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(Circulation. 2004;109:2103-2108.)
© 2004 American Heart Association, Inc.

Clinical Investigation and Reports

Genome Scan for Familial Abdominal Aortic Aneurysm Using Sex and Family History as Covariates Suggests Genetic Heterogeneity and Identifies Linkage to Chromosome 19q13

Hidenori Shibamura, MD, PhD; Jane M. Olson, PhD; Clarissa van Vlijmen-van Keulen, MD; Sarah G. Buxbaum, PhD; Doreen M. Dudek, MS; Gerard Tromp, PhD; Toru Ogata, MD; Magdalena Skunca, MS; Natzi Sakalihasan, MD, PhD; Gerard Pals, PhD; Raymond Limet, MD, PhD; Gerald L. MacKean, MD; Olivier Defawe, MS; Alain Verloes, MD; Claudette Arthur, BN, MBA; Alan G. Lossing, MD; Marjorie Burnett, BS; Taijiro Sueda, MD, PhD; Helena Kuivaniemi, MD, PhD

From the Center for Molecular Medicine and Genetics (H.S., G.T., T.O., M.S., H.K.) and Department of Surgery (H.K.), Wayne State University School of Medicine, Detroit, Mich; Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio (J.M.O., S.G.B., D.M.D.); Departments of Vascular Surgery (C.v.V.–v.K.) and Clinical Genetics (G.P.), Free University Medical Center, Amsterdam, the Netherlands; Departments of Cardiovascular Surgery (N.S., R.L., O.D.) and Human Genetics (A.V.), University Hospital of Liège, Liège, Belgium; Department of Surgery, Dalhousie University, Halifax, Nova Scotia, Canada (G.L.M., C.A.); Department of Surgery, University of Toronto, Toronto, Ontario, Canada (A.G.L., M.B.); and Department of Surgery, Hiroshima University, Hiroshima, Japan (T.S.). Dr Buxbaum is now at Department of Human Genetics, University of Pittsburgh, Pittsburgh, Pa; Dr Verloes is now at Clinical Genetic Unit, Robert Debre Hospital, Paris, France; and Dr Shibamura is now at Department of Surgery, Hiroshima University, Hiroshima, Japan.

Correspondence to Helena Kuivaniemi, MD, PhD, Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, 3106 Scott Hall, 540 E Canfield Ave, Detroit, MI 48201. E-mail kuivan{at}sanger.med.wayne.edu

Received August 1, 2003; de novo received November 15, 2003; revision received January 27, 2004; accepted February 4, 2004.

	Abstract

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Background— Abdominal aortic aneurysm (AAA) is a relatively common disease, with 1% to 2% of the population harboring aneurysms. Genetic risk factors are likely to contribute to the development of AAAs, although no such risk factors have been identified.

Methods and Results— We performed a whole-genome scan of AAA using affected-relative-pair (ARP) linkage analysis that includes covariates to allow for genetic heterogeneity. We found strong evidence of linkage (logarithm of odds [LOD] score=4.64) to a region near marker D19S433 at 51.88 centimorgans (cM) on chromosome 19 with 36 families (75 ARPs) when including sex and the number of affected first-degree relatives of the proband (N_aff) as covariates. We then genotyped 83 additional families for the same markers and typed additional markers for all families and obtained a LOD score of 4.75 (P=0.00014) with sex, N_aff, and their interaction as covariates near marker D19S416 (58.69 cM). We also identified a region on chromosome 4 with a LOD score of 3.73 (P=0.0012) near marker D4S1644 using the same covariate model as for chromosome 19.

Conclusions— Our results provide evidence for genetic heterogeneity and the presence of susceptibility loci for AAA on chromosomes 19q13 and 4q31.

Key Words: aorta • aneurysm • genetics • mapping

	Introduction

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Approximately 15% of patients with abdominal aortic aneurysms (AAAs) and without any recognizable connective tissue disorder, such as Ehlers-Danlos syndrome or Marfan syndrome, have a positive family history for AAA.¹ Two segregation studies favored a genetic model in explaining the familial aggregation of AAA and suggested the presence of a major gene effect.^2,3 Finding a susceptibility gene for AAA could lead to a simple DNA test to identify individuals at risk for developing an AAA. Such a test could be extremely useful because surgery for unruptured AAA is highly successful, with low mortality and morbidity.⁴ However, diagnosing AAAs is difficult because most AAAs are asymptomatic before their rupture, and population-based ultrasonography screening to detect AAAs is not used routinely.

