Published online before print January 22, 2004, doi: 10.1161/01.STR.0000110788.45858.DC
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(Stroke. 2004;35:443.)
© 2004 American Heart Association, Inc.
Original Contributions |
Collagen Type I 
2 (COL1A2) Is the Susceptible Gene for Intracranial Aneurysms
From the Department of Neurosurgery, Neurological Institute (T.Y., H.K., H.O., H.A., T.H.) and Maternal and Perinatal Center (K.H.), Tokyo Women’s Medical University; and Division of Genetic Diagnosis, Institute of Medical Science, University of Tokyo (T.Y., H.A., T.N., I.I.), Tokyo, Japan.
Correspondence to Ituro Inoue, MD, Division of Genetic Diagnosis, Institute of Medical Science, University of Tokyo, Shirokanedai 4-6-1, Minato-ku, Tokyo 108-8639, Japan. E-mail ituro{at}ims.u-tokyo.ac.jp
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Abstract |
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Background and Purpose— The collagen
2(I) gene (COL1A2) on chromosome 7q22.1, a positional and functional candidate for intracranial aneurysm (IA), was extensively screened for susceptibility in Japanese IA patients.
Methods— Twenty-one single nucleotide polymorphisms (SNPs) of COL1A2 were genotyped in genomic DNA from 260 IA patients (including 115 familial cases) (mean age, 59.9 years) and 293 controls (mean age, 61.6 years). Differences in allelic and genotypic frequencies between the patients and controls were evaluated with the 
2 test. Circular dichroism spectrometry was monitored with collagen-related peptides that mimic triple-helical models of type I collagen with Ala-459 and Pro-459 to estimate the conformation and stability of alterations.
Results— Significant genotypic association in the dominant model was observed between an exonic SNP of COL1A2 and familial IA patients (2=11.08; df=1; P=0.00087; odds ratio=3.19; 95% CI, 2.22 to 6.50). This SNP induces Ala to Pro substitution at amino acid 459, located on a triple-helical domain. Circular dichroism spectra showed that the Pro-459 peptide had a higher thermal stability than the Ala-459 peptide.
Conclusions— The variant of COL1A2 could be a genetic risk factor for IA patients with family history.
Key Words: aneurysm • collagen • genetics • subarachnoid hemorrhage
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Introduction |
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The rupture of intracranial aneurysms (IA) (MIM105800) causes subarachnoid hemorrhage (SAH), a disease of high morbidity and mortality that continues to be a major public health problem.1–3 The annual incidence of SAH due to aneurysmal rupture is 18 to 23/100 000.4 Approximately 3% to 6% of the population aged >30 years harbors unruptured aneurysms with no evident symptoms, and up to 30% of patients with IA have multiple aneurysms. Although both genetic and environmental factors are thought to play important roles in the pathogenesis of IA,5–7 recent advances in molecular genetics, in particular the Human Genome Project, have made it possible to investigate the genetic determinants directly. We previously reported a genomewide linkage study of IA in 104 affected Japanese sib pairs in which positive evidence of a linkage on chromosomes 5q22-31, 7q11, and 14q22 was detected.8 It is well recognized that linkage analysis alone cannot provide the necessary resolution to identify the gene underlying the disease, especially in complex diseases.9,10 Fine mapping of the linked regions could be accomplished with the use of linkage disequilibrium analysis with single nucleotide polymorphisms (SNPs).
Recently, gene expressions in various tissues have been extensively investigated with the use of cDNA microarray and other methods to elucidate the molecular pathology and pathogenesis. The differential gene expression between IA and the superficial temporal artery was investigated by Peters et al11 using SAGE analysis. In this report the genes of extracellular matrix proteins such as fibronectin, collagen families, elastin, and others were overexpressed in IA. Because the collagen 2(I) gene (COL1A2) is overexpressed in IA and is located on 7q22.1 where the best evidence of linkage was detected, we considered that COL1A2 could be a positional and functional candidate for IA.12 We genotyped 21 SNPs of COL1A2 in 553 individuals, including IA patients and controls, for an allelic association study. We identified a variant leading to an amino acid substitution that is genetically associated with IA and may have functional significance for IA formation.
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Subjects and Methods |
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Subjects
The Ethical Committee of Tokyo Women’s Medical University approved the study protocols, and all the participants gave written informed consent. The DNA samples for the association study and genotyping were from 260 consecutive IA patients and 293 age-matched controls. The IA patients included both familial IA patients (78 probands from nuclear families that had been used in our linkage study and 37 patients having first-degree relatives with IA) and sporadic IA patients (145 patients with no known family history of SAH).8,13 Patients had an IA >5 mm in diameter, as diagnosed by conventional angiography, 3-dimensional CT angiography, MR angiography, or surgical findings. The 293 unrelated controls were outpatients with diseases other than IA, such as headache, at the Department of Neurosurgery, Neurological Institute, Tokyo Women’s Medical University, and affiliated hospitals in Japan. All subjects were Japanese. Genomic DNA was extracted from peripheral blood according to a standard method.
