(Circulation. 2001;103:2461.)
© 2001 American Heart Association, Inc.
Clinical Investigation and Reports |
Familial Thoracic Aortic Aneurysms and Dissections
Genetic Heterogeneity With a Major Locus Mapping to 5q13-14
From the Department of Internal Medicine, University of Texas–Houston Medical School (D.G., S.H., S.-Q.K., H.C., D.M.M.); Department of Medicine, Cornell University Medical College, New York Hospital, New York, NY (C.J.V., C.T.B.); Human Genetic Center and Institute of Molecular Medicine, University of Texas Health Science Center at Houston (E.B.); Department of Pediatrics, Rhode Island Hospital and Brown University School of Medicine, Providence, RI (D.A.); Howard Hughes Medical Institute and Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Md (H.C.D.); and Department of Epidemiology, University of Texas M.D. Anderson Cancer Center, Houston (S.S.S.).
Correspondence to Dianna M. Milewicz, MD, PhD, Department of Internal Medicine, University of Texas–Houston Medical School, 6431 Fannin, MSB 1.614, Houston, TX 77030. E-mail dianna.m.milewicz{at}uth.tmc.edu
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Abstract |
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Background—Aneurysms and dissections affecting the ascending aorta are associated primarily with degeneration of the aortic media, called medial necrosis. Families identified with dominant inheritance of thoracic aortic aneurysms and dissections (TAA/dissections) indicate that single gene mutations can cause medial necrosis in the absence of an associated syndrome.
Methods and Results—Fifteen families were identified with multiple members with TAAs/dissections. DNA from affected members from 2 of the families was used for a genome-wide search for the location of the defective gene by use of random polymorphic markers. The data were analyzed by the affected-pedigree-member method of linkage analysis. This analysis revealed 3 chromosomal loci with multiple markers demonstrating evidence of linkage to the phenotype. Linkage analysis using further markers in these regions and DNA from 15 families confirmed linkage of some of the families to 5q13-14. Genetic heterogeneity for the condition was confirmed by a heterogeneity test. Data from 9 families with the highest conditional probability of being linked to 5q were used to calculate the pairwise and multipoint logarithm of the odds (LOD) scores, with a maximum LOD of 4.74, with no recombination being obtained for the marker D5S2029. In 6 families, the phenotype was not linked to the 5q locus.
Conclusions—A major locus for familial TAAs and dissections maps to 5q13-14, with the majority (9 of 15) of the families identified demonstrating evidence of linkage to this locus. The condition is genetically heterogeneous, with 6 families not demonstrating evidence of linkage to any loci previously associated with aneurysm formation.
Key Words: aorta • aneurysm • genetics
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Introduction |
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Aneurysms and dissections of the aorta result primarily from degenerative changes in the aortic wall. Prominent among the factors that lead to this degeneration are aging, arteriosclerosis, hypertension, and specific infectious, inflammatory, or autoimmune diseases that involve the aorta focally or diffusely. Arteriosclerotic lesions are associated with aneurysms and dissections that affect primarily the descending thoracic and abdominal aorta (thoracoabdominal aortic aneurysms, abdominal aortic aneurysms, and type III dissections). In contrast, aneurysms and dissections that affect the ascending aorta are primarily due to lesions that cause degeneration of the aortic media, a poorly understood pathological process called medial necrosis (also called cystic medial necrosis by Erdheim1 ). Medial necrosis is characterized by degeneration and fragmentation of elastic fibers, loss of smooth muscle cells, and interstitial collections of basophilic-staining ground substance.
