Transcript Association of ADAMTS13 levels and polymorphisms with

Lower levels of ADAMTS13 are associated
with cardiovascular disease
Bongers T.N, Bruijne E, Dippel D, Jong A, Deckers J, Poldermans D. Lower
levels of ADAMTS13 are associated with cardiovascular disease.
Atherosclerosis. (In Press), doi:10.1016/j. atherosclerosis.2009.04.013.
by Supakanya Lasom
Master Degree Student of Medical Sciences,
Cardiovascular disease (CVD)
 CVD is the leading cause of
death worldwide
 CVD includes Coronary
Heart Disease or diseases
of the arteries
(Arteriosclerosis, including
hardening of the arteries,
or Atherosclerosis)
http://www.clivir.com/pictures/heart_disease/MI.gif
Atherothrombosis: A Generalized and Progressive Process
 Coronary heart disease (CHD)
 Angina - intense chest pain
 Heart attack - myocardial
infarction
 Congestive heart failure
 Cerebrovascular disease
 Transient ischaemic attacks (TIA)
or “mini strokes”
 Strokes
 Peripheral vascular disease
(PVD)
 Aneurysms
Adapted from Libby P. Circulation. 2001;104:365-372.
Multiple Risk Factors for Atherothrombosis
Lifestyle
•Smoking
•Diet
•Lack of exercise
Generalize disorders
•Age
•Obesity
Genetic trait
•gender
Atherothrombotic
Manifestations
(AMI and stroke)
Local factor
•Blood flow pattern
•Shear stress
•Vessel diameter
•Arterial wall structure
•% atherostenosis
Systemic
conditions
•Hypertension
•Hyperlipidemia
•Diabetes
•Hypercoagulable
states
Inflammation
•Elevated CRP
http://www.nutrizone.co.za/slides/100/pages/ss1s3_JPG.htm
Platelets and CVD
Willoughby et al, European Journal of Cardiovascular Nursing.1;2002:273–288
von Willebrand factor (vWF)
www.vwf.group.shef.ac.uk/pictures.html
• large glycoprotein encoded by a gene on
chromosome 12p13.3
• synthesized by vascular endothelial cells and
megakaryocytes
• Size: 270-20,000 kDa
von Willebrand factor (vWF)
 vWF is stored in Weibel-Pallade bodies of endothelial cells
and the α-granules of both megakaryocytes and platelets
 VWF multimers (UL-vWF), can bind better to the extracellular
matrix than regular multimers and form higher strength bonds
with platelet GPIb-IX-V than plasma vWF
 UL-vWF are rapidly degraded into smaller forms , do not bind
platelets spontaneously by ADAMTS13
ADAMTS13 (a disintegrin and metalloproteinase with a
thrombospondin type 1 motif, member 13)
von Willebrand factor-cleaving protease (vWF-CP)
Gene location: 9q34, 29 exons, 1427 aa
Multi-domain protein
Synthesized by hepatic cell
ADAMTS13
• Degrades ultralarge vWf multimers, generating smaller form
and decreasing their activity
• Directly cleaves the peptide bond between Tyr1605 and
Met1606 of the VWF A2 domain
http://hematology.wustl.edu/faculty/sadler/vwf.gif
ADAMTS13 regulate vWF adhesive properties
ccforum.com/content/figures/cc5064-1-l.jpg
Deficiency or severely reduced activity of ADAMTS13 leads
to accumulation of ULVWF multimers in plasma and results in
a thrombotic diseases.
Hypothesis
• Low level of ADAMTS13 will result in an
increased risk of cardiovascular disease
Objectives
To investigate the relationship between
ADAMTS13, vWF activity, the genetic
variation in ADAMTS13 and the risk of
cardiovascular disease in young
individuals.
Method
 Patients: cases=374, controls=332
• Cases: Coronary heart disease (CHD)= 218
: Ischemic stroke (IS)= 109
: Peripheral artery disease (PAD)= 47
• Age: <45 years old in male, <55 years old in
 Genotyping of ADAMTS13
 rs2301612
 rs2073932
 rs652600
 rs603551
female
• Blood collection: 1-3 months after the first
ischemic event
• Biochemical analysis
– vWF antigen measured by in-house ELISA
– vWF activity measured by in-house ELISA
– ADAMTS13 antigen and activity measured
by Technozym ADAMTS13 kit
 The genotype assays
determined by allele-specific
Taqman analysis
Table 1: Baseline characteristics of case and control group
Table 2: Plasma ADAMTS13 antigen, ADAMTS13 activity, vWF antigen
and vWF;CB activity levels in all cases and controls.
Table 3: Relationship between levels of vWF, ADAMTS13 and risk on
cardiovascular disease
p<0.001
p<0.004
p<0.012
Figure 1: The relationship between low levels of ADAMTS13, high
levels of vWF and risk of cardiovascular disease.
OR 7.7, 95% CI 3.3-17.7, p<0.001
Individuals who were both in the highest tertile of ADAMTS13 and in the lowest tertile
of vWF were use as reference. *P<0.05; **p<0.001.
Subgroup analysis
Table 4: Plasma ADAMTS13 antigen and ADAMTS13 activity levels in
CHD subgroup and controls.
Individuals in the lowest tertile for ADAMTS13 antigen
have an eight times increased risk for CHD compared with
individuals in the highest tertile (OR 8.2, 95% CI 4.5-14.7)
Genetic variation of ADAMTS13
Table 5: ADAMTS13 gene polymorphisms in cases and controls
Genetic variation of ADAMTS13
Table 5: ADAMTS13 gene polymorphisms in cases and controls
14% lower activity in the
controls and 8% lower in the
cases compare with the CGAT ,
p=0.05
Haplotype GAAT was associated with a decreased
risk of PAD (OR 0.5,95% CI 0.3-1.0, p=0.06)
Discussion
Levels of ADAMTS13 are lower and levels of vWF are
higher in young patients with CVD.
Low levels of ADAMTS13 are associated with a higher
risk of cardiovascular disease. The relationship was
strongest in the subgroup of patients with CHD(OR
8.2, 95% CI 4.5-14.7, p<0.001).
Individuals who have the lowest levels of ADAMTS13
combined with the highest levels of vWF have the
highest risk of CVD.
Discussion
The lowest levels of ADAMTS13 were seen in
haplotype GAAT that associated with the risk of PAD.
To confirm this association, the larger studies
are required.
Genetic variation in ADAMTS13 does not play a
major role in the reduction of ADAMTS13 levels
found in patients with CVD.
Conclusion
Reduced levels of ADAMTS13 are associated
with an increased risk of cardiovascular
disease, but the genetic variation does not
play a major role.
Thank you for
your attention