SNP Selection of COL1A2 and Genotyping for Association Study
SNPs of COL1A2 were identified in the National Center for Biotechnology Information (NCBI) database (http://www.ncbi.nlm.nih.gov/SNP/) (Figure 1), and the polymorphisms were confirmed by sequencing 8 patients with IA. In addition, all the coding regions and exon-intron junctions of COL1A2 were sequenced to detect SNPs in the 8 subjects. After the identification of SNPs in COL1A2, those without complete linkage disequilibrium were selected for further genotyping. Genomic DNA was subjected to polymerase chain reaction (PCR) amplification followed by sequencing with BigDye Terminator cycle sequencing with the use of an ABI PRISM 3700 DNA analyzer (Applied Biosystems). The primer sets to amplify each COL1A2 segment were designed with the use of genomic sequences obtained from the GenBank database, accession No. GI:22050628. Ten nanograms of genomic DNA was amplified in 10 µL of reaction mixture containing 1x AmpliTaq Gold Buffer (Applied Biosystems), 300 nmol/L of each primer, 200 nmol/L of dNTP, 1.5 mmol/L of MgCl2, and 0.2 U of AmpliTaq Gold DNA Polymerase (Applied Biosystems). The PCR conditions were as follows: initial denaturation at 95°C for 12 minutes was followed by 35 cycles of denaturation at 94°C for 15 seconds, annealing at 55°C for 15 seconds, and extension at 72°C for 30 seconds and was completed by a final extension at 72°C for 10 minutes with the use of a thermal cycler (GeneAmp PCR System model 9700, Applied Biosystems).
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Statistical Analysis
Allelic association with IA was evaluated with the use of the 2 test for each SNP in the cases and controls. Linkage disequilibrium was estimated as D=xij-pipj, where xij is the frequency of haplotype A1B1, and p1 and p2 are the frequencies of alleles A and B, respectively. A standardized linkage disequilibrium coefficient, r, is given by D/(p1p2q1q2)1/2, where p2 and q2 are the frequencies of the other alleles at loci A and B, respectively.14 Lewontin’s coefficient, D', is given by D'=D/Dmax, where Dmax=min(p1q2,p2q1) when D<0 or Dmax=min(p1q1,p2q2) when D>0.15 These statistics were generated with the use of SNPAlyze (Dynacom).
Collagen-Related Peptides and Circular Dichroism Spectra
Standard fluorenylmethoxycarbonyl-based solid-phase peptide synthesis methods were used to prepare the collagen-related peptides and polypeptides GPP (GlyProPro)10 and GPA (GlyProPro)4GlyProAla(GlyProPro)5 (Sigma). The peptides were purified by high-performance liquid chromatography (C18 8-µm column with a linear gradient of 80% acetonitrile/H2O plus 0.1% trifluoroacetic acid) with >90% purity and verified by electrospray mass spectrometry.
The circular dichroism (CD) spectra were recorded in 50 mmol/L acetic acid at 10°C after incubation for 24 hours at 4°C on a JASCO J-820 equipped with a thermostatically controlled cell holder.16 The peptides (0.23 mmol/L) were incubated in 50 mmol/L acetic acid for 24 hours at 4°C. Ellipticity at 225 nm was monitored by CD spectroscopy, while the sample temperature was raised from 5°C to 95°C in increments of 0.5°C at a rate of 50°C per hour.
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Results |
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Clinical Background of Subjects
The clinical background of the subjects is summarized in Table 1. There was a significant difference in sex between the IA patients and the controls, reflecting the high incidence of aneurysmal SAH in women. Patients with ruptured aneurysms (SAH) accounted for 76% of the total IA patients. IA was observed most frequently in the middle cerebral artery, followed by the anterior communicating artery and the internal carotid posterior communicating artery. The frequency of IA in each position, except the internal carotid artery, and the percentage of patients with multiple IAs were similar to the results of a large autopsy study in Japan.17
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Allelic Association Study With SNPs of COL1A2
A total of 57 SNPs of COL1A2 were identified, and 21 SNPs without complete linkage disequilibrium (r2=1) were subjected to further genotyping. The results of the allelic association study are summarized in Table 2. The genotype frequencies for all the SNPs met Hardy-Weinberg expectations in both cases and controls (data not shown). Three SNPs—28, 36, and 50—showed significant differences in allelic frequency between the controls and familial cases and between the controls and total case samples. These differences in allelic frequency were more evident in IA patients with family history than in overall IA patients. The most significant allelic association was observed with SNP28 (2=10.59; P=0.001; odds ratio=3.00; 95% CI, 2.11 to 6.00). The genotype frequency of SNP28 also showed significant association with familial IA in the dominant model (2=11.08; P=0.00087; odds ratio=3.19; 95% CI, 2.22 to 6.50) (Table 3).
