Common variants on 9p21.3 are associated with brain arteriovenous malformations with accompanying arterial aneurysms

Abstract

Objective To investigate whether previously reported 9p21.3 single nucleotide polymorphisms (SNPs) are associated with risk of brain arteriovenous malformations (BAVMs), which often have accompanying arterial aneurysms. Common variants in the 9p21.3 locus have been reported to be associated with multiple cardiovascular phenotypes, including coronary artery disease and intracranial aneurysms (rs10757278 and rs1333040). Methods We used data from 338 BAVM cases participating in the University of California, San Francisco-Kaiser Brain AVM Study Project and 504 healthy controls to evaluate genotypes for seven common SNPs (minor allele frequency>0.05) that were imputed using 1000 Genomes Phase 1 European data (R2>0.87). Association with BAVM was tested using logistic regression adjusting for age, sex and the top three principal components of ancestry. Subgroup analysis included 205 BAVM cases with aneurysm data: (a) 74 BAVM with aneurysm vs. 504 controls, and (b) 131 BAVM without aneurysm vs. 504 controls. Results We observed suggestive association with BAVM and rs10757278-G (OR=1.23, 95% CI=0.99–1.53, P=0.064) and rs1333040-T (OR=1.27, 95% CI=1.01–1.58, P=0.04). For rs10757278-G, the association was stronger in BAVM cases with aneurysm (OR=1.52, 95% CI=1.03–2.22, P=0.032) than in BAVM without aneurysm (OR=0.98, 95% CI=0.72–1.34, P=0.91). Similar patterns of effects were observed for rs1333040 and for other SNPs in linkage disequilibrium (r2>0.8) with rs10757278. Conclusions Common 9p21.3 variants showed similar effect sizes for association with BAVM as previously reported for aneurysmal disease. The association with BAVM appears to be explained by known associations with aneurysms, suggesting that BAVM associated aneurysms share similar vascular pathology mechanisms with other aneurysm types.

Clinical Features of Superficially Located Brain Arteriovenous Malformations with Transdural Arterial Communication

“…Though the definite pathogenesis of brain AVMs remains unknown, recent studies have suggested an association between genetic factors and sporadic AVMs [5][6][7] . Meanwhile, other studies have suggested that brain AVMs are caused by an abnormal response to injuries as a result of trauma or radiation [8][9][10] .…”

“…Possible explanations for brain AVM development have been discussed in the literature, but these discussions are few in number, especially ones that discuss TAC in superficial AVMs [5][6][7][8][9][10] . The most common and widely recognized clinical features of AVMs are seizures, headaches and neurological deficits related to intracere-bral hemorrhage.…”

Genome-wide association study of sporadic brain arteriovenous malformations

“…[29] Interestingly, CDKN2B–AS1 is a non-coding RNA located within the CDKN2A–CDKN2B gene cluster on 9p21, the strongest genetic locus for cardiovascular diseases and linked to intracranial aneurysm. [32] More recently, the 9p21 SNP rs1333040 has been associated with BAVM,[15, 33] and replicated in our discovery cohort (Phase 1). However, this genetic association appears to be explained by the presence of BAVM-associated aneurysms.…”

“…However, this genetic association appears to be explained by the presence of BAVM-associated aneurysms. [33, 34]…”

“…[13] The lack of association with BAVM for the other 4 of 6 previously reported candidate SNPs in our cohort could represent non-replication, or could be due to population differences, low power to replicate small effects, and, in the case of the 9p21 SNP (rs1333040), differences in the prevalence of associated feeding artery aneurysms. [33, 34]…”