(Stroke. 2005;36:2068.)
© 2005 American Heart Association, Inc.
Letters to the Editor |
Collagen Morphology Is Not Associated With the Ala549Pro Polymorphism of the COL1A2 Gene
Department of Neurology, University of Heidelberg, Heidelberg, Germany
Department of Dermatology, University of Heidelberg, Heidelberg, Germany
Kliniken Schmieder Heidelberg, Heidelberg, Germany
To the Editor:
We read with interest the study by Yoneyama et al1 concerning the genetics of intracranial aneurysms (IA). These authors found a significant association between IA and the collagen 
2 (I) gene (COL1A2). Previously, they mapped a candidate locus for intracranial aneurysm to chromosome 7q11 and suggested the tropoelastin encoding gene (ELN) as a possible candidate.2 Mutations in ELN, however, were not identified. Moreover, the association between ELN and IA was not confirmed in a subsequent European study.3 The COL1A2 gene that was proposed as susceptible gene for IA subsequently is also located on chromosome 7q. However, it is separated from ELN by a considerable genetic distance of approximately 25 cM.
Yoneyama et al found a particularly strong association with the Ala549Pro encoding SNP in exon 28 of COL1A2 (rs42524). Synthetic collagen-related peptides for both alleles showed differences in thermal denaturation, which might suggest an altered stability of the collagen fibril. These findings suggest, according to the authors, that the functional SNP28 of COL1A2 has an impact on collagen structure with possible effects on the integrity vessel wall and proneness to IA formation. The presence of morphologic aberrations in the dermal collagen fibrils in patients with IA4 previously suggested that genes involved in the biosynthesis of collagen might be among the susceptibility genes for IA.
These findings motivated us to look for a possible association between the COL1A2 SNP28 (rs42524) and the presence of an abnormal ultrastructural morphology of collagen fibrils in a series of well-characterized skin biopsies from German patients with cervical artery dissections. We did not find such an association (Table), because the genotypes of rs42524 are similar in both groups (patients with abnormal connective tissue morphology vs patients with normal connective tissue morphology). Moreover, we did not find significant genetic differences between a series of 125 healthy control subjects and a larger sample of 98 consecutive patients with cervical artery dissections (skin biopsies were studied in 54 of these 98 patients). These findings suggest that the morphologic connective tissue abnormalities, that are typically found in patients with IA as well as in patients with cervical artery dissections, are not associated with the COL1A2 SNP28, at least not in a German sample of patients with cervical artery dissections. We, therefore, have difficulties believing that the Ala549Pro encoding SNP in exon 28 of COL1A2 has a significant impact on the rigidity or the elasticity of the vascular wall, because we do not find an association with collagen fibril morphology. The interesting results of the thermal denaturation of short-model peptides by Yoneyama et al are unlikely to explain the complex structural and functional features of in vivo collagen fibrils in human adults.
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References
- Yoneyama T, Kasuya H, Onda H, Akagawa H, Hashiguchi K, Nakajima T, Hori T, Inoue I. Collagen type I alpha2 (COL1A2) is the susceptible gene for intracranial aneurysms. Stroke. 2004; 35: 443–448.
[Abstract/Free Full Text] - Onda H, Kasuya H, Yoneyama T, Takakura K, Hori T, Takeda J, Nakajima T, Inoue I. Genomewide-linkage and haplotype-association studies map intracranial aneurysm to chromosome 7q11. Am J Hum Genet. 2001; 69: 804–819.[CrossRef][Medline] [Order article via Infotrieve]
- Hofer A, Hermans M, Kubassek N, Sitzer M, Funke H, Stogbauer F, Ivaskevicius V, Oldenburg J, Burtscher J, Knopp U, Schoch B, Wanke I, Hubner F, Deinsberger W, Meyer B, Boecher-Schwarz H, Poewe W, Raabe A, Steinmetz H, Auburger G. Elastin polymorphism haplotype and intracranial aneurysms are not associated in Central Europe. Stroke. 2003; 34: 1207–1211.
[Abstract/Free Full Text] - Grond-Ginsbach C, Schnippering H, Hausser I, Weber R, Werner I, Steiner HH, Luttgen N, Busse O, Grau A, Brandt T. Ultrastructural connective tissue aberrations in patients with intracranial aneurysms. Stroke. 2002; 33: 2192–2196.
[Abstract/Free Full Text]
Response:
Division of Genetic Diagnosis, Institute of Medical Science, University of Tokyo, Tokyo, Japan
Department of Neurosurgery, Neurological Institute, Tokyo Women’s Medical University, Tokyo, Japan
We gratefully acknowledge that Drs. Arnold, Grond-Ginsbach, Hausser, and Brandt have thoroughly read and made comments on the article researched and written at our institution.1
Regarding their comparison of patients with intracranial aneurysms (IA) with those with cervical artery dissection (CAD), we would like to remark that their findings and arguments are based on the examination of patients with CAD. To our knowledge, there have been a number of publications, also by the authors themselves,2 that cannot lead to a connection between mutations seen in patients with intracranial aneurysms and CAD, eg, as is the case in endoglin,3,4 and several matrix-metalloproteinase genes.5–7 Several publications have also shown the varying results of genetic research within different ethnic groups.8–11 Moreover, the 7 of 21 patients with IA presenting morphologic aberration in the dermal collagen fibrils, that Grond-Ginsbach et al refer to, were presumably of white origin and some of them harbored multiple aneurysms. The skin aberrations then resembled those that can be found in different types of Ehlers-Danlos disease.12 This could mean that in white patients with multiple aneurysms, the presence of ultrastructural skin aberrations similar to those seen in Ehlers-Danlos disease could be given. This does not conclude, however, that in Japanese patients with intracranial aneurysms, there is a similar abnormal ultrastructural morphology. This group can hardly be compared with patients of German/white origin with CAD in the lack of comparative data.
