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1. Fibulin-2 exhibits high degree of variability, but no structural
changes concordant with abdominal aortic aneurysms
Kuivaniemi H, Marshall A, Ganguly A, Chu ML, Abbott WM, Tromp G
EUROPEAN JOURNAL OF HUMAN GENETICS
6: (6) 642-646 NOV-DEC 1998
Abstract:
We used conformation sensitive gel electrophoresis and direct
sequencing of PCR products to screen for mutations in the cDNA for
fibulin-2, an extracellular matrix protein, from 11 patients with
abdominal aortic aneurysms and two controls, When compared with the
published reference sequence, a total of 14 single-base sequence
variations were detected, Seven of the changes were neutral in that
they did not result in an amino acid substitution, There were five
missense changes at sites not conserved between human and mouse, and
two missense changes at sites conserved between human and mouse, All
but two of the sequence variants studied were also present in an
additional set of 102 control alleles analyzed, One of these two
changes was a missense mutation, but it did not segregate with
abdominal aortic aneurysms in the family, whilst the other change was
neutral, In conclusion, fibulin-2 has a large number of sequence
variations in comparison with our previous analyses of type III
collagen, and these variations will be useful in association studies,
There was an excellent overall agreement between direct sequencing of
PCR-products and conformation sensitive gel electrophoresis.
Comment by mdt: POOF ! There goes another interesting candidate gene.
2. Analysis of coding sequences for tissue inhibitor of
metalloproteinases 1 (TIMP1) and 2 (TIMP2) in patients with aneurysms
Wang XJ, Tromp G, Cole CW, Verloes A, Sakalihasan N, Yoon S,
Kuivaniemi H
MATRIX BIOLOGY
18: (2) 121-124 APR 1999
Abstract:
Aneurysms are characterized by dilation, i.e. expansion and thinning
of all the arterial wall layers, which is accompanied by remodeling of
the connective tissue. Genes involved in the regulation of tissue
remodeling are therefore candidate genes. We analyzed TIMP1 and TIMP2
coding sequences in 12 individuals with abdominal aortic aneurysms
(AAA), one individual with AAA and intracranial aneurysms (IA), four
individuals with IA and two clinically unaffected individuals. We
identified two nucleotide variants in both the TIMP1 and the TIMP2
coding sequences. All differences occurred in the third base positions
of codons and were neutral polymorphisms. A significant difference was
observed in the frequency of TIMP2 nt 573 polymorphism between 168
alleles from AAA patients and 102 control alleles. (C) 1999 Elsevier
Science B.V./International Society of Matrix Biology. All rights
reserved.
Comment by mdt: Yes, we found one of the transitions in TIMP 1 several years ago
(Tilson MD, Reilly JM, Brophy CM, Webster EL, Barnett TR. Expression and sequence
of the gene for tissue inhibitor of metalloproteinases in patients with abdominal
aortic aneurysms. J Vasc Surg 18: 266-70, 1993.), but now the picture is
more complete.
3. Genetic analysis of MMP3, MMP9, and PAI-1 in Finnish patients with
abdominal aortic or intracranial aneurysms
Yoon S, Tromp G, Vongpunsawad S, Ronkainen A, Juvonen T, Kuivaniemi H
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
265: (2) 563-568 NOV 19 1999
Abstract:
MMP3, MMP9, and PAI-1 are present at increased levels in abdominal
aortic aneurysms (AAAs), The promoters of these genes contain
polymorphisms, with alleles that exhibit different transcriptional
activities in vitro. Association studies were performed using these
polymorphisms and DNA isolated from 47 AAA patients, 57 intracranial
aneurysm (IA) patients, and 174 controls, all from Finland, PAI-1 and
MMP9 genotypes did not associate with aneurysms, The frequency of the
5A MMP3 allele was somewhat higher in the AAA than that in the control
group (P = 0.0609 after Bonferroni correction), whereas the MMP3
allele frequencies in the IA group did not differ from those of the
controls (P = 0.9667), These findings suggest that the
transcriptionally more active 5A MMP3 allele might be a genetic risk
factor for AAA among Finns. They are in agreement with previous
studies demonstrating higher level of MMP3 expression in AAA than in
controltissues. (C) 1999 Academic Press.
Comment by mdt: I've seen data with a much lower p than .06 fizzle, so I wouldn't
look for too much here.
4. Immunoglobulin A antibodies against Chlamydia pneumoniae are
associated with expansion of abdominal aortic aneurysm
Lindholt JS, Juul S, Vammen S, Lind I, Fasting H, Henneberg EW
BRITISH JOURNAL OF SURGERY
86: (5) 634-638 MAY 1999
Abstract:
Background: The aim of this study was to examine the possible
association between the progression of small abdominal aortic aneurysm
(AAA) and chronic infection with Chlamydia pneumoniae.
Methods: Patients from a hospital-based mass screening programme for
AAA with annual follow-up (mean 2.7 years) were included. After
initial interview, 139 men aged 65-73 years with a small AAA underwent
examination and blood sampling. Immunoglobulin (Ig) G and IgA titres
against C. pneumoniae were measured by a microimmunofluorescence test.
Results: Some 83 (95 per cent confidence interval 74-93) per cent of
the men had an IgA titre of 20 or more, or an IgG titre of 32 or more.
Men with an IgA titre of 20 or more had a 48 per cent higher AAA
expansion rate than those with a titre of less than 20 (3.1 versus 2.1
mm/year; P < 0.05). Multiple linear and logistic regression analyses
showed that an IgA titre of 20 or more was a significant independent
predictor of increased AAA expansion, adjusted for known risk factors
of expansion. Initial AAA size and serum total cholesterol level were
also predictors of expansion.
Conclusion: A high proportion of men with a small AAA had signs of
chronic infection with C. pneumoniae. Aneurysm progression correlated
with evidence of chronic C. pneumoniae infection.
Comment by mdt: I wonder why... One possibility is that chlamydia is a molecular
mimic of a structural aortic microfibrillar protein, as we have suggested may be
the case with cytomegalovirus, some herpes viruses, and T. Pallidum. I have not
noticed similarities to chlamydia in sequences that we have published, but it
looks like there is going to be a whole family of tissue specific (and non-
specific) microfibrillar proteins.
Another possibility is that as an aneurysm enlarges, there is a greater area of
flow surface exposed to reduced shear conditions; and that would have the
predictable consequence of increasing the burden of atherosclerotic plaque. Since
chlamydia seems to like keeping house in plaque, the increased burden of plaque
might make infection with the organism more likely.
And, as I once heard Judah Folkman say, if you can think of two good explanations
for a scientific fact, there are likely to be six others you haven't thought of
yet.