Although the pathogenesis of medial necrosis is not understood, it is almost certainly not a single disease entity. Medial necrosis occurs with normal aging of the aorta but can be accelerated by such conditions as hypertension. Medial necrosis of the aorta also occurs in association with genetic syndromes, such as Marfan syndrome (MFS), but is more frequently found in the absence of an associated phenotypic syndrome. Descriptions of families with autosomal dominant inheritance of aortic aneurysms/dissections with medial necrosis on pathological examination indicate that single gene mutations can cause medial necrosis in the absence of an associated syndrome.2 3 In addition, medial necrosis of the proximal aorta with aneurysms/dissections is associated with a number of other conditions, including Turner syndrome (45,X0), Noonan syndrome, Ehlers-Danlos syndrome type IV, bicuspid aortic valve, coarctation of the aorta, and adult polycystic kidney disease.4 5 6 7
MFS is an autosomal dominant condition characterized by skeletal, ocular, and cardiovascular complications.8 9 The cardiovascular complications are thoracic aortic aneurysms and dissections (TAA/dissections), along with valvular abnormalities. Medial necrosis observed in MFS patients is the result of mutations in a specific component of the elastic fiber, fibrillin-1. The elastic fiber is composed both morphologically and biochemically of a core made of the protein elastin surrounded by a peripheral mantle of 10-nm microfibrils. Microfibrils contain several proteins, with the major component being fibrillin-1, encoded by FBN1 on chromosome 15.10 Numerous FBN1 mutations have been identified in MFS patients, the vast majority of which are unique to the affected family or individual.11 A second locus for MFS has been identified at 3p24.2-p25 on the basis of linkage analysis of a large French family with skeletal and cardiovascular features of the disorder, but the findings in this family have been controversial.12 13
Fifteen families with autosomal dominant inheritance of TAA/dissections have been identified, and linkage to FBN1 was excluded. The aortic disease in these families is characterized by aneurysms involving the ascending aorta leading to type I and II aortic dissections in the absence of hypertension. The age of onset of the aortic disease is variable, and there is decreased penetrance of the disorder in the families. This article presents data mapping a locus for this condition to 5q. Genetic heterogeneity for the disorder is demonstrated, but the majority of the families (9 of 15) demonstrate evidence of linkage to the 5q locus. A second locus for TAA/dissections has been reported separately,14 and we have determined that 5 of 15 of our families are not linked to either locus, indicating that there is at least 1 more locus for this condition.
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Methods |
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Families and Sample Collection
Clinical descriptions of 4 of the families participating in these studies have been published.2 Another 11 families with multiple members with TAAs and/or dissections were identified and clinically characterized. Individuals were identified as affected if they had a true aneurysm or dissection of the thoracic or abdominal aorta. Patients were diagnosed by any imaging modality, including ultrasound, 2D echocardiography, CT scan, MRI, and angiography, or preaneurysmal dilatation of the patient’s proximal aortic root measured echocardiographically at the sinuses of Valsalva and plotted against nomograms derived from normal values.15 The affected individuals in these families did not have any features of MFS or any other connective-tissue disorder. The majority of the families are Caucasian, except TAA003 (Iranian) and TAA014 (Japanese). There is no known consanguinity in the families.
The Institutional Review Committee at the University of Texas Health Science Center at Houston approved this study. After the appropriate consent was obtained, buccal cells, blood, autopsy samples, and/or skin biopsies were collected from the family members, and genomic DNA was isolated. Cultured fibroblast cell strains were established from the 3-mm skin biopsies by mincing the tissues and placing them into 60-mm culture dishes secured by glass coverslips. The primary cultures were maintained in DMEM with 10% FCS and supplemented with antibiotics and antimycotics. Aortic smooth muscle cells were purchased from American Type Culture Collection.
Genotyping
Genomic DNA was extracted from fibroblasts and blood
samples with a PureGene genomic DNA isolation kit (Gentra Systems).
Fluorescence-tagged primers (CHLC Human Screening Set, version
8.0, Research Genetics) were used to amplify polymorphic sequences
spaced 
10 cM throughout the genome. The DNA fragments were
analyzed on an ABI Prism 377 Genetic Analyzer. Primers
to analyze other polymorphic microsatellite markers were
designed according to the information from the Cooperative Human
Linkage Center16 and the
Genome Database.17 Twelve
markers located at 3 chromosome regions were used to further define and
verify putative TAA loci, including
D3S1279,
D3S4523,
D3S1744,
D3S1763,
D5S2500,
D5S1725,
D5S1462,
D5S1453,
D5S2501,
D16S3253,
D16S3396, and
D16S2624. Twenty-one
markers spanning 52 cM of chromosome 5q were chosen for fine genetic
mapping and identifying the critical interval, including
D5S2500,
D5S2089,
D5S637,
D5S1982,
D5S424,
D5S1977,
D5S1962,
D5S1501,
D5S806,
D5S1464,
D5S253,
D5S2029,
D5S626,
D5S641,
D5S107,
D5S428,
D5S1725,
D5S1462,
D5S495,
D5S1453, and
D5S2501.
