Impact of LIMK1, MMP2 and TNF-α variations for intracranial aneurysm in Japanese population

Abstract

Genetic factors are known to have an important role in intracranial aneurysm (IA) pathogenesis. The purpose of this study is to identify single-nucleotide polymorphisms (SNPs) that are associated with IA in Japanese population. A total of 2050 IA patients and 1835 controls recruited in Biobank Japan, The University of Tokyo were used in this study. In all, 45 SNPs in 24 genes encoding proteins, which have been considered to be possible risk factors to IA pathogenesis, were genotyped using multiplex PCR-invader assay. Association analysis was evaluated by logistic regression analysis before and after adjustment of age, smoking and hypertension status. This case-control association study revealed a SNP, rs6460071 located on LIMK1 gene (P¼0.00069) to be significantly associated with increased risk of IA. In addition, two SNPs, rs243847 (P¼0.00086) and rs243865 (P¼0.00090), on matrix metallopeptidase 2 (MMP2) gene and one SNP rs1799724 (P¼0.0026) on tumor necrosis factor-a (TNF-a) gene, are marginally associated with IA in male-and female-specific manner, respectively. In conclusion, a large-scale case-control association study was conducted to verify genetic variations associated with IA in Japanese population. This study gave insights on the importance of stratified analysis between genders, and suggested that the underlying mechanism of IA pathogenesis might differ between females and males.

Biomechanical wall properties of human intracranial aneurysms resected following surgical clipping (IRRAs Project)

“…A recent case-control study (Low et al, 2011) on 4000 patients based on genetic variation suggests that the underlying mechanism for intracranial aneurysm pathogenesis may differ between male and female subjects, underlining the importance of a stratified analysis between genders. A significant difference in biomechanical parameters between ruptured and unruptured aneurysms was observed in our data within each gender group (Tables 3, 4, 5), therefore supporting the above statement.…”

Biology of Intracranial Aneurysms: Role of Inflammation

“…Building on this prior work, Jayaraman et al (2008) report that elevated TNFa in human IA correlates with increased expression of intracellular calcium release channels that regulate intracellular calcium, Toll like receptors that mediate innate immunity and a reduction in expression of TIMP-1. Further indirect support of a role for TNFa in aneurysm pathogenesis includes association of TNFa gene polymorphisms with IA (Fontanella et al, 2007;Low et al, 2011). In summary, data suggest that TNFa may be an important factor in IA pathogenesis but additional investigation is necessary to more clearly elucidate its role.…”

A single-nucleotide polymorphism inMMP9is associated with decreased risk of steroid-induced osteonecrosis of the femoral head

“…For example, rs1053605 and rs243849 polymorphisms are associated with stroke outcome [16], but not with obesity [17], thoracic aortic dissection [18], or endometriosis [19]. rs243847 polymorphism might increase the risk of non-vertebral osteoporotic fractures [20] and intracranial aneurysms in male patients [21]. rs243832 and rs7201 polymorphisms are associated with an increased risk of endometriosis [19].…”