PROJECT

Papers of the Month - Jan 2000

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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.