الفهرس 
IntroductionOnly 14 pages are availabe for public view
 |  | from | 156 |  |  |
| | | from | 156 | | |
Abstract
Introduction & rational
Introduction and Rational
Coronary artery disease (CAD) is the leading cause of cardiovascular
mortality worldwide, with >4.5 million deaths occurring in the developing world.
(Okrainec et al., 2004).
Between 1999 and 2020, the proportion of worldwide deaths from
cardiovascular disease is projected to increase from 28.9% to 36.3%, accounting
for more than one-third of deaths throughout the world. (Murray et al., 1996).
Given that myocardial infarction (MI) is a leading cause of death in the
Western world and markedly impairs the quality of life by causing heart failure or
refractory arrhythmias, prevention of this disease is an important public health goal
(Yamada et al., 2002).
In Egypt and other developing countries, there is a definite increase in the
incidence of CAD. In a hospital based survey at Cairo University, Cardiology
Department, a decline in University hospital admissions of rheumatic valvular
heart diseases and an increase in number ofhospitalizations secondary to CAD and
its sequelae. were detected (lbrahim, 1998).
MI is a complex multifactorial and polygenic disorder that is thought to
result from an interaction between a person’s genetic makeup and various
environmental factors (Marenberg et al., 1994).
The incidence of M[ increases additively as a function of the number of
conventional risk factors, including hypertension, diabetes mellitus, and
hypercholesterolemia (Nora et al., 1980). Although each risk factor itself is partly
under genetic control, a family history of MI is also an independent predictor,
suggesting the existence of additional susceptibility genes for this condition
” (Marenberg et al., 1994).
Introduction & rational
Furthermore, some patients who have had MI do not have any conventional
risk factors, suggesting the contribution of an uncharacterized genetic component
(Yamada et al., 2002).
The genetic defect(s) underlying a hereditary predisposition for MI has been
frustratingly difficult to identify and corroborate (Zwicker et al, 2006).
Several genetic studies have associated members of the thrombospondin
(TSP) gene family with premature cardiovascular disease (Kato et al., 2003,
Peyvandi et al., 2003, Wessel et al., 2004).
Thrombospondin was first described by Baenziger et al. (1972) as a
”thrombin sensitive platelet protein” secreted from blood platelets upon stimulation
by thrombin.
Since then an even increasing number of cell types were reported to produce,
secrete and weave TSP into the extracellular matrix in culture. These cells include
endothelial cells and fibroblasts in addition TSP was found in basement membrane
of tissues in vivo. Thus from a platelet- specific protein associated with platelet
activation, it became a widespread protein associated with the extracellular matrix
(Lahav. 1993).
The initial clue that TSP might be implicated in MI came from the first
large-scale application of new, high throughput strategies for gene analysis to
cardiac patients. In GeneQuest study, that test relationships between a large
number of single nucleotide polymorphisms (SNPs) in multiple candidate genes
and coronary artery disease or MI .The 3 SNPs that had statistically significant
associations with MI resided in genes of 3 different members of the TSP, the
likelihood that 3 members, TSP-l, TSP-2, and TSP-4, of the 5-memberTSP family
would have a disease association by chance is extremely remote (P < 10-5) (Stenina .
et al., 2007).
Introduction & rational
TSPs constitute a group of five structurally related extracellular matrix
proteins (TSP-1-5) that affect processes as disparate as synaptogenesis in the
developing central nervous system and aggregation of activated platelets in
homeostasis ( Koch et al., 2008).
The TSP-2 gene is located on chromosome 6q27 (Topol et al., 2001).
The mechanism by which TSP-2 affects atherosclerosis may involve the
regulation of matrix metalloproteinase-2, a protein linked to the vulnerability of
atherosclerotic plaque. T P2-null fibroblasts produce a 2-fold quantity of this
protein, which was shown to be lower in CAD patients than in controls (Noji et al.,
2001).