The following markers were used to study linkage to FBN1 on chromosome 15q: MTS2, MTS4, D15S119, D15S126, and D15S209.18
Sequencing
Polymerase chain reaction (PCR) amplification
from genomic DNA was performed with fluorescence-labeled
(6-FAM, HEX) and tailed primers. The reactions were carried out
in 12.5 µL with 10 to 50 ng genomic DNA by use of
HotStarTaq DNA polymerase (Qiagen Inc) with a
2-step amplification program (PE, Applied Biosystem), and the PCR
products were analyzed on an ABI Prism 310 DNA sequencer
(Applied Biosystems). Primer sequences used in this study are available
in an online data supplement available at
http://www.circulationaha.org.
Total cellular RNA was isolated from dermal fibroblast cell culture by Trizol reagents (Gibco-BRL). The first-strand cDNAs were synthesized by SuperScript II reverse transcriptase (RT; Gibco-BRL), and the PCRs were performed in 12.5 µL by use of HotStarTaq DNA polymerase. The forward and reverse primers were designed according to the published cDNA sequences to obtain overlapping fragments.
Statistical Analysis
The genome-wide scan marker data were
analyzed by the affected-pedigree-member method of linkage
analysis.19 The test
for heterogeneity was performed as previously
reported.20
Pairwise and multipoint logarithm of the odds (LOD) scores were calculated with MLINK and LINKMAP programs of the computer software FASTLINK, version 3.P.21 22 Allele frequencies for each marker were obtained by use of the founders in the pedigrees. Penetrance values were deduced from the proportion of affected individuals in the pedigrees. The penetrance for the homozygous and heterozygous carriers of the rare disease allele was found to be age dependent, with 10% for individuals age <30 years, 30% between 30 and 40 years, 70% between 40 and 60 years, and 90% for individuals >60 years of age.
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Results |
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Genome-Wide Search, Fine Mapping, Haplotype Analysis, and Definition of the Critical Region for the Location of TAA/Dissection Gene
As an initial step toward defining the genetic basis of the TAA/dissection in 15 families identified, linkage to FBN1 was excluded as the cause of TAA in these families by use of DNA from the families and markers within and surrounding FBN1. We then proceeded with a genome-wide scan for the genetic defect causing this syndrome using only affected members from TAA002 and TAA003 (Figure 1A
), the 2 families with the most affected members.
This approach was used in an attempt to avoid problems in mapping the
gene due to the decreased penetrance and possible genetic
heterogeneity. Multilocus analysis revealed 3
loci with multiple linked markers showing highly statistically
significant regions of linkage for the TAA/dissection gene in these
families
(Table 1). Three loci, a 38-cM region of chromosome
3q, a 52-cM region of chromosome 5q, and a 26-cM region of chromosome
16q, showed multiple linked markers significantly associated with the
disease.
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Microsatellite markers were used to further analyze
chromosomal regions on 3q, 5q, and 16q and verify the observed linkage.
Linkage analysis was performed with DNA from 5 families
(Figure 1
, TAA001, 002, 003, 005, and 010, which included 18
affected, 33 status unknown, and 14 unaffected individuals) and the
following markers: D3S1279,
D3S4523,
D3S1744,
D3S1763,
D5S2500,
D5S1725,
D5S1462,
D5S1453,
D5S2501,
D16S3253,
D16S3396, and
D16S2624. This analysis
excluded the 3q and 16q loci as the location of the defective gene
causing TAAs/dissections. Three of the 5 families studied, however,
showed evidence of linkage to 5q markers.
Analysis of more families confirmed linkage to markers on 5q. Fifteen TAA/dissection families in which linkage of the phenotype to FBN1 had been excluded were genotyped by use of 21 markers on 5q. In the following families, a 5q haplotype segregated with the disease: TAA002, 001, 009, 010, 012, 013, 014, 015, and 034. Some unaffected individuals in some of these families also had the affected haplotype, which is consistent with the decreased penetrance of the disorder.
