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(Circulation. 2004;110:3727-3733.)
© 2004 American Heart Association, Inc.

Stroke

Genome-Wide Scan for Japanese Familial Intracranial Aneurysms

Linkage to Several Chromosomal Regions

Shigeki Yamada, MD^*; Maki Utsunomiya, MPH^*; Kayoko Inoue, MD, MPH; Kazuhiko Nozaki, MD, PhD; Sumiko Inoue, PhD; Katsunobu Takenaka, MD, PhD; Nobuo Hashimoto, MD, PhD; Akio Koizumi, MD, PhD

From the Department of Health and Environmental Sciences (S.Y., M.U., K.I., S.I., A.K.) and the Department of Neurosurgery (S.Y., K.N., N.H.), Kyoto University Graduate School of Medicine, Kyoto, Japan; and the Department of Neurosurgery, Takayama Red Cross Hospital (K.T.), Gifu, Japan.

Correspondence to Dr Akio Koizumi, Department of Health and Environmental Sciences, Graduate School of Medicine Kyoto University, Konoe-cho, Yoshida, Sakyo-ku, Kyoto, 606-8501, Japan. E-mail koizumi{at}pbh.med.kyoto-u.ac.jp

Received May 20, 2004; revision received July 15, 2004; accepted August 2, 2004.

	Abstract

Top Abstract Introduction Methods Results Discussion Conclusions References

 
Background— Genetic factors have an important role in the pathogenesis of intracranial aneurysm (IA). The results of previous studies have suggested several loci.

Methods and Results— From 29 IA families with 3 individuals affected by IA, we used nonparametric (model-free) methods for linkage analyses, using GENEHUNTER and Merlin software. Genome-wide linkage analyses revealed 3 regions on chromosomes 17cen (maximum nonparametric logarithm of the odds score [MNS] = 3.00, nominal P=0.001), 19q13 (MNS=2.15, nominal P=0.020), and Xp22 (MNS=2.16, nominal P=0.019). We tested 4 candidate genes in these regions: the microfibril-associated protein 4 gene (MFAP4) and the promoter polymorphism of the inducible nitric oxide synthase gene (NOS2A) on chromosome 17cen, the epsilon genotypes of the apolipoprotein E gene (APOE) on chromosome 19q13, and the angiotensin I converting enzyme 2 gene (ACE2) on chromosome Xp22. Associations of their polymorphisms with IA were evaluated by a case-control study (100 cases: 29 probands from IA families and 71 unrelated subjects with IAs, 100 unrelated control subjects [unaffected members with IAs and absence of family history of IAs]). However, the case-control study showed that none of the polymorphisms of the examined genes had associations with IA.

Conclusions— A genome-wide scan in 29 Japanese families with a high degree of familial clustering revealed 1 suggestive linkage region on chromosome 17cen and 2 potentially interesting regions on chromosomes 19q13 and Xp22. These regions were consistent with previous findings in various populations.

Key Words: aneurysm • cerebrovascular disorders • genes • stroke

	Introduction

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Family members of patients with subarachnoid hemorrhage (SAH) have been documented to have a high risk of SAH and a high prevalence of unruptured intracranial aneurysms (IAs).^1,2 The risk of ruptured IAs in first-degree relatives of patients with aneurysmal SAH is 4 times higher than that in the general population.² Genetic and environmental factors play important roles in the pathogenesis of IA, and recent progress in molecular genetics enables the genetic determinants to be approached directly.

Genome-wide linkage analyses for familial IA have been reported by 2 groups.^3,4 Onda et al³ suggested linkage to regions on chromosomes 5q22–31 (maximum LOD score [MLS] 2.24), 7q11 (MLS 3.22), and 14q22 (MLS 2.31) in 104 Japanese affected sibling pairs. The linkage to 7q11 was replicated by another study in a white population,⁵ although we could not confirm the linkage to this locus in Japanese.⁶ Olson et al⁴ found suggestive linkages on chromosomes 19q12–13 (MLS 2.58) and Xp22 (MLS 2.08) in 48 Finnish affected sibling pairs, a linkage confirmed by another study.⁷ These results suggest that multiple genes determine susceptibility to IA.

In the present study, we conducted a family-based approach because high degrees of familial clustering of IAs can raise relative risks and thereby provide us a better chance to isolate the major locus.⁸ We recruited 29 families with 3 affected members and report here the results of genome-wide linkage analysis.

