abdominal aortic aneurysm (AAA), providing clues to potential treatment strategies.

In AAA, which affects about 4 percent of the US population over the age of 65, the infrarenal aorta expands progressively and eventually ruptures, resulting in about 41,000 annual deaths.

Using array-based genotyping profiles and clinical clues for 39,221 AAA cases and nearly 1.1 million unaffected controls from more than a dozen prior studies, the researchers performed a genome-wide association study meta-analysis that highlighted 141 variants with independent ties to AAA — work they presented in Nature Genetics on Monday.

That set encompassed two dozen variants implicated in AAA in the past, the team reported, along with 97 new loci — results explored in more detail using quantitative PCR analyses on 97 more AAA cases and 36 unaffected controls, together with data from a prior transcriptome-wide association study done in mice.

By bringing in gene set enrichment and functional data, the team focused in on pathways involved in processes ranging from TGF-beta signaling, growth factor activity, or cytokine functions to lipid metabolism. They included the PCSK9 gene, which dials down low-density lipoprotein cholesterol (LDL-C) clearance by interacting with LDL-C receptors.

"Our findings highlight not only lipid metabolism but also vascular development and remodeling, extracellular matrix dysregulation, and inflammation as key mechanisms in the pathogenesis of AAA," co-senior and co-corresponding authors Scott Damrauer, a researcher affiliated with the Corporal Michael Crescenz VA Medical Center and UPenn, and Cristen Willer, an investigator at the University of Michigan, and their colleagues wrote.

While some of the same pathways have been flagged in prior studies focused on mouse models or affected tissues from individuals with AAA, the team explained, the current study provides additional genetic evidence for such relationships, hinting at a "likely role in upstream causation" as well as an apparent overlap with pathways such as TGF-beta that appear to boost the risk of AAA and other aortic conditions.

When they delved into the data further using Mendelian randomization, meanwhile, the researchers saw ties between AAA risk, blood levels of LDL-C, and PCSK9, pointing to the possibility of treating or preventing the condition with drugs already used to inhibit PCSK9 or otherwise reduce LDL-C levels.

"[O]ur results lend human genetic support to PCSK9 inhibition as a potential therapeutic strategy for AAA," the authors suggested. "Although current data on the effects of statins on aortic expansion are conflicted, human genetic evidence has overwhelmingly suggested that LDL-C reduction is likely to reduce AAA risk."

Finally, the team's findings provided the basis for a polygenic risk score (PRS) that appeared to outperform traditional clinical factors when attempting to predict AAA risk in several validation cohorts, including the UK Biobank's UK Aneurysm Growth Study, the Aneurysm Consortium-Wellcome Trust Case Control Consortium, and the Utrecht Cardiovascular Cohort's Second Manifestations of Arterial Disease, or SMART, study.

"These results are demonstrative of how large-scale analyses of human genetic variation coupled with clinical data can be leveraged and used for treatment of understudied diseases," the authors concluded.