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AAS
Quarterly E-Newsletter
June
2009
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Hello once again, It is hard to believe that 2009 is
half over! It does mean that the Annual Scientific Meeting is approaching.
There is information about the ASM in this newsletter. Also after a short
absence FH Corner returns with an update kindly provided by Frank van
Bockxmeer and his colleagues. See you all at Melbourne! |
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President's Report Australia was represented by a sizeable contingent at the recent
International Atherosclerosis Symposium in Boston. The meeting was as
informative as ever, and it provided an appropriate launching pad for raising
awareness of the meeting in 2012. Following his election to the post of
President-elect of the IAS, Professor Philip Barter took the opportunity to
show a DVD promoting the appeal of holding the Symposium in Australia, whilst
Chairperson of the meeting, Professor Kerry-Ann Rye, described the
preparations so far and issued an invitation to all present. The symposium and its associated satellite meetings will provide
a wonderful opportunity for our society, but the recent meeting in Boston
made it clear that it will require a huge amount of effort, particularly in
the setting of the current subdued economic climate. Please be responsive to
requests that may be made for assistance in the planning phases. Whilst the
opportunity to arrange satellite meetings provides an appealing opportunity
to interact closely with international experts, please keep in mind that each
satellite will need to be economically self-sufficient. Endorsement of
satellite meetings by the main symposium will involve a formal process for
which an application form will soon be available via Meetings First. The other notable feature of the recent symposium was the
remarkable success rate of our young investigators who secured a
disproportionately high percentage of awards. Winners are invited to submit
their names and the title of their presentations so that they can be duly
recognised in the next issue. |
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AAS Annual
Scientific Meeting 13 – 16 October 2009 Novotel St Kilda, Melbourne
He will be joined by Professor Willa Hsueh, Professor of
Medicine at the Diabetes Research Centre, Division of Diabetes, Obesity and
Lipids in Houston, Texas. We are sure that both speakers will share novel findings
and provide a comprehensive international, state of the art update in their
area of research at the Annual Scientific Meeting. Looking forward to see you there! Karin Jandeleit-Dahm and Terri Allen Chairs, POC, AAS Annual Scientific Meeting, Melbourne 2009 |
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Familial
Hypercholesterolaemia (FH) Corner: DNA-based Cascade Screening UK NICE Guidelines
for FH The UK NICE Guidelines for FH recommend that DNA testing be used
to detect new cases of FH. Health economic analysis indicates greater
cost-effectiveness of the DNA approach compared with phenotypic (lipid)
testing (Gerald Watts, AAS Quarterly Newsletter, March 2009). NICE also
recommends that diagnosis of FH in the UK should be based on the Simon Broome
Criteria modified for age-adjusted LDL cholesterol (LDLc) levels and that
this should be the sole tool for the phenotypic diagnosis of FH in children
from the age of 10 years. However, a study of 200 Dutch families with mutation-proven
FH showed that diagnosis based on LDLc resulted in a false positive and
negative test result rate of 1 in 4 for children aged 5 to 15 years. That
rate increased alarmingly to ~ 1 in 2 by age 40 years. Clearly, DNA-based
diagnosis of FH will form the cornerstone for developing optimal strategies
for both the unambiguous identification of adult FH heterozygotes in the
community and cascade screening for the early detection and treatment of
affected individuals in their extended families. Regionally, FH mutation analysis is available at two
laboratories in Australia- David Sullivan and Ron Trent (Sydney) and Royal
Perth Hospital, Perth, Western Australia, and Peter George in Christchurch,
New Zealand. The AAS-FH special
interest group The AAS-FH special interest group was formed in 2007 and has
been developing its own Model of Care (MoC) for FH within an Australian and
New Zealand context. As well as Simon Broome Criteria, the Australian
initiative takes into account the extensive data available from the Dutch
Lipid Clinic Network established in 1994 for the detection and treatment of
FH in that country. The MoC is essentially based on a document developed in
Western Australia as a partnership program involving academics, clinicians,
Royal Perth Hospital and the Health Department of WA for the screening and
management of FH (Watts GF, Dimmitt S, Redgrave T, Bates T, Emery J, Burnett
J, van Bockxmeer F, Poke S, Maxwell S, O’Leary P, Powell M, Southwell L.
