Collagen Type I α2 (
            <i>COL1A2</i>
            ) Is the Susceptible Gene for Intracranial Aneurysms

Yoneyama, Taku; Kasuya, Hidetoshi; Onda, Hideaki; Akagawa, Hiroyuki; Hashiguchi, Kazunari; Nakajima, Toshiaki; Hori, Tomokatsu; Inoue, Ituro

doi:10.1161/01.str.0000110788.45858.dc

Cited by 70 publications

(57 citation statements)

References 32 publications

(25 reference statements)

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“…We previously found KLF2 to be the most significant hypoxia-related gene that distinguished BOECs from donors NAR versus those AR of childhood stroke [3]. Another transcription factor, regulatory factor X1 (RFX1), represses the expression of collagen Type I a2 [10], a molecule associated with chronic inflammation [11] and aneurismal dilatation of cerebral vessels [12]. RFX1 may also downregulate expression of protooncogene c-myc [13], which drives cell growth and angiogenic proliferation.…”

Section: Introductionmentioning

confidence: 99%

Proinflammatory phenotype with imbalance of KLF2 and RelA: Risk of childhood stroke with sickle cell anemia

et al. 2009

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Altered inflammation signaling within the cerebral vasculature may be an important risk factor for stroke in children with sickle cell anemia (SCA). This study examines how differential expression of NFjB/p65 (RelA), KLF2, and other transcription factors may act as switches in inflammation signaling leading to observed differences between non-SCA (NS) African Americans and African Americans with SCA who are either at risk (AR) or not at risk (NAR) of childhood stroke based on occurrence of Circle of Willis disease. Clover/ Transfac analysis was used to identify overrepresented transcription factor binding motifs on genes associated with inflammation. Transcription factor binding motifs for the NFjB family and RFX1 were overrepresented on inflammation signaling gene set analysis. Variations in protein expression were determined by flow cytometry of blood outgrowth endothelial cells (BOECs) from NS, AR, and NAR donors and Western blots of protein extracts from both unstimulated and TNFa/IL1b-stimulated BOECs. BOECs from patients with SCA had more cytoplasmic-derived RelA compared with NS BOECs. Sickle BOECs also had heightened responses to inflammatory stimuli compared with NS BOECs, as shown by increased nuclear RelA, and intracellular adhesion molecule (ICAM) response to TNFa/IL1b stimulation. Multiple control points in RelA signaling were associated with risk of childhood stroke. The ratio of proinflammatory factor RelA to anti-inflammatory factor KLF2 was greater in BOECs from AR donors than NS donors. Group risk of childhood stroke with SCA was greatest among individuals who exhibited increased expression of proinflammatory transcription factors and decreased expression of transcription factors that suppress inflammation. Am. J. Hematol. 85:18-23, 2010. V

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Section: Introductionmentioning

confidence: 99%

Proinflammatory phenotype with imbalance of KLF2 and RelA: Risk of childhood stroke with sickle cell anemia

et al. 2009

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“…Given a risk allele frequency of 0.2, a prevalence of 0.01 and a relative risk of 1.5, 240 cases and 240 controls are needed for an alpha of B0.05 with 80% power according to the Genetic Power Calculator (http://pngu.mgh.harvard.edu/*purcell/ gpc/), supposing that a marker allele is in complete LD with a disease allele. However, the relative risks of susceptibility genes for IA were less than 1.5 in most recent studies (Yoneyama et al 2004;Akagawa et al 2006;Inoue et al 2006;Ruigrok et al 2006aRuigrok et al , 2006bWeinsheimer et al 2007), and a marker allele is unlikely to be in complete LD with a disease allele because of the low coverage of SNP markers in theGeneChip 10 K mapping array. Thus, the power of the present study may not be sufficient to detect a relevant polymorphism for IA formation.…”