TSP-2 has chemotactic and mitogenic activities for vascular smooth muscle
cells. activities also displayed by TSP-l. These common functions may be central
to the roles of the thrornbospondins in coronary artery disease and myocardial
infarction (Stenina et al .. 2007).
TSP-2 S P T3949G, which is located in an 3’untranslated region of TSP-2
mRNA and may affect the processing/translation ofmR A and the protein level as
a result, is protective from III and exerts its effect in a recessive manner (only TT
genotype is protective) (Adams. 2001).
The TSP-4 gene is located on chromosome 5q13 (Topol et al.,
2001).Functions ascribed to the TSP-4 protein are limited and include its capacity
to support myoblast adhesion (Adams and Lawler, 1994), neurite outgrowth (Arber
and Caroni, 1995) and interaction with collagenous and non-collagenous matrix
proteins (Narouz-Ott et al., 2000).
TSP-4 mR A is detected in both embryonic and adult rat heart and
neuromuscular tissue, and these same adult human tissues express transcripts. TSP-
4 protein expression was demonstrated in bovine tendon and rat tissues. mRNA for
TSP-4 is expressed by endothelial and smooth muscle cells in vascular wall, and
Introduction & rational
brain endothelial cells produce the protein both in vivo and in cell culture,
localization consistent with its pro-atherogenic effects (Stenina et al., 2004).
THBS-4 appears to be more specific to cardiac and skeletal muscle.
Recently, a variant in exon 9 (G29926C) of the TSP-4 gene (located on
chromosome 5q13), leading to a missense variant A387P, was associated strongly
with the presence of CAD and MI in an American population, and those with the
TSP-4 variant 387P had an 89%greater risk of a heart attack (Zhou et al., 2004).
This variant in the coding region of THBS-4 gene, 1186GNC (A387P)
(rs 1866389), is predicted to affect folding and secretion of the protein and
disruption of the calcium binding site and may affect the cellular dynamics of the
vessel wall. The inhibitory effects of the THBS-4 1186GNC on endothelial cell
repair functions, coupled with its stimulatory effects on smooth muscle cell, may
predispose the vasculature to the initiation and development of atherosclerotic
lesions (Cui et al., 2004).
TSP-4 regulates the functions of endothelial and smooth muscle cells and
that P387 can affect the function of TSP-4. The P387 TSP-4 exerts a ”gain-of-
function” activity, interfering with endothelial cell adhesion and proliferation. The
inhibitory effects of the P387 TSP-4 on endothelial cell repair functions, critical to
maintain vessel wall integrity and function, coupled with the stimulatory effects of
TSP-4 on smooth muscle cell proliferation, a key event in development of
atherosclerotic lesion, can account for the association with coronary artery disease
(Stenina et af, 2003). Moreover, although the adhesion of neutrophils is equally
supported by both TSP-4 variants, neutrophil activation is more robust in presence
of P387 (TSP-4). This observation suggests that P387 (TSP-4) could play a role in
inflammatory processes in the vascular wall (Stenina et al, 2007).
The original results about the association between SNPs in TSP genes and
MI were not consistently corroborated in replication studies. The GG genotype of
Introduction & rational
the SNP in THBS2 has been linked with a higher or lower risk of MI than the TT
genotype (Topol et aI, 2001; Boekholdt et al., 2002; McCarthy et al., 2004;
Morgan et al., 2007), and the CC genotype of the SNP in THBS4 has been
implicated with a higher or lower risk ofMI than the GG genotype (Wessel et al.,
2004; Cui et al., 2006; Boekholdt et al., 2002; Cui et al., 2004). Alternatively, the
GC genotype of the SNP in THBS4 has been connected with MI (Topol et aI,
2001; McCarthy et al., 2004) or an association was not found (Morgan et al., 2007;
Asselbergs et al., 2006; Zhou et al., 2004; Hirashiki et al., 2003).
Because of the potential importance of TSPs in thrombotic disease and
existing uncertainty about the effect of variations in their genes on the risk of MI,
we have determined the genotypes related to the SNPs in THBS2, and THBS4 in a
case-control study.