	Methods

Top Abstract Introduction Methods Results Discussion Conclusions References

 
Families
From collaborating hospitals in the western part of Japan, we recruited patients with IA who had a family history of IAs or SAH. If they had 3 family members with IAs or SAH and 2 including the proband were alive, their families were regarded as suitable subjects for the present study. "Affected" status of participants was determined in 2 ways. First, if participants had been diagnosed with IAs or SAH, they were confirmed as having saccular IAs from their medical records. Second, if participants aged 30 years did not know whether they had had IAs, they underwent magnetic resonance angiography (MRA) for screening of IAs. All MRA images were examined by 3 neurosurgeons or neuroradiologists. If IAs were suspected by MRA, additional examinations, such as digital subtraction angiography and 3-dimensional computed tomography, were conducted. Families with known heritable diseases associated with IAs, such as Ehlers-Danlos syndrome type IV, Marfan syndrome, neurofibromatosis type 1, or autosomal dominant polycystic kidney disease, were excluded from this study.^9,10 Details of the methods of participation and data collection have been reported previously.⁶ The methods used in this study conformed to the tenets of the Declaration of Helsinki and received approval from the Ethics Committee of Kyoto University.

Genotyping
Genomic DNA was extracted from blood samples (in 2 cases, from a preserved umbilical cord) with a QIAamp DNA Blood Mini Kit (Qiagen Inc). Polymerase chain reaction (PCR) amplification from genomic DNA was performed with fluorescence-labeled (6-FAM, HEX, NED) and tailed primers. PCR primers to analyze microsatellite markers comprised an 10-cM human index map (ABI Prism Linkage Mapping Set Version 2: 382 markers for 22 autosomes and 18 markers for the X chromosome), and other microsatellite fine markers were designed according to information from the UniSTS map.¹¹ PCR reactions were carried out in 7.5 µL with 50 ng genomic DNA, using AmpliTaq Gold DNA Polymerase (Applied Biosystems) in a 2-step amplification program. DNA fragments were analyzed on an ABI Prism 3100 Avant Genetic Analyzer. Genotyping errors and inconsistent relationships were checked with the use of SimWalk2 and Merlin software.^12,13 If the results of genotyping were missed or ambiguous, we treated them as an unknown genotype for the linkage analysis.

Linkage Analysis
Unaffected members who were 60 years of age and underwent MRA screening and affected members were included for the linkage analysis. The inheritance patterns of familial IA have not been determined, though autosomal dominant, recessive, and undetermined modes have been reported in familial IA^9,14; we thus used only a nonparametric method. In addition, the phenotype of unaffected members was assigned as "unknown" in this study. The purpose of including unaffected members was to increase the accuracy of haplotype estimation in affected members, although inclusion did not increase the statistical power. Multipoint nonparametric analyses for autosomes and X chromosome were run with 1-tailed probability values (P), using GENEHUNTER (Version 2.0 and 1.3) and Merlin software.^13,15 Population allele frequencies for each microsatellite marker were estimated from the founders of IA families. We used a 2-stage design: First, all chromosomal regions were screened by genotyping at an 10-cM density (screening), and the region, of which nominal P<0.05 of the nonparametric logarithm of the odds (NPL) score, was considered as a potentially interesting region. Second, these regions were further finely mapped at 1- to 2-cM densities (fine mapping). Nominal P<0.05 regions were again considered as potentially interesting regions or nominal P<0.001 regions were considered as suggestive linkage regions.¹⁵

We evaluated statistical power through the use of simulations, as previously reported.⁶ Simulations were run 1000 times by GENEHUNTER to obtain a false-negative rate (ie, sensitivity, percentage) when the threshold of nominal P was equal to 0.05 under conditions of 75%, 50%, and 25% of locus heterogeneities among families for the linkage analysis.

Case-Control Study
To test associations of polymorphisms of candidate genes (described below) in suggestive linkage or potentially interesting regions with IA, we conducted a case-control study. In the case-control study, 100 cases and 100 control subjects were enrolled from collaborating hospitals in western Japan. Control subjects had the following characteristics: (1) confirmation of not harboring IA by digital subtraction angiography, 3-dimensional computed tomography, or MRA, (2) age at the time of diagnosis 40 years, (3) no medical history of any stroke including IAs or SAH, and (4) no family history of IAs or SAH in first-degree relatives. Cases were composed of unrelated subjects whose presence of IA had been confirmed by angiography or operation and family probands.