The aim of the present study was to find susceptibility loci for AAA with the use of linkage analysis with covariates to allow for locus heterogeneity.^5–7 We used affected-relative-pair (ARP) linkage analyses, methods recognized as useful for identifying genes in complex genetic diseases.⁸ Additionally, we chose the 2-phase/2-stage design for cost-effectiveness and for minimizing the effort required in genotyping while maintaining statistical power to detect linkage.⁹

	Methods

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Subjects and Phenotyping
Families with at least 2 members with AAA¹⁰ were identified; details on the family collection have been reported previously¹¹ and are summarized in Table 1. An accepted definition of arterial aneurysm¹⁰ was used.^12–14 Patients were identified from surgery records at vascular surgery units and were then contacted; consent was obtained, and family histories were collected. A certified vascular surgeon led the effort to identify AAA patients and affected family members. Family histories of any new patients presenting for surgical repair of AAAs at these sites were obtained in interviews conducted by a research nurse specifically trained for this work. In most cases, only a limited amount of information was available from relatives of second degree or greater. A specific questionnaire assessing skin and skeletal manifestations characteristic of Ehlers-Danlos syndrome type IV or Marfan syndrome was used to identify individuals with these disorders. Families with these disorders were excluded from the study. Whenever possible, the AAA diagnosis of a deceased family member was verified by requesting autopsy or medical records. Some family members, if aged 50 years, were examined by ultrasonography and were identified as affected if the infrarenal aortic diameter was 3.0 cm, a cutoff point used previously.¹⁴ Occurrences of isolated iliac artery or other aneurysms (such as thoracic or thoracoabdominal) were noted but were not included in the study. All families were white: 42 Canadian, 36 Dutch, 23 Belgian, 10 American, 3 British, 3 Finnish, 1 Italian, and 1 Swedish. The study was approved by the institutional review boards of Wayne State University School of Medicine and each patient recruiting center,¹¹ and the subjects gave informed consent.

View this table: [in this window] [in a new window]   TABLE 1. Characteristics of AAA Families

Design for DNA Linkage Study
We used an ARP design because the mode of inheritance of AAA is unknown and because an unaffected individual may develop an AAA subsequently or carry the susceptibility gene with incomplete penetrance. A 2-phase/2-stage design for DNA linkage analysis was chosen,⁹ in which a 10- to 15-centimorgan (cM) genome scan is performed on a relatively small number of ARPs (stage 1 of phase I), followed by typing of additional markers in regions detected in stage 1 (stage 2 of phase I), and finally followed by additional typing of new ARPs (phase II) in all positive regions obtained in the first phase. For the combined data set of 213 affected sibling pairs (ASPs) and 22 other ARPs from 119 families (groups 1 and 2; Table 1), we had at least 95% power to detect "significant linkage" (logarithm of odds [LOD] score of 3.6)¹⁵ for a locus with a locus-specific relative risk of 2.3 in the absence of locus heterogeneity.

Genotyping
We isolated genomic DNA from peripheral blood using a Puregene kit (Gentra Systems, Inc). A whole-genome scan was performed by the Mammalian Genotyping Service with the use of screening set 10 with 405 highly polymorphic microsatellite markers and an average marker-to-marker distance of 10 cM.¹⁶ Additional microsatellite markers on chromosome 19 were genotyped as described previously.¹⁷ Before genotyping polymerase chain reactions were performed, a whole-genome amplification was carried out to increase the amount of template DNA available for genotyping and to ensure that limited resources were used cost-effectively.¹⁸ Additional genotyping on chromosomes 3, 4, 5, 6, 9, 14, and 21 after the whole-genome scan was performed by deCODE Genetics Inc. A slightly smaller number (116 ARPs) of samples were genotyped in group 2 for these chromosomes compared with the number of samples genotyped for chromosome 19 (157 ARPs) in our own laboratory, where new ARPs were included into the study continuously. In addition, 2 new ASPs and 1 other new ARP were identified in group 1 families while the study was in progress, and they were included in chromosome 19 analyses.