Linkage analysis of all 15 families showed that some
of the families had significant positive LOD scores, whereas some had
significant negative LOD scores. Therefore, a
heterogeneity test was performed to determine whether
the families with positive LOD scores are linked to the marker and the
families with negative LOD scores are unlinked to the marker
locus.20 This
analysis was done for the marker
D5S2029 because this marker
demonstrated the highest LOD score in some families. This
analysis supported genetic heterogeneity for
the condition (P=0.004). The
estimate of 
, the proportion of families that are linked, was found
to be 0.45. Nine families with the highest conditional probability of
being linked to 5q were used for the multipoint analyses
(families in
Figure 1A [TAA002 only] and
Figure 1B).
Pairwise and multipoint LOD scores were calculated, and
Table 2 indicates the markers on chromosome 5q that yielded
positive LOD scores. A maximum LOD score (Zmax)
of 4.74 at no recombination (
=0) was obtained for the marker
D5S2029. Family TAA002 has the
highest LOD score of 1.75 for this marker.
Figure 2 shows 3-point analysis results assuming the
following order between the markers:
D5S1464 to 1.5
cM–D5S253 to 0.6
cM–D5S2029 to 0.4
cM–D5S626 to 1.0
cM–D5S641. The 3-point and
4-point results also showed significant linkage and localized the
TAA/dissection gene near
D5S2029.
Table 3 indicates the contributions of the individual
families to the total LOD score for the 4 markers demonstrating the
highest LOD scores. Note that
FBN2, the gene that is altered
in the Marfan-related syndrome called congenital contractural
arachnodactyly, maps distal to this location. An intragenic
FBN2 marker demonstrated a
number of recombinants between the phenotype and the marker in
these families.
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The 5q haplotype constructed by use of the 21
polymorphic markers on 5q revealed 2 recombinants in affected
individuals in TAA002 and TAA013
(Figure 3A). These results suggest that the critical interval
containing the defective gene lies in the 7.8-cM region, bordered
distally by D5S806 and
proximally by D5S641
(Figure 3B).
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One of the TAA families demonstrated segregation of the
disease with chromosome 11q markers (TAA011), where another locus for
familial aortic aneurysms and dissections has been
mapped.14 Therefore, 5
families were not linked to markers on either 5q or 11q (families in
Figure 1A [TAA003 only] and
Figure 1C). Because linkage to
FBN1 and 3p24 has already been
excluded as the cause of aortic disease in these families, these data
suggest that there is another locus for
TAA/dissection.
Sequencing of Candidate Genes in the
Critical Interval
Versican, a large chrondroitin sulfate proteoglycan
that is found in the extracellular matrix of many tissues, including
the aorta, mapped into the critical
interval.23 24
Intron-based, exon-specific primers based on the genomic sequence were
designed to amplify exons 3 through 13 of the versican gene. The 2
largest exons, exons 7 and 8, were amplified by use of overlapping
primers spaced throughout the exons. Translation begins in exon 2, and
exon 2 and part of exon 1 were sequenced with RNA from fibroblasts and
RT-PCR. Versican was sequenced by use of genomic DNA from TAA002/675,
TAA014/1755, and TAA007/1076; the versican cDNA was sequenced by use of
fibroblasts from TAA002/675 and TAA014/1755. Eleven single
nucleotide alterations were identified
(Table 4). All of these alterations were identified in the
largest exon of the gene, exon 8, which encodes the protein domain that
attaches the large chrondroitin side chains. Six of the 15
nucleotide changes did not alter an amino acid; the other
alterations did alter an amino acid, with 3 of these alterations being
nonconservative changes. Analysis of the segregation of the
nucleotide changes within the families indicated that all
the identified alterations were present in unaffected individuals
and also in control DNA.
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Thrombospondins are a family of extracellular
calcium–binding proteins that are involved in cell proliferation,
adhesion, and migration. Thrombospondin 4 also mapped into the 5q
interval and is expressed in cardiac and skeletal muscle, including by
aortic smooth muscle
cells.25 26 The
thrombospondin 4 cDNAs from TAA014/1755 and TAA002/784
fibroblasts were sequenced. Six expressed polymorphisms were
identified in both cell strains, confirming that both alleles were
expressed
(Table 4).
