Genetic associations of intracranial aneurysm formation and sub-arachnoid hemorrhage

Abstract

Risk factors for cerebral aneurysms typically include age, hypertension, smoking, and alcohol usage. However, the possible connection of aneurysms with genetic conditions such as Marfan's syndrome, polycystic kidney disease, and neurofibromatosis raises the question of possible genetic risk factors for aneurysm, and additionally, genetic risk factors for rupture. We conducted a literature review using the PubMed database for studies regarding genetic correlation with cerebral aneurysm formation as well as rupture from December 2008 to Jun 2015. Twenty-one studies related to IA formation and 10 concerning IA rupture that met our criteria were found and tabulated. The most studied gene and the strongest association was 9p21/CDKN2, which is involved in vessel wall remodelling. Other possible genes that may contribute to IA formation include EDNRA and SOX17; however, these factors were not studied as robustly as CDKN2. Multiple factors contribute to aneurysm formation and rupture and the contributions of blood flow dynamics and comorbidities as mentioned previously, cannot be ignored. While these elements are important to development and rupture of aneurysms, genetic influence may predispose certain patients to formation of aneurysms and eventual rupture.

Polymorphisms in Lysyl Oxidase Family Genes Are Associated With Intracranial Aneurysm Susceptibility in a Chinese Population

“…A disrupted balance between ECM synthesis and degradation may be the pathophysiological basis for IA formation ( 13 , 14 ). For example, some single nucleotide polymorphisms (SNPs) of endothelin receptor type A ( EDNRA ), alpha 1 type III collagen ( COL3A1 ), transcription factor SOX-17 ( SOX17 ), and lysyl oxidase-like 2 ( LOXL2 ), which are mainly involved in ECM reconstruction, are associated with IA ( 15 – 18 ). The LOXL2 gene belongs to the lysyl oxidase (LOX) family that comprises LOX and lysyl oxidase-like 1–4 ( LOXL1 , LOXL2 , LOXL3 , and LOXL4 ) ( 19 ).…”

Genome-Wide Association between the 2q33.1 Locus and Intracranial Aneurysm Susceptibility: An Updated Meta-Analysis Including 18,019 Individuals

“…Among nine eligible studies, four studies were excluded from the final analysis because they lacked the outcomes of interest [18] or were meta-analyses [10] or review studies [8,19]. Finally, a total of seven independent cohort studies in five articles were selected for the meta-analysis: Two European GWASs including Finnish and Dutch populations [20]; two Japanese GWASs [5,20]; one European-ancestry candidate gene study including populations from North America, New Zealand, and Australia [21]; one Japanese candidate gene study [22]; and one Korean GWAS (Figure 1) [11].…”

Aneurysm Formation, Growth, and Rupture: The Biology and Physics of Cerebral Aneurysms

“…[33][34][35] A systematic literature review showed that the 9p21/CDKN2, a loci which is implicated in vessel wall remodeling, had the strongest association with aneurysm rupture (Odds ratio: 1.42; p=0.01). 36 Another large scale genome-wide association study with approximately 2,000 patients with CAs and 8,000 controls reported single nucleotide polymorphisms in the 2q33.1, 8q11.23 and 9p21.3 loci, which are thought to be associated with sporadic and familial CAs. 37 Candidate genes that have been studied are MMPs, angiotensin-converting enzyme, phospholipase C, NOS, transforming growth factor-beta receptor among others.…”