Statistical Analyses
The genotype data were analyzed for genetic linkage with the multipoint model-free ARP LOD score analysis with the use of the computer program LODPAL from S.A.G.E. (version 4.2).¹⁹ To allow for covariate-related locus heterogeneity, we applied a covariate-based ARP LOD score method.⁶ The model is a 1-parameter modification of the conditional logistic parameterization of the ASP LOD score introduced by Olson.⁶ An optimal mode of inheritance parameter²⁰ is specified that allows one to fit only a single additional parameter per covariate. The model is parameterized in terms of offspring recurrence risk ratio (₁), conditional on K covariates x_k, as follows

where ß is a parameter that measures the "average" linkage in the sample, and the _k are covariate-specific parameters that measure the change in linkage as a function of the covariates and in terms of the recurrence risk ratio for monozygotic twins (₂), conditional on K covariates x_k, as follows

To simplify specification of constraints on parameter estimates, to improve numerical stability, and so that ß reflects average allele sharing, all covariates are centered around their sample mean before inclusion. In general, the values of ß and _k depend on the choice of "coding scheme" for the covariates; a linear transformation of the covariate changes neither the LOD score nor the estimates of covariate-specific recurrence risk ratios. More importantly, conclusions about the existence of locus heterogeneity and the extent or nature of locus heterogeneity do not depend on the estimated value of ß (which may equal zero).

Asymptotic distributions of the resulting likelihood ratio tests were used to obtain probability values.⁶ We report as LOD scores the likelihood ratio statistics (LRSs) divided by 4.605 (ie, 2log_e10). Critical values for the LRSs were obtained as follows. The distribution of the LRS for the basic 1-parameter model is a 50:50 mixture of a point mass at zero and a ² distribution with 1 df. Addition of K covariates gives an LRS with a distribution that is a 50:50 mixture of a ² with K df and a ² with K+1 df. The difference in LRS between nested models that differ by J covariates has a ² distribution with J df. One can therefore test both the significance of the contribution of a covariate and the overall evidence for linkage. The overall evidence for linkage includes information about both the "average" linkage for the sample and the change in linkage as a function of the covariate.

	Results

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A whole-genome scan was performed with 36 AAA families, including 62 ASPs and 13 other ARPs (group 1; Table 1). We performed a model-free multipoint linkage analysis and identified 4 regions, on chromosomes 3, 4, 6, and 21, as significant at the =0.05 level (baseline values in Table 2). We then extended the analyses to include sex and number of affected first-degree relatives of the proband (N_aff) as covariates, and a total of 12 regions on chromosomes 3, 4, 5, 6, 9, 14, 19, and 21 were identified with a covariate effect significant at the =0.01 level, suggesting the presence of genetic heterogeneity (Table 2).

View this table: [in this window] [in a new window]   TABLE 2. Group 1 and 2 LOD Scores for Baseline and Covariate Models for Regions With Largest LOD Scores for Group 1

Twelve regions that were significant in the whole-genome scan were selected for a follow-up study, and additional microsatellite markers were genotyped in the 36 families and in 83 new AAA families that included 151 ASPs and 9 other ARPs (groups 1 and 2; Table 1). Three loci (68 and 132 cM on chromosome 4, and 141 cM on chromosome 5) showed some evidence of linkage in group 2 (Table 2), and these regions were selected for detailed analyses (Table 3). Table 3 shows the LOD scores and parameter estimates for groups 1 and 2 as well as the total sample at the location that gave the highest LOD score for the total sample. In the combined analysis with groups 1 and 2 together, the locus on chromosome 5 did not appear significant (Table 3). The region at 140 cM on chromosome 4 had a LOD score of 3.73 (P=0.0012) (Table 3). The 70-cM region had a peak LOD score of 3.13 (P=0.0042), although the parameter estimates were unstable (not shown), and we therefore report the LOD score of 2.41, which was 4 cM away from the peak, to be able to give more accurate parameter estimates (Table 3).