Familial Hypercholesterolaemia. Perth Western Australia 2008). The pilot
program is funded by the Commonwealth Government under its “Better Health
Initiative” and was denoted as one of nine Flagship Projects for 2009. The
MoC provides written protocols for the identification of index cases, geno- and
phenotypic cascade screening, and, assessment and management of FH in adults
and children. An important feature of this model is the inclusion of an
algorithm for the definitive ascertainment of FH at a DNA level. DNA cascade
screening for FH The main challenges for population screening for FH at a DNA
level are the costs and feasibility of screening thousands of patients
suspected to have FH, even with current high throughput DNA sequencing
technology, compounded by the knowledge that FH has significant genetic
heterogeneity that differs with populations. In most nations, about 95% of FH
is caused by mutations in the LDLR gene, the remainder being due to defects
in the APOB gene rendering LDL incapable of binding to its receptor and ~1 %
due to gain-of-function defects in PCSK9 that interfere with normal
intracellular catabolism of LDL. Most diagnostic laboratories use the ‘gold
standard’ approach of nucleotide sequencing of each of the 18 exons and
flanking splice regions (exon by exon sequence analysis, EBESA) of the LDLR
gene to detect one or more of the ~1000 mutations so far reported. It is now
appreciated that (9–15) % of FH cannot be detected by conventional EBESA due
to an inability of EBESA to detect large duplications and deletions in the LDLR.
A commercial kit for detecting this type of “copy number variation” in the
LDLR based on Multiplex Ligation Probe Amplification (MLPA) for each of its
18 exons has been developed by MRC-Holland. However, EBESA and MLPA are
expensive and labour-intensive methods not suitable for large scale
population screening. In 2008, Progenika (Spain) and TEPNEL (UK) have
respectively developed commercial array (LIPOCHIP) and multiplex ARMS
(Elucigene FH20) assays for FH that reduce the need for EBESA. These platforms
detect mutations in the LDLR, APOB and PCSK9 genes that are known to commonly
occur in these nations. Although very cost effective with rapid turn around
times, obviously, many mutations cannot be detected by these methods. The
results of a UK pilot using the Elucigene FH20 kit are of particular interest
to Australia and New Zealand. Twenty of the mutations considered to be the
most frequently occurring were found in 52% of FH heterozygous patients- a
remarkably cost effective result. Approximately 85% of Australians are either
born in the UK or to parents/grandparents originally from the UK. The TEPNEL
kit should therefore be highly relevant to some 20 million residents of
Australia and New Zealand with links to the UK. Although EBESA and MLPA would
be expected to have near 100% sensitivity and specificity for the detection
of LDLR gene mutations, the false positive and negative rates for the
LIPOCHIP and Elucigene FH20 platforms are not known. A false negative test
result in any FH cascade screening protocol would seriously jeopardise its
cost effectiveness and clinical utility. FHWA pilot
screening program The protocol adopted for the WA cascade screening program is
based on the sequential application of both the Elucigene FH20 and the MLPA
kits followed by complete EBESA of the LDLR gene. The rationale for the
latter is to be able to detect all causative mutations over and above the 20
expected to be common and at the same time capture compound heterozygosity
should it be present, as well as identify any false negative and false
positive calls with the Elucigene FH20 kit. The results obtained with the
first 120 cases diagnosed on clinical grounds to be FH using Dutch Lipid
Clinic Scores (DLC) are shown in the figure. The DLC is an indicator of
disease severity that is obtained from assigning numeric values to phenotypic
parameters such as the degree of LDLc elevation, co-existence of strongly
prognostic diagnostic features including tendon xanthomata and a family
history of dyslipidaemias and manifestation and age of onset of coronary
heart disease (CHD). The results from our WA
pilot are striking in that with a DLC score of 8 or higher (“definite FH”)
detection of causative mutations occurred in 4 out of 5 patients, with the
success rate dropping off markedly with lower scores. The Elucigene FH20 kit
together with MLPA could detect a mutation in about half of FH patients.
Interestingly, MLPA-detectable LDLR variants appear to be particularly
pathogenic being associated with severe disease and high DLC scores. A
significant proportion of the “probable” and “possible” FH patients were
found to harbour the familial ligand-defective apoB-100 (FDB) mutation in the
APOB gene, consistent with the finding of a milder clinical phenotype and
lower DLC scores in that disease. These figures compare favourably with best
success rates achieved overseas. To date, we have identified and recruited
450 relatives of the 120 index cases in the first 18 months of the pilot
program and we expect to increase that number in the future through continued
family contact. Cascade screening in 2009 of the first 21 families known to
be mutation positive has so far yielded 75 relatives of whom 38 were
identified as new FH mutation-positive cases- very close to the 50%
theoretically (Hardy-Weinberg) predicted. The latter have been much younger
than the adult index cases (typically in their teens or early twenties) and
still largely asymptomatic, thereby providing excellent opportunities for
aggressive cardiovascular risk minimisation through dietary and drug
strategies coupled with appropriate lifestyle interventions, especially
avoidance of smoking and overweight.