The allele frequencies of candidate genes in cases and control subjects were compared by the contingency table of 2 test statistics, with the use of SAS software (Version 8.2, SAS Institute Inc).

Candidate Genes
To search for mutations or polymorphisms of the microfibril-associated protein 4 gene (MFAP4, GenBank accession number = NT_030843) and the angiotensin I converting enzyme (ACE) 2 gene (ACE2, NT_011757), genomic DNA from the probands was used as a template to generate PCR products, which then were sequenced directly. Forward and reverse PCR primers for each coding exon were selected in an intronic sequence 50 bp away from the intron/exon boundaries (Data Supplement Table I). PCR products were run on 2% agarose gel, and the appropriate bands were excised and then purified with the use of the QIAquick Gel Extraction Kit (Qiagen). PCR and sequencing primers are shown in Data Supplement Table I. Sequencing results were analyzed on an ABI Prism 3100 Avant DNA sequencer (Applied Biosystems). Any polymorphic sites identified through our sequencing were searched for registered single nucleotide polymorphisms (SNPs) at the web site of the National Center for Biotechnology Information database SNP (dbSNP).¹⁶

Restriction enzymes to determinate the genotypes of found polymorphisms were BbvCI for the MFAP4, AluI for the ACE2, and HhaI for the apolipoprotein E (APOE, NT_011109),¹⁷ respectively. The bi-allelic AAAT-repeat located 2.45 kbp upstream from the start codon of the inducible nitric oxide synthase (iNOS) gene (NOS2A, NT_010799) was determined by the length of the PCR products amplified by using primers designed according to a DNA sequence found from GenBank (D29675).¹⁸

	Results

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Characterization of Families
Twenty-nine families met our criteria (3 affected members in a family) and were enrolled in this study (Figure 1). In the 29 families, 116 asymptomatic family members (59 men, 57 women, 30 to 82 years of age; mean, 50.0 years) without a history of IAs or SAH underwent MRA examinations. Of the 116 examinees, 22 (8 men [13.6%] and 14 women [24.6%]) were found to have IAs. Of a total 105 affected members (35 men, 70 women) in the 29 families, 70 affected members (66.7%) had SAH and 35 affected members (33.3%) have or have had unruptured IAs. The mean age at the time of diagnosis with SAH among the 70 affected members was 55.4 years (51.7 among 23 men, 57.3 among 47 women). Eighteen affected members had died of SAH.

View larger version (45K): [in this window] [in a new window]   Figure 1. Twenty-nine families in genetic linkage analysis. , Male; , female; , affected members (IA or SAH); •, individual died. *Participation in linkage analysis: P, proband; SAH, subarachnoid hemorrhage; ST, stroke; SD, sudden death by unknown cause; E, examination with MRA; and d, age at death.

Linkage Analysis
Eighty-seven living affected members were genotyped through blood DNA; 2 affected members who had died (IV-1 in Pedigree 5 and III-10 in Pedigree 29) were genotyped through DNA from their preserved umbilical cords. Genotypes of 4 deceased affected members (II-4 in Pedigree 1, II-5 in Pedigree 2, II-1 in Pedigree 14, and II-1 in Pedigree 27) were reconstructed from the genotypes of offspring and spouses. In total, 93 affected members (31 men, 62 women; mean age at diagnosis, 55.2 years) and 27 unaffected members (13 males, 14 females, aged 60 years) were included in the linkage analysis. Characteristics of these members are shown in Table 1. The genome-wide linkage results in the screening are shown in Figure 2. Regions of potentially interest (nominal P<0.05) by multipoint NPL scores were observed on chromosomes 12q11–13, 15q21, 17cen, 19q13, and Xp22 (Table 2 and Data Supplement Table II).

View this table: [in this window] [in a new window]   TABLE 1. Characteristics of Family Members in the Linkage Analysis

View larger version (29K): [in this window] [in a new window]   Figure 2. Multipoint nonparametric logarithm of odds score in genome-wide screening. Bars at bottom of chart indicate regions genotyped further in fine mapping.

View this table: [in this window] [in a new window]   TABLE 2. Maximum Multipoint NPL Scores

The statistical power of this screening was 52%, 93%, and 99% when the locus heterogeneity was 75%, 50%, and 25%, respectively.