View this table: [in this window] [in a new window]   TABLE 3. Multiple Regression Analysis of Chromosome 4 and 5 Regions

The chromosome 19 region was also analyzed further because (1) it had the second highest LOD score in the original genome scan (Table 2); (2) we have recently identified a putative locus for intracranial aneurysms on chromosome 19¹⁷; and (3) it contains a large number of biologically plausible candidate genes.²¹ The highest LOD score on chromosome 19 for group 2 was 4.12 (P=0.00054) near D19S416 and 58.69 cM from the p-terminus when sex, N_aff, and their interaction were used as covariates (Table 4). In the combined analysis with groups 1 and 2, including 213 ASPs and 22 other ARPs, the maximum LOD score was 4.75 (P=0.00014) at 58 cM, just proximal to D19S416, with sex, N_aff, and their interaction as covariates (Table 4). The interaction term (sex*N_aff) was significant in the total sample (P=0.00317) as well as in the 2 subsamples. These results suggested that female-female pairs from families with larger numbers of affected persons are most at risk from this locus, although this locus also gives substantial risk to male-male pairs from families with fewer affected persons. Both groups 1 and 2 had the peak LOD score at same location on chromosome 19 (Figure). The best, most parsimonious model was the one with N_aff as a covariate in group 1 and a model using sex, N_aff, and their interaction as covariates in group 2 (Table 4).

View this table: [in this window] [in a new window]   TABLE 4. Multiple Regression Analysis of Chromosome 19 at 58.69 cM (D19S416)

View larger version (19K): [in this window] [in a new window]   A, Multipoint LOD score plot for AAA on chromosome 19. Sex and Naff were used as covariates. The x axis shows distance in centimorgans on chromosome 19; y axis, LOD score. B, A higher-resolution plot for the region between 55 and 62 cM on chromosome 19, illustrating that several closely spaced markers support the peak shown in A.

	Discussion

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We found no evidence of linkage unless sex and number of affected persons were included as covariates in the linkage model. How then should our results be interpreted? As Dizier and coworkers²² have shown, absence of a linkage signal can be due to a factor on which the siblings differ, such as a characteristic of the disease (eg, severity), or an environmental factor. For common diseases that are genetically complex, such situations may be the rule rather than the exception.^5–7 By allowing for heterogeneity in the analysis by including covariates chosen a priori, we avoid these concerns and are able to detect linkage signals obscured by the presence of heterogeneity.

No prior DNA linkage studies with AAA exist, although 3 studies investigated familial thoracic aortic aneurysms and dissections (TAAD) and identified linked loci on 5q,²³ 11q,²⁴ and 3p24–25.²⁵ Because our collection of AAA families excluded patients with TAAD¹¹ and the AAA loci do not overlap with the TAAD loci, different genetic risk factors are probably involved in the development of TAAD and AAA.

There are several plausible candidate genes in the 2 regions with the highest LOD scores, such as IL15 (interleukin 15; a plausible candidate gene with respect to inflammation in AAA), GAB1 (GRB2-associated binding protein 1; an important mediator of branching tubulogenesis and a central protein in cellular growth response, transformation, and apoptosis), and EDNRA (endothelin receptor type A; an endothelin-1 receptor expressed in many human tissues with the highest level in the aorta) around 140 cM on chromosome 4, as well as LRP3 (LDL receptor–related protein 3), HPN (transmembrane protease, serine 1; a serine-type peptidase involved in cell growth and maintenance), PDCD5 (programmed cell death 5; a protein expressed in tumor cells during apoptosis independent of the apoptosis-inducing stimuli), and PEPD (peptidase D; an Xaa-Pro dipeptidase important in collagen catabolism) on chromosome 19.^21,26 LRP3 is particularly interesting because conditional knockout mice for LRP1, another member of the gene family, developed arterial aneurysms and atherosclerosis.²⁷

It is likely that additional AAA loci will be identified by testing other possible covariates, such as smoking, hypertension, and coronary artery disease, which was not possible in this study because these risk factors are so common both in the general population and in patients with AAA that the relatively small number of families in this study did not provide enough power to study them.

	Acknowledgments

 
This study was supported in part by grants HL64310, HG01577, and RR03655. Some of the results were obtained with the use of S.A.G.E. (supported by RR03655). We thank Dr J. Weber and the NHLBI Mammalian Genotyping Service at the Marshfield Medical Research Foundation, Marshfield, Wis, for the whole-genome scan.

	References

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This Article Abstract Full Text (PDF) All Versions of this Article: 109/17/2103    most recent 01.CIR.0000127857.77161.A1v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Shibamura, H. Articles by Kuivaniemi, H. Search for Related Content PubMed PubMed Citation Articles by Shibamura, H. Articles by Kuivaniemi, H. Pubmed/NCBI databases OMIM UniSTS Medline Plus Health Information Aortic Aneurysm Related Collections Genetics of cardiovascular disease