CRTL1 encodes
cartilage link protein, and expression of this gene in aortic smooth
muscle cells was confirmed through RT-PCR using mRNA isolated from
aortic smooth muscle cells.
CRTL1 has only 5 exons, which
were sequenced from genomic DNA from individuals TAA001/765 and
TAA002/675. Four polymorphisms were identified
(Table 4).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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This article describes the mapping of a locus that causes TAAs and dissections inherited in an autosomal dominant manner with variable expression and decreased penetrance. A genome-wide linkage scan was completed with only affected members of 2 families because of the decreased penetrance of the disorder and to avoid possible problems encountered as a result of genetic heterogeneity. Linkage analysis using polymorphic markers at 3 genomic regions identified in the original scan and 6 families with TAA/dissections indicated evidence of linkage of some of the families to a 5q locus. A test for genetic heterogeneity using the 15 families with TAA/dissection supported genetic heterogeneity for this condition. Linkage to the 5q locus results in an LOD score >3.0 with 3 markers, D5S253, D5S2029, and D5S626. The highest LOD score obtained was with D5S2029, which gave an LOD score of 4.74 at a
of 0.
Genetic heterogeneity for TAA/dissections
was confirmed by genetic analysis of an unrelated family with
autosomal dominant inheritance of TAAs and
dissections.14 The clinical
features in this family differed from the families in this study; the
disorder demonstrated complete penetrance at a young age, along with
aneurysms and dissections involving both the ascending and
descending aorta. A genome-wide scan for the defective gene in this
family determined that the phenotype was linked to markers at a
distinct locus on 11q23. Analysis of 6 families not linked to
5q determined that 1 family demonstrated evidence of linkage to 11q
(TAA011,
Figure 1C), although the limited number of affected
individuals in this family prevented confirmation of this
linkage.
Five families did not demonstrate evidence of linkage to markers on either 5q or 11q and were not linked to markers within and closely linked to FBN1. On that basis, we hypothesize that there is a third locus of this condition. Review of the clinical manifestations of the aortic disease in these families that were not linked to either locus failed to reveal any clinical features to differentiate these families from those linked to 5q.
The cardiovascular complications of the families with TAA/dissection that are linked to 5q are similar to those observed in MFS patients. In addition, the condition is inherited in an autosomal dominant manner, which raises the possibility that the defective gene encodes a connective-tissue protein. On that basis, we hypothesized that the defective gene was a connective-tissue protein. Three genes in the critical interval that encoded for the connective tissue proteins versican, thrombospondin 4, and cartilage-linked protein were sequenced with DNA from affected individuals from 2 or 3 of the families linked to 5q. These analyses failed to reveal any variation that accounts for the disease phenotype or segregates with the disease in the families. Single nucleotide polymorphisms were identified in all 3 genes.
The critical interval for the defective gene causing TAA/dissection is defined by recombinants in 2 of the families. The interval is defined proximally by marker D5S806 and distally by marker D5S641, an interval of 7.8 cM. This region of chromosome 5 has been extensively sequenced, but the contigs have not been assembled (no gaps are thought to exist in this region because of the amount of redundant sequencing of bacterial artificial chromosomes in this region). The following genes map into the region and are thought to be poor candidates for the defective gene involved in TAAs/dissections because of their function: ribosomal protein S23, secretory carrier membrane proteins (membrane components of recycling vesicles), RAS-p21 protein activator, creatine kinase (mitochondrial 2), HMG-CoA reductase, arylsulfatase B, betaine-homocysteine methyltransferase, hydroxyacyl glutathione hydrolase, dihydrofolate reductase, x-ray repair complementing defective repair gene, corticotropin-releasing hormone-binding protein, and antiquitin 1 (regulates turgor pressure in plants).