After fine mapping, 2 of 5 regions, 19q13 (maximum NPL score [MNS] = 2.15, nominal P=0.020) and Xp22 (MNS=2.16, nominal P=0.019), remained potentially interesting regions (Table 2 and Data Supplement Table III). The region on chromosome 17cen turned out to be a suggestive linkage region (MNS=3.00, nominal P=0.001). The sizes of regions with nominal P<0.05 were 17.7 cM (D17S921–D17S1800) on chromosome 17, 7.9 cM (D19S198–D19S596) on chromosome 19, and 10.1 cM (DXS987–DXS7593) on chromosome X. Physical localization of microsatellite markers in these regions and candidate genes are shown in Table 3.

View this table: [in this window] [in a new window]   TABLE 3. Physical Localization of Microsatellite Markers and Candidate Genes

Case-Control Study for Candidate Genes
We searched putative candidate genes in 1 suggestive linkage and 2 potentially interesting regions after considering physiological functions and documented evidence: chromosomes 17cen (NOS2A and MFAP4), 19q13 (APOE), and Xp22 (ACE2) (Table 3). In NOS2A, there was the 4-bp (AAAT) deletion (R4)/insertion (R5) polymorphism in the regulatory region, and R5 was a high-risk allele of hypertension and coronary artery stenosis.^18–20 We therefore tested the association of this polymorphism. Characteristics of the case versus control subjects are shown in Table 4. All cases and control subjects had an R4/R4 genotype (100%) (Table 5).

View this table: [in this window] [in a new window]   TABLE 4. Characteristics of Cases vs Controls

View this table: [in this window] [in a new window]   TABLE 5. Case-Control Study for Candidate Genes

We next checked whether the epsilon () genotypes of APOE were involved in IA because the APOE -4 genotype has been reported as a risk factor for SAH among Japanese.²¹ The relevant allele frequencies in 100 cases were –2=4%, –3=85%, and –4=11%, which were not different from 100 control subjects (Table 5) and the Japanese general population.²² Six genotype frequencies were –2/–2=0%, –2/–3=7.0%, –2/–4=0.5%, –3/–3=69.9%, –3/–4=20.6%, and –4/–4=2.0% in cases, being the same in control subjects. These did not differ significantly from those expected from the Hardy-Weinberg equilibrium. Furthermore, there was no family in which the –4 allele of APOE was segregated with IA (data not shown).

We sequenced entire coding regions of MFAP4 and ACE2 in the 29 probands of the IA families (Data Supplement Table I). However, we found no polymorphism in the coding regions of these genes. One novel SNP was identified in intron 4 of MFAP4, of which the allele frequency (G/A) was essentially the same between 200 case and 200 control chromosomes (Table 5). One registered SNP (dbSNP: rs2285666) was identified in intron 3 of ACE2, in which allele frequency (C/T) did not differ between 200 case and 200 control chromosomes (Table 5).

	Discussion

Top Abstract Introduction Methods Results Discussion Conclusions References

 
Linkage Analysis
We found 1 suggestive linkage region on chromosome 17cen and 2 potentially interesting (nominal P<0.05) regions on chromosomes 19q13 and Xp22. The suggestive linkage region on chromosome 17cen was in accord with the results of a previous Japanese sib-pair analysis (nominal P=0.027),³ whereas 2 potentially interesting regions on chromosomes 19q13 and Xp22 were reported as candidate regions in a Finish population.⁴ The region on chromosome 19q13 was also replicated by another Finish study.⁷ The region on chromosome 19q13 may thus not be specific to Finnish population. Collectively, candidate regions that have to date been replicated in >1 study include 7q11 (Onda et al and Farnham et al) and 19q13 (Olson et al and Van Der Voet et al).^3–5,7 The regions of 17cen (Onda et al³) and Xp22 (Olson et al⁴) are extended in the present study. Such concordant regions should be considered as high-priority loci and provide promising scaffolds for future studies to identify the exact genetic mechanisms for IA. On the other hand, scattering over various chromosomes may suggest some complexity to the pathophysiology of IAs; such complexity represents the complexity of interactions among many genetic and environmental risk factors that contribute in different degrees with different populations.

It is well known that female sex is a risk factor for IA. The reasons for this increased prevalence are unknown, but there could be a genetic basis as demonstrated in this study. It has recently been shown that many genes ("escapees") on chromosome Xp22 escape inactivation,²³ which may explain the sex differences in susceptibility to IA by gene dosage effects.