Section: Discussionmentioning

confidence: 97%

“…Linkage to 2p13 (Roos et al 2004) was shown in a large consanguineous family, but this finding has been retracted because newly diagnosed affected siblings did not show linkage to this locus (Ruigrok 2006). Among these nine linkage regions, the perlecan gene (HSPG2) at 1p36.1-36.4 (Ruigrok et al 2006a), the versican gene (CSPG2) at 5q14.3 (Ruigrok et al 2006b), elastin (ELN) and LIM domain kinase 1 (LIMK1) genes at 7q11 (Onda et al 2001;Akagawa et al 2006), collagen alpha 2(I) (COL1A2) at 7q22 (Yoneyama et al 2004), tumor necrosis factor receptor, superfamily member 13B (TNFRSF13B) at 17cen , and kallikrein at 19q13 (Weinsheimer et al 2007) have been proposed as susceptibility genes for IA. However, there has been a failure to replicate the linkage to 7q11 and the association of ELN polymorphisms with IA in several studies (Berthelemy-Okazaki et al 2005;Hofer et al 2003;Krex et al 2004;Mineharu et al 2006;Yamada et al 2003b), and linkage to 17cen also could not be replicated in a study of the same ethnic group .…”

Section: Introductionmentioning

confidence: 99%

Association analyses confirming a susceptibility locus for intracranial aneurysm at chromosome 14q23

Mineharu

Inoue

et al. 2008

J Hum Genet

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Previous linkage analyses of intracranial aneurysm (IA) have proposed several genetic susceptibility loci; however, some loci remain contradictory. The objective of this study was to confirm these loci in a Japanese population using allelic and haplotype association analyses. We set high-density single nucleotide polymorphism markers in previously suggested IA loci and conducted an association analysis in 29 cases and 35 controls from a small community in Akita, Japan. Genotyping was carried out using the GeneChip 10 K mapping array, and the association analysis was performed using GeneSpring GT2 software. The result was confirmed in a replication cohort consisting of 237 cases and 253 controls from all over Japan. Only one variant, rs767603, at chromosome 14q23, was significantly associated with IA, both in allelic analysis (p = 0.00017, Bonferroni-corrected p = 0.021) and haplotype analysis (p = 0.00178, Bonferroni-corrected p = 0.048). This association was confirmed in the replication cohort (p = 0.0046 for allelic association, p = 0.0060 for haplotype association). Our findings confirm 14q23 to be a susceptibility locus for intracranial aneurysm.

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“…The collagen type 1 A2 gene was analyzed in a Japanese population. 33 Three different SNPs, of which one results in an amino acid substitution, showed significant differences in allelic frequencies between cases and controls, especially the SNP resulting in an amino acid substitution in familial cases (Pϭ0.0009). This SNP may be a functional variant involved in the development of intracranial aneurysms.…”

Section: Candidate Genesmentioning

confidence: 99%

Genetics of Intracranial Aneurysms

Ruigrok

Rinkel

2008

Stroke

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Background and Purpose-Genetic determinants probably play a role in the development of intracranial aneurysms. We review the present knowledge on this issue. Methods-This work entailed a comprehensive search of the literature, a critical appraisal of the identified papers, and a personal view of limitations and future directions. Results-We identified 10 genome-wide linkage studies in families and sib pairs with intracranial aneurysms. These studies have identified several loci, but only 4 (1p34.3-p36.13, 7q11, 19q13.3, and Xp22) have been replicated in different populations. For the loci on 1p34.3-p36.13 and 7q11 association with positional candidate genes has also been demonstrated: for locus on 1p34.3-p36.13 association with the perlecan gene and for 7q11 association with the elastin and collagen type 1 A2 genes. Conclusions-The progress in identifying genetic determinants for intracranial aneurysms is modest. Reasons for this modest progress include limitations of the present studies, limitations because of the nature of the disease, and limitations in our concept of aneurysms and aneurysm development. Future studies may benefit from strict definitions of familial aneurysms, reduced phenotypic heterogeneity (separating ruptured from unruptured aneurysms, and within these subsets probably also reduce morphological heterogeneity, eg, by grouping similar sites of aneurysms), taking into account age and other risk factors of the patients with aneurysms, and sufficiently large numbers of patients.In future studies we should not only look for genetic determinants of aneurysms, but also for genetic determinants of rupture of aneurysms. This would help in selecting patients for preventive treatment of aneurysms.

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Collagen Type I α2 ( COL1A2 ) Is the Susceptible Gene for Intracranial Aneurysms

Cited by 70 publications

References 32 publications

Proinflammatory phenotype with imbalance of KLF2 and RelA: Risk of childhood stroke with sickle cell anemia

Proinflammatory phenotype with imbalance of KLF2 and RelA: Risk of childhood stroke with sickle cell anemia

Association analyses confirming a susceptibility locus for intracranial aneurysm at chromosome 14q23

Genetics of Intracranial Aneurysms

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