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.

Middle cerebral artery aneurysms: aneurysm angiographic morphology and its relation to pre-operative and intra-operative rupture

“…This imbalance between local hemodynamic stress and arterial wall strength makes the arterial wall prone to aneurysm formation, and factors such as the above-mentioned make them prone to rupture. There is some evidence showing that biologic changes at the cellular and molecular levels are related to a higher risk of aneurysm formation 10,11,12,13 . Human samples and animal models show a common pathway for the intracranial birth, progression and subsequent rupture, initiating with the endothelial dysfunction and progressing with inflammation and degenerative changes that culminate with aneurysm rupture 11,12 .…”

IGF-1 deficiency in a critical period early in life influences the vascular aging phenotype in mice by altering miRNA-mediated post-transcriptional gene regulation: implications for the developmental origins of health and disease hypothesis

“…Importantly, genome-wide association studies identify EDNRA as a possible factor in the pathogenesis of intracranial aneurysms (Low et al 2012;Yasuno et al 2011). The proteoglycan versican has a key role in extracellular matrix assembly and contributes to the pathogenesis of intracranial aneurysms (Sathyan et al 2014). Changes in the O-linked-N-acetylglucosamine (O-GlcNAc) modification of cytoplasmic and nuclear proteins, catalyzed by O-GlcNAc transferase, regulates a wide range of cellular functions and have been associated with a number of age-related diseases (Fulop et al 2008).…”

Study of PDMS characterization and its applications in biomedicine: A review

“…Some other factors that may be related to the appearance of an aneurysm are hypertension, smoking, excessive alcohol use, increase in age, and it also tends to have a higher occurrence in females. The rupture of an aneurysm may represent a very high risk of death [52], as it estimates that 2.6% of the general population has an intracranial aneurysm and accounts for almost 85% of subarachnoid hemorrhages [53].…”