Figure. Success rate for mutation detection in FH index cases. Conclusions and
future directions Currently, less than 2% of the ~40,000 FH carriers in Australia are
estimated to have been detected with the vast majority not on effective
statin therapy. Through the AAS-FH and WA FH programs, we appear to be on the
threshold in Australia of cost-effective DNA screening paradigms for FH of
considerable clinical utility. Next generation mutation screening technology
should markedly enhance these efforts leading to automated, high throughput
technologies with modest reagent and platform unit costs. Mention should be
made of work in Australia and New Zealand for screening approaches for
mutation detection using novel technologies that avoid the need for costly
and time consuming EBESA that appear very promising. Andrew Laurie and Peter
George (Christchurch, New Zealand) have developed a High Resolution (DNA)
Melting (HRM) analysis method for detecting LDLR gene mutations without the
need for comprehensive EBESA (Clin Biochem 2009; 42:528-535). This approach
has also been validated and extended in Steve Humphries’ lab (London, 2009)
and complements our efforts in WA for the detection of FDB also by HRM
(Liyanage KE, Hooper AJ, Defesche JC, Burnett JR, van Bockxmeer FM. Ann Clin
Biochem 2008; 45:170-176). Author Frank van Bockxmeer on behalf of Amanda Hooper, Lan Nguyen and John Burnett Cardiovascular Genetics Laboratory PathWest Laboratory Medicine WA Royal Perth Hospital, Perth, Western Australia |
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Membership News If
you have not renewed your membership, please click here to
visit the Meetings First website and renew online. Alternatively, please click here to download a copy of the
paper registration form. The Australian Atherosclerosis Society always welcomes new
members. Please encourage your students and work colleagues to join the AAS.
Remember, that members receive thew following: -
A
monthly email that includes, job opportunities, information on meetings
relating to atherosclerosis and regular updates on similar interests. -
A new
quarterly newsletter that will feature different articles each quarter. -
Discounted
rates to attend AAS Annual Scientific Meetings. -
Networking
opportunities and involvement. -
Opportunity
to receive student travel grants and present your research at the Annual
Scientific Meeting. -
Opportunity
to apply for AAS Trust travel grants |
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Foundation for
High Blood Pressure Research 2010 – 2011 Postdoctoral Research Fellowship The Foundation is offering a two-year postdoctoral fellowship for
a research project in hypertension or related fields in basic, clinical or
public health areas at an Australian institution. Applications from
biomedical, clinical and public health researchers are invited. Applications are open to Australian citizens or permanent
residents. It is expected that the successful applicant will have had not
less than five and not more than ten years' postdoctoral experience. The
fellowship provides a salary and modest project maintenance costs. 2010 ISH Visiting Postdoctoral Award The ISH Visiting
Postdoctoral Award has been designed to encourage experienced researchers
from countries other than Australia to work in Australia for up to two years
on a specific research project in hypertension or a related field in basic, clinical
or public health areas. The ISH Visiting Postdoctoral Award will be awarded to an
Australian research institution, as a contribution towards the salary of a
postdoctoral researcher who is not an Australian citizen or permanent
resident. Application
Procedures For information on
how to apply please contact: FHBPR Secretariat Department of
Physiology University of
Melbourne Parkville 3010 Victoria. Australia Email: jkelly@unimelb.edu.au Applications close on Friday 28 August 2009 |
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5th Joint Meeting
of the Societies for Free Radical Research Australasia and Japan held in
conjunction with the Mutagenesis and Experimental Pathology Society of
Australia 1 – 5 December 2009 University of Sydney Veterinary Conference Centre http://www.pathology.usyd.edu.au/sfrra2009.htm This meeting will
mix established scientists while highlighting our younger researchers and will
cover a cross-section of free radical and redox-related research ranging from
chemistry through to pharmacology and related health sciences. There will be
a half-day Symposium held in conjunction with ASCEPT on Oxidative Stress and
Cardiovascular Disease, with the Plenary Lecture given by Prof John Keaney
(Boston, USA).
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Forthcoming Meetings 10th International Symposium on the Maillard
Reaction 29 August – 1 September 2009, Palm Cove,
Australia Click here for more
information 5th Joint Meeting of the Societies for Free
Radical Research Australasia and Japan held in conjunction with the
Mutagenesis and Experimental Pathology Society of Australia 1 – 5 December 2009, University of Sydney
Veterinary Conference Centre Click here for more information EDDP 2010 – International Conference on
Early Disease Detection and Prevention Click here for more
information 23rd Scientific Meeting of the International
Society of Hypertension 26 – 30 September 2010 Click here for more
information APSAVD Congress 2010 26 – 29 October
2010, Cairns, Australia Further information coming soon! |
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International
Atherosclerosis Society Please click here to
view the May E-Newsletter. Please click here to
view the May E-Literature. |
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E-News The next E-News will be sent out on Friday 17 July
2009. If there is information you would like to include, please email it to aas@meetingsfirst.com.au
by Friday 13 July 2009. Please do not hesitate to contact me
if you have any queries. Kind Regards, AAS Secretariat 4/184 Main Street Lilydale VIC 3140 Phone +61 3 9739 7697 Fax +61
3 9739 7076 Email aas@meetingsfirst.com.au |