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SNP28 is located on exon 28, resulting in an amino acid substitution, Ala to Pro at 459.18 SNP36 is located on exon 32, resulting in a synonymous change in amino acid. SNP50 is an intron.
Characteristics of Collagen-Related Triple-Helical Models
Collagen model peptides mimicking our target variants were prepared and designated as GPP and GPA to investigate the effect of the variant at amino acid position 459 on the structure of the triple helix (Figure 2a). The conformational properties of the peptide homotrimer were assessed with the use of the CD spectrum. GPP is known to form a homotrimer showing a characteristic triple-helical CD of 225 nm maximum in the native state, and GPA showed identical spectra, suggesting that GPA also forms a triple helix (Figure 2b). The thermal stability of the model peptides was measured on the basis of their thermal denaturation with CD spectroscopy (Figure 2c). For equilibrium melting temperature (Tm) transitions (or the transition midpoint), the ellipticity at 225 nm was monitored (Figure 2d). The value of the Tm of 2 triple helices differed, ie, GPP had a higher Tm than GPA.
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Discussion |
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In this study COL1A2 was extensively investigated as a positional and functional candidate in an association study with Japanese IA patients.8,11 We identified significant associations between IA and the 3 SNPs of COL1A2, especially in familial IA patients. The best evidence of allelic association was observed with SNP28 on exon 28, Ala to Pro substitution at amino acid residue 459, which corresponds to the Y position of the Gly-X-Y repeat of the triple-helical domain (P=0.001) (Figure 1 and Table 2). Genotypic association of SNP28 in the dominant model was observed in familial IA patients (P=0.00087) (Table 3). These results indicate that SNP28 could be a functional variant leading to IA formation. The amino acid substitution has been reported previously; however, the functional impact of the variant is not known.18 The other SNPs less significantly associated with IA were SNP36, located on exon 32 with no amino acid substitution, and SNP50, located on intron 46. Using cultured primary smooth muscle cells obtained from human umbilical arteries with distinct genotypes of SNP28 and other SNPs, we used reverse transcriptase–PCR analysis to test whether the variant affects splicing because many collagen-related diseases are caused by splicing variants.19,20 Thus far, no splicing variant of COL1A2 due to the SNP28 genotype has been detected in cultured smooth muscle cells (data not shown).
Type I collagen is by far the most abundant collagen of the vertebrate connective tissue and is found in a large number of tissues, including vessels.21 It is well known that type I collagen is a key structural component of broad tissues; however, it also has many physiological functions, such as specific interactions with various molecules and cells. Among the interaction sites, Ala-459 in the triple helix domain of type I collagen is a location for keratan sulfate proteoglycan binding.22 Conformational alteration due to amino acid substitution was investigated with the use of collagen-related peptides on a CD spectrum. We synthesized 2 collagen-related peptides, GPP and GPA, that mimic Pro-459 and Ala-459 of the collagen type I 2-chain, respectively (Figure 2a). Both peptides form a triple-helical structure in solution (Figure 2b).23 The differences in stability between GPP and GPA were assessed by Tm transition in a thermal stability test. The Tm value for GPP was higher than that for GPA (Figure 2c and 2d), indicating that the triple helix of GPP is more stable than that of GPA, which may lead to overall structural stability of the Pro-459 variant.
Connective tissue alterations were observed in skin specimens from IA patients, and the active expression of matrix metalloproteinases may be associated with IA.24–26 The deposition of interstitial type I collagen was documented at the surfaces of smooth muscle cells or along elastin filaments in the cerebral vascular wall, and type I collagen may thus play a role in the rigidity and elasticity of the vascular wall.21 It is therefore speculated that the causative Pro-459 variant of type I collagen 2-chain may affect the rigidity or elasticity of the vascular wall because altered thermal stability was demonstrated in the model peptide (Figure 2). It is also possible that local conformational change due to amino acid substitution could affect interaction with other molecules, eventually altering the vascular wall strength.27
In conclusion, SNP28 of COL1A2 is possibly susceptible to IA, and the functional SNP results in stability changes that may lead to IA formation. However, because the allelic frequency of SNP28 is low, the variant could account for only a portion of IA susceptibilities.
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Acknowledgments |
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This work was supported in part by a Research for the Future program grant from the Japan Society for the Promotion of Science (to Dr Inoue), a grant from the Ministry of Public Health and Welfare Research on Human Genome, Tissue Engineering Food Biotechnology (to Drs Inoue and Kasuya), a grant-in-aid for scientific research from the Japanese Ministry of Education, Science, Sports, and Culture (to Drs Kasuya and Onda), and the research fund of the Mitsukoshi Health and Welfare Foundation 2002 (to Dr Onda). We would like to thank the following participants in this study: T. Moriyama (Moriyama Hospital), K. Arai and T. Mitsuyama (Shimodate Citizen’s Hospital), and Y. Terada for technical support.
Received June 26, 2003; revision received September 18, 2003; accepted October 14, 2003.
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