Association of Versican (VCAN) gene polymorphisms rs251124 and rs2287926 (G428D), with intracranial aneurysm

Abstract

Intracranial aneurysm (IA) accounts for 85% of Subarachnoid Hemorrhage (SAH) and is mainly caused due to the weakening of arterial wall. The structural integrity of the intracranial arteries is mainly influenced by the extracellular matrix (ECM) remodeling. The Proteoglycan Versican plays an important role in extracellular matrix assembly and plays a major role in the pathogenesis of IA. The linkage studies also indicated VCAN as a putative candidate gene for IA in the 5q22-31 region. Using a case-control study design, we tested the hypothesis whether the variants in VCAN gene, nonsynonymous variants in the coding region of Glycosaminoglycan α (GAG-α) and GAG-β and two reported SNPs involved in splicing rs251124 and rs173686 can increase the risk of aSAH among South Indian patients, either independently, or by interacting with other risk factors of the disease. We selected 200 radiologically confirmed aneurysmal cases and 250 ethnically, age and sex matched controls from the Dravidian Malayalam speaking population of South India. The present study reiterated the earlier association of rs251124 with intracranial aneurysm (P = 0.0002) and also found a novel association with rs2287926 (G428D) in exon 7 coding for GAG-α with intracranial aneurysm (P = 0.0015). Interestingly, both these SNPs contributed to higher risk for aneurysm in males. In-silico analysis predicted this SNP to have the highest functional relevance in the gene which might have a potentially altered regulatory role in transcription and splicing. Using meta-analysis with available literature rs251124 was found to be the strongest intracranial aneurysm marker for global ethnicities. This study with a novel functional SNP rs2287926 (G428D) further substantiates the potential role of VCAN in the pathogenesis of IA.

Keywords: AVM, Arteriovenous malformation; CI, Confidence intervals; Case–control; ECM, Extracellular matrix; Extracellular matrix remodeling; GAG-α, Glycosaminoglycan α; GAG-β, Glycosaminoglycan β; IA, Intracranial aneurysm; Intracranial aneurysm; LD, Linkage disequilibrium; LOX, Lysyl oxidase; Polymorphism; SNP, Single nucleotide polymorphism; South India; VCAN, Versican; Versican; WFNS, World Federation of Neurosurgical Societies; aSAH, aneurysmal Subarachnoid Hemorrhage.

Fig. 1

Metanalysis of VCAN gene variants rs251124 (a) and rs173686 (b) with intracranial aneurysm.