Impact of Inherited Genetic Variants Associated With Lipid Profile, Hypertension, and Coronary Artery Disease on the Risk of Intracranial and Abdominal Aortic Aneurysms

Abstract

Background— Epidemiological studies show that an unfavorable lipid profile and coronary artery disease (CAD) are risk traits for abdominal aortic aneurysms (AAAs) but not for intracranial aneurysms (IAs), and that hypertension is a main risk trait for IAs but not for AAAs. To evaluate these observations, we investigated single-nucleotide polymorphisms associated with serum lipid levels, hypertension, and CAD and tested their contribution to AAA and IA risk. Methods and Results— We defined sets of single-nucleotide polymorphisms previously reported to be associated with serum lipid levels, CAD, and blood pressure. From previously collected genome-wide data, we extracted genotypes for these single-nucleotide polymorphism sets in 709 IA cases and 2692 controls and 807 AAA cases and 1905 controls (all of Dutch origin). We computed genetic scores for each individual by summing the observed number of risk alleles weighted by their previously published effect size. Using logistic regression, we tested the genetic scores for association with IAs and AAAs and found significant associations for genetic scores of total cholesterol ( P =3.6×10 -6 ), low-density lipoprotein-cholesterol ( P =5.7×10 -7 ), and CAD ( P =0.0014) with AAAs and for the blood pressure score with IAs ( P =0.0030). Conclusions— We demonstrate that genetic risk profiles of lipid factors and CAD are associated with AAAs but not with IAs, and the genetic risk profile of blood pressure is associated with IAs but not with AAAs. These findings are consistent with epidemiological observations.

Guidelines for the Management of Patients With Unruptured Intracranial Aneurysms

“…A variety of genes or chromosomal regions have been identified in both familial and sporadic cases of IAs. [59][60][61][62][63][64][65][66][67][68][69][70][71][72][73] In linkage studies, regions on chromosomes 1p34.3-p36.13, 7q11, 19q13.3, and Xp22 have been associated with IAs. Genome-wide association studies identified replicated associations on chromosome 4q31.23 (EDNRA), 8q12.1 (SOX17), 9p213 (CDKN2A/CDKN2B/CDKN2BAS), 10q24.32 (CNNM2), 12q22, 13q13.1 (KL/STARD13), 18q11.2 (RBBP8), and 20p12.1, with the strongest evidence for the CDKN2BAS and SOX17 genes.…”

Genome-wide association studies of late-onset cardiovascular disease

“…[41, 45] Polygenic risk scores incorporating variants associated with LDL cholesterol and CAD have also been linked to abdominal aneurysms, confirming links between these disorders. [46] For thoracic aortic disease, the gene encoding fibrillin-1 has been associated with risk and is the same gene in which loss-of-function mutations cause Marfan’s syndrome, characterized by thoracic aortic disease as well as other arteries. Fibrillin-1 is an extracellular matrix protein which anchors smooth muscle cells to the extracellular matrix, mutations in which are considered to disrupt mechanosensing and signaling in the aortic wall.…”

Myeloperoxidase Is Increased in Human Cerebral Aneurysms and Increases Formation and Rupture of Cerebral Aneurysms in Mice

“…1 The etiology of CA involves hemodynamic stress and inflammation, with similarities and important differences to abdominal aortic aneurysms (AAA). 1–4 Treatment for both unruptured and ruptured CA is surgical, with coiling and clipping to prevent rupture and re-rupture; there is no pharmacological treatment. 5,6 …”