CHICAGO, IL — Dyslipidemia may be a cause of abdominal aortic aneurysms (AAAs) in ways that aren’t entirely like its relationship to coronary disease, suggests a genomic analysis that researchers say hints that current lipid-modifying treatments may be useful to lower the risk of AAA[1]. They also say it means lipids could be added to the mix of factors used to select persons for AAA screening.
In a meta-analysis that used Mendelian randomization of >50,000 cases and controls, the presence of several single-nucleotide polymorphisms (SNPs) linked with higher levels of LDL cholesterol and triglycerides and lower levels of HDL cholesterol correlated significantly with AAA.
“This is further evidence that patients with abdominal aortic aneurysm are at high risk and should have aggressive LDL-C lowering,” said Dr Seamus C Harrison (University of Cambridge, UK), lead author on the study’s report published November 29, 2017 in JAMA Cardiology.
“The relationship between the different lipid subfractions and AAA is pretty poorly defined in the observational literature,” he told theheart.org | Medscape Cardiology. So the current study helps firm that up, “and certainly it suggests that [CAD and AAA] do have overlapping pathological pathways—which is not an enormous surprise, but I think this is the first definitive large-scale genetic analysis that really proves that.”
Of note, Harrison said, “Our study would suggest that HDL cholesterol plays a causal role in abdominal aortic aneurysm, and that hasn’t been a consistent finding in coronary artery disease.”
The findings also have implications for precision medicine, “understanding different pathways of the different types of cardiovascular disease, so treatment can be tailored to the individual. We’re clearly a long way off from that here, but it sort of fits in with that,” he said.
The study focused on specific SNPs chosen for their associations with lipid subfractions and for their functions as mediators of the molecular targets of known lipid-modifying agents. Those targets were HMG-coenzyme A reductase for statins, proprotein convertase subtilisin/kexin type 9 (PCSK9) for the PCSK9 inhibitors, and cholesteryl ester transfer protein (CETP) for the CETP inhibitors.
The study looked at SNPs associated with the lipid subfractions and the treatment targets among 4914 cases of AAA and 48,002 non-AAA controls from five genomewide association studies, each in different countries.
Based on genetic risk scores derived from a meta-analysis of the study populations, comparing SNP-based proxies for different forms of dyslipidemia, a one–standard-deviation genetic elevation in LDL-C was associated with an odds ratio (OR) of 1.66 (95% CI 1.41–1.96) for AAA. The corresponding OR for triglyceride elevation was 1.69 (95% CI 1.38–2.07).
The OR for AAA for a one-standard-deviation increase in HDL-C was 0.67 (95% CI 0.55–0.82).
P values for all three ORs were orders of magnitude smaller than 0.001.
The allele of rs12916 associated with reduced LDL-C in the HMG-coenzyme A reductase gene HMGCR conferred an OR 0.93 (95% CI 0.89–0.98, P=0.009) for risk of AAA.
Among LDL-C-reducing alleles of PCSK9, rs11206510 was “weakly associated” with lower AAA risk (OR 0.94, 95% CI 0.88–1.00; P=0.04), while rs2479409 showed no association (OR 0.97, 95% CI 0.84–1.02; P=0.28).
With the recent availability of PCSK9 inhibitors for lowering LDL-C, Harrison said, “typically patients with aneurysms aren’t considered in the trials of these new drugs, and perhaps they should be.”
The allele of rs3764261 in CETP associated with increased HDL-C levels conferred an OR of 0.89 (95% CI 0.8–0.94; P<0.0001) for risk of AAA. The report acknowledges that the allele is also associated with lower LDL-C and triglyceride levels.
Also, the report notes, the study didn’t have the data to control for such potential confounders as concurrent dyslipidemia therapy, one of its limitations.
Still, Harrison said, the findings indicate that “patients who have abdominal aortic aneurysm have a high burden of genetic polymorphisms that predispose them to higher LDL cholesterol.” And that may suggest a possible role for the SNPs in aneurysm screening.
In the UK, he noted, all males 65 and older are screened for AAA; women are not screened due their much smaller AAA prevalence. “But there is a good deal of interest in targeted screening in females, and understanding lipid profiles may help us in that regard.” It could potentially consider AAA risk factors like smoking and dyslipidemia.
Statins aren’t routinely offered when small aneurysms are detected, “and that’s perhaps something that ought to be looked at, because these patients with small aneurysms are at high risk of cardiovascular events. They’re a particularly high-risk group [at which] we could target LDL lowering,” Harrison said.
“What we need to know, but this study doesn’t say, is whether aggressively treating lipids can change the natural history of progression of AAA, maybe keep it from being one that ruptures, and so that will be a future goal for research.”
Harrison had no relevant financial relationships. Disclosure for the coauthors are listed in the paper.
Follow Steve Stiles on Twitter: @SteveStiles2. For more from theheart.org | Medscape Cardiology, follow us on Twitter and Facebook.
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