The present study has several limitations. First, because we took a family-based approach, it was hard to narrow down the candidate regions to 1-cM resolution. These candidate regions still have 8- to 18-cM sizes, and further efforts will be needed to find susceptibility genes for IA. For this goal, linkage disequilibrium (LD) mapping will be required. The second limitation is associated with the statistical power and specificity. Although the statistical power is highly dependent on the locus heterogeneity, it is hard to predict what degrees of locus heterogeneity exist among the 29 families. Simulation could, however, provide a prediction of the statistical power; >90% power was obtainable if the locus heterogeneity was <50%.

Candidate Genes
At least 2 mechanisms are hypothesized to play critical roles in the development of IA. These include defects in the maintenance of extracellular matrix and in remodeling. These hypotheses suggest MFAP4 and iNOS on chromosome 17cen^9,10,24–26 and ACE2 on chromosome X p22^27–29 as candidate genes. On the other hand, an epidemiological study among Japanese ranked APOE high as a candidate gene on chromosome 19q13.²¹ However, in the case-control study, albeit with very limited numbers of plausible genes, candidate genes including APOE failed to show positive associations with IA. Obviously, LD mapping covering entire regions is required to search for clues to susceptibility genes.

	Conclusions

Top Abstract Introduction Methods Results Discussion Conclusions References

 
Linkage analyses in 29 IA families with 3 affected members showed 1 suggestive linkage region on chromosome 17cen (17.7 cM) and potentially interesting regions on chromosomes 19q13 (7.9 cM) and Xp22 (10.1 cM). These 3 loci provide promising scaffolds for searching for genes determining susceptibility to IA. We also showed evidence that 4 candidate genes, MFAP4, ACE2, a promoter variant of NOS2A, and APOE genotypes, did not have LD with an unknown susceptibility gene for IA. Further efforts are clearly needed to identify susceptibility genes for IA.

	Acknowledgments

 
This work was supported by a grant from the Ministry of Education, Science, Sports, and Culture of Japan (Kiban Kenkyuu A: 14207016) and a grant from the Japan Society for the Promotion of Science (15012231). We are grateful to Dr Mark G. Lathrop (The Centre National de Genotypage, Evry, France) for critical reading of the manuscript. We thank Miho Yoshida and Norio Matsuura for technical assistance and the following doctors for patient recruitment and help in ascertaining MRA examinations: Susumu Miyamoto (National Cardiovascular Center), Shiro Nagasawa and Nobuhisa Mabuchi (Soseikai General Hospital), Yasuhiko Tokuriki and Tomoo Tokime (Fukui Red Cross Hospital), Takaaki Kaneko and Nozomu Murai (Hikone Municipal Hospital), Shunichi Yoneda and Yoshito Naruo (Nihonbashi Hospital), Sen Yamagata (Kurashiki Central Hospital), Kenji Hashimoto (Hyogo Prefectural Tsukaguchi Hospital), Atsushi Okumura and Yoshihiko Uemura (Kyoto City Hospital), Tomohiko Iwai (Gifu Municipal Hospital), Hiroyasu Yamakawa (Geroonsen Hospital), Shingo Sugimoto (Sumi Hospital), Atsushi Kawarazaki (Kawarazaki Hospital), Kiyohiro Houkin and Osamu Honmou (Sapporo Medical University School of Medicine), Akira Ogawa and Miyuki Abe (Iwate Medical University), Masayuki Matsuda (Shiga University of Medical Science), Michiyasu Suzuki and Sadahiro Nomura (Yamaguchi University School of Medicine), Izumi Nagata (Nagasaki University School of Medicine), Masatsune Ishikawa (Kitano Hospital), Shinichiro Okamoto (Osaka Red Cross Hospital), Yoshinori Akiyama (Tenri Hospital), Takeshi Nishihara (Kouseikai Takeda Hospital), Hiroshi Kajikawa and Shinichi Wakabayashi (Kajikawa Hospital), Akihiro Doi and Junji Yoshioka (Okayama Kyokuto Hospital), Kazunori Kajihara and Yuji Okamoto (Saiseikai Yahata Hospital), Ichiro Nakahara and Toshio Higashi (Kokura Memorial Hospital), and Takashi Yoshizawa and Kenjiro Ito (Yokohama Shintoshi Neurosurgical Hospital).

	Footnotes

 
*Drs Yamada and Utsunomiya contributed equally to this work.

The online-only Data Supplement, which contains Tables I through III, is available with this article at http://www.circulationaha.org.

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