Identification of the defective gene at 5q13-14 causing TAAs and dissections will allow for the timely identification of individuals at risk for this life-threatening condition. The disorder demonstrates decreased penetrance in families, which raises the possibility that sporadic cases of TAAs and dissections result from inherited mutations, putting future generations at risk for aortic aneurysms and dissections. Alternatively, sporadic cases of aneurysms and dissections could result from new mutations in the gene, which could also increase the risk of aortic disease in the offspring. Identification of the defective gene will also allow for new insight into the proteins that are important for maintaining structural integrity of the aortic wall throughout a lifetime.
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Acknowledgments |
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This work was supported by the following funds: an American Heart Association Established Investigator Award (Dr Milewicz), the Roderick Duncan McDonald Foundation at St Luke Episcopal Hospital (Dr Milewicz), NIH grant R01-AR-41135 (Dr Dietz), Howard Hughes Medical Institute (Dr Dietz), and a University of Texas–Houston Medical School Clinical Research Grant (M01-RR-02558). We would like to thank the families for participating in this study, Madeline Ottosen for her excellent nursing assistance, Carlos Infante for his technical assistance, and Dr Elizabeth Petty for recruiting families.
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Footnotes |
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A list of primer sequences used in this study can be found Online at http://www.circulationaha.org.
Guest Editor for this article was Robert Roberts, MD, Baylor College of Medicine, Houston, Tex.
Received November 28, 2000; revision received February 23, 2001; accepted March 3, 2001.
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L. A. Pape, T. T. Tsai, E. M. Isselbacher, J. K. Oh, P. T. O'Gara, A. Evangelista, R. Fattori, G. Meinhardt, S. Trimarchi, E. Bossone, et al. Aortic Diameter >=5.5 cm Is Not a Good Predictor of Type A Aortic Dissection: Observations From the International Registry of Acute Aortic Dissection (IRAD) Circulation, September 4, 2007; 116(10): 1120 - 1127. [Abstract] [Full Text] [PDF]
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P. K. Van Kien, F. Mathieu, L. Zhu, A. Lalande, C. Betard, M. Lathrop, F. Brunotte, J.-E. Wolf, and X. Jeunemaitre Mapping of Familial Thoracic Aortic Aneurysm/Dissection With Patent Ductus Arteriosus to 16p12.2-p13.13 Circulation, July 12, 2005; 112(2): 200 - 206. [Abstract] [Full Text] [PDF]
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H. Shibamura, J. M. Olson, C. van Vlijmen-van Keulen, S. G. Buxbaum, D. M. Dudek, G. Tromp, T. Ogata, M. Skunca, N. Sakalihasan, G. Pals, et al. Genome Scan for Familial Abdominal Aortic Aneurysm Using Sex and Family History as Covariates Suggests Genetic Heterogeneity and Identifies Linkage to Chromosome 19q13 Circulation, May 4, 2004; 109(17): 2103 - 2108. [Abstract] [Full Text] [PDF]
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T. S. Absi, T. M. Sundt III, W. S. Tung, M. Moon, J. K. Lee, R. R. Damiano Jr, and R. W. Thompson Altered patterns of gene expression distinguishing ascending aortic aneurysms from abdominal aortic aneurysms: complementary DNA expression profiling in the molecular characterization of aortic disease J. Thorac. Cardiovasc. Surg., August 1, 2003; 126(2): 344 - 357. [Abstract] [Full Text] [PDF]
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S. Kakko, T. Raisanen, M. Tamminen, J. Airaksinen, K. Groundstroem, T. Juvonen, A. Ylitalo, P. Uusimaa, and M. J. Savolainen Candidate locus analysis of familial ascending aortic aneurysms and dissections confirms the linkage to the chromosome 5q13-14 in Finnish families J. Thorac. Cardiovasc. Surg., July 1, 2003; 126(1): 106 - 113. [Abstract] [Full Text] [PDF]
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S. N. Hasham, M. C. Willing, D.-c. Guo, A. Muilenburg, R. He, V. T. Tran, S. E. Scherer, S. S. Shete, and D. M. Milewicz Mapping a Locus for Familial Thoracic Aortic Aneurysms and Dissections (TAAD2) to 3p24-25 Circulation, July 1, 2003; 107(25): 3184 - 3190. [Abstract] [Full Text] [PDF]
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