We do agree with the authors that to what degree the amino acid substitution of Ala to Pro at 459 has an effect on human structures, especially the extracellular matrix, remains to be examined. Presumably, the altered protein function is so subtle that it does not show its detectable effect in skin. On the other hand, the authors described that even in patients with a EDS type IV-like electron microscopic morphology, sequencing of the encoding region of the COL3A1 gene revealed no mutations.12 This means that the genetic association between structural skin changes and aneurysms still remains to be found.13 Furthermore, we propose skin biopsy examination of more patients with cervical artery dissection as compared with the examined number of 28 patients with abnormal morphology of the dermal tissue. This would undermine the findings that there is no connection between an Ala459-Pro encoding SNP and morphologic skin changes in patients with cervical artery dissection.
Regarding the ultrastructural change within the vessel wall of intracranial aneurysms, light and electron microscopy of the tissue of an affected patient could substantiate our suspicion of the collagen1A2 being responsible for the change in the extracellular matrix.
References
- Yoneyama T, Kasuya H, Onda H, Akagawa H, Hashiguchi K, Nakajima T, Hori T, Inoue I. Collagen type I alpha2 (col1a2) is the susceptible gene for intracranial aneurysms. Stroke. 2004; 35: 443–448.
[Abstract/Free Full Text] - Grond-Ginsbach C, Thomas-Feles C, Werner I, Weber R, Wigger F, Hausser I, Brandt T. Mutations in the tropoelastin gene (eln) were not found in patients with spontaneous cervical artery dissections. Stroke. 2000; 31: 1935–1938.
[Abstract/Free Full Text] - Onda H, Kasuya H, Yoneyama T, Hori T, Nakajima T, Inoue I. Endoglin is not a major susceptibility gene for intracranial aneurysm among japanese. Stroke. 2003; 34: 1640–1644.
[Abstract/Free Full Text] - Takenaka K, Sakai H, Yamakawa H, Itoh T, Murase S, Brandt T. Analysis of phospholipase c gene in patients with subarachnoid hemorrhage due to ruptured intracranial saccular aneurysm. Neurol Res. 1999; 21: 368–372.[Medline] [Order article via Infotrieve]
- Krex D, Kotteck K, Konig IR, Ziegler A, Schackert HK, Schackert G. Matrix metalloproteinase-9 coding sequence single-nucleotide polymorphisms in Caucasians with intracranial aneurysms. Neurosurgery. 2004; 55: 207–212;discussion 212–203.
- Wagner S, Kluge B, Koziol JA, Grau AJ, Grond-Ginsbach C. MMP-9 polymorphisms are not associated with spontaneous cervical artery dissection. Stroke. 2004; 35: e62–e64.[Medline] [Order article via Infotrieve]
- Zhang B, Dhillon S, Geary I, Howell WM, Iannotti F, Day IN, Ye S. Polymorphisms in matrix metalloproteinase-1, -3, -9, and -12 genes in relation to subarachnoid hemorrhage. Stroke. 2001; 32: 2198–2202.
[Abstract/Free Full Text] - Hofer A, Hermans M, Kubassek N, Sitzer M, Funke H, Stogbauer F, Ivaskevicius V, Oldenburg J, Burtscher J, Knopp U, Schoch B, Wanke I, Hubner F, Deinsberger W, Meyer B, Boecher-Schwarz H, Poewe W, Raabe A, Steinmetz H, Auburger G. Elastin polymorphism haplotype and intracranial aneurysms are not associated in central Europe. Stroke. 2003; 34: 1207–1211.
[Abstract/Free Full Text] - Onda H, Kasuya H, Yoneyama T, Takakura K, Hori T, Takeda J, Nakajima T, Inoue I. Genomewide-linkage and haplotype-association studies map intracranial aneurysm to chromosome 7q11. Am J Hum Genet. 2001; 69: 804–819.[CrossRef][Medline] [Order article via Infotrieve]
- Yamada S, Utsunomiya M, Inoue K, Nozaki K, Inoue S, Takenaka K, Hashimoto N, Koizumi A. Genome-wide scan for Japanese familial intracranial aneurysms: linkage to several chromosomal regions. Circulation. 2004; 110: 3727–3733.
[Abstract/Free Full Text] - Wills S, Ronkainen A, van der Voet M, Kuivaniemi H, Helin K, Leinonen E, Frosen J, Niemela M, Jaaskelainen J, Hernesniemi J, Tromp G. Familial intracranial aneurysms: an analysis of 346 multiplex Finnish families. Stroke. 2003; 34: 1370–1374.
[Abstract/Free Full Text] - Grond-Ginsbach C, Schnippering H, Hausser I, Weber R, Werner I, Steiner HH, Luttgen N, Busse O, Grau A, Brandt T. Ultrastructural connective tissue aberrations in patients with intracranial aneurysms. Stroke. 2002; 33: 2192–2196.
[Abstract/Free Full Text] - Kuivaniemi H, Prockop DJ, Wu Y, Madhatheri SL, Kleinert C, Earley JJ, Jokinen A, Stolle C, Majamaa K, Myllyla VV, et al. Exclusion of mutations in the gene for type III collagen (COL3A1) as a common cause of intracranial aneurysms or cervical artery dissections: results from sequence analysis of the coding sequences of type III collagen from 55 unrelated patients. Neurology. 1993; 43: 2652–2658.
[Abstract/Free Full Text]
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