Servicio de Cardiología y Genética Molecular,
Hospital Central de Asturias,
Oviedo, Spain
To the Editor:
In a recent study published in your journal by Carter et
al,1 strong evidence was found of an association
between the PlA2 allele of the
glycoprotein IIb/IIIa gene and myocardial infarction in men
younger than 47 years old. In addition, a relationship of this
polymorphism with cholesterol levels and the extent of
coronary artery disease was also observed in
multivariate analyses.
Association of the PlA2 genotype and
coronary disease is controversial. After the original study of
Weiss et al2 reporting an association of
PlA2 and coronary disease, others failed
to find the same association.3 4
A study based on a population of 178 men younger than 50 years old and
diagnosed with coronary disease was recently performed by our
group in Spain. The prevalence of PlA2 was 24%
in case subjects compared with 26% in age- and sex-matched control
subjects. We also investigated whether the PlA2
allele was associated with other risk
factors.5 We found that 43 patients who were
PlA2 carriers showed significantly higher
concentrations of LDL cholesterol. For the 43
patients (24%) with the PlA2 allele, LDL
cholesterol was 4.3±1.9 mmol/L; for the 135 (76%)
who had the PlA1A1 allele, LDL
cholesterol was 3.7±0.9 mmol/L
(P=0.02).
Finally, we agree with these authors that differences in
PlA prevalence may represent either a
type I statistical error or differences in the phenotype
according to the studied populations. Furthermore, the association
between high LDL cholesterol levels and the
PlA2 allele could explain the relationship
found between this polymorphism and the extent of coronary
artery disease.
References
1.
Carter AM, Ossei-Gerning N, Wilson IJ, Grant PJ.
Association of the platelet PlA polymorphism of
glycoprotein IIb/IIIa and the fibrinogen Bß 448
polymorphism with myocardial infarction and extent of
coronary artery disease. Circulation. 1997;96:1424–1431.
2.
Weiss EJ, Bray PF, Tayback M, Schulman SP, Kickler TS,
Becker LC, Weiss JL, Gerstenblith G, Goldschmidt-Clermont PJ. A
polymorphism of a platelet glycoprotein receptor as
an inherited risk factor for coronary thrombosis. N
Engl J Med. 1996;334:1090–1094.
3.
Marian AJ, Brugada R, Kleiman NS. Platelet
glycoprotein IIIa PlA polymorphism and
myocardial infarction. N Engl J Med. 1996;334:1071–1072. Letter.
4.
Carter AM, Ossei-Gerning N, Grant PJ. Platelet
glycoprotein IIIa PlA polymorphism and
myocardial infarction. N Engl J Med. 1996;334:1072–1073. Letter.
5.
Batalla A, Reguero JR, Cubero GI, Coto E, Cortina A.
Polymorphisms of the platelet receptor IIIa and lipid levels in
early coronary disease.
Atherosclerosis. 1997;134:65.
Abstract.
Unit of Molecular Vascular Medicine,
Research School of Medicine,
University of Leeds,
Leeds General Infirmary,
Leeds, United Kingdom
As Batalla and colleagues point out, a number of studies have
failed to confirm the associations of PlA2 with
atherothrombosis observed by Weiss et al1 and
ourselves2 ; however, a recent study by Walter et
al3 described a significant association of
PlA2 with coronary stent thrombosis. The
identification of genetic risk factors for atherothrombosis is hampered
by complex interactions with a variety of environmental factors in the
pathogenesis of this disorder. These factors will cluster differently
in different populations, which may explain the inconsistent
findings with regard to PlA reported so far. Age
is an important factor to consider in genetic association studies
because it is likely that the greatest contribution of genetic factors
to the pathogenesis of atherothrombosis will be observed in young
subjects.4 However, potential interactions with
other classic risk factors should always be considered when the
associations of genetic polymorphisms with atherothrombosis
are analyzed.
We have found a significant interaction of PlA
with cholesterol in young subjects with myocardial
infarction,2 and similarly Batalla and colleagues
report higher levels of LDL cholesterol in
PlA2-positive individuals with coronary
artery disease than in PlA1 homozygotes. In
addition, in 505 subjects with acute atherothrombotic stroke and 435
healthy control subjects, we have found a significant association of
PlA2 with stroke in nonsmokers but no significant
association in smokers, as well as a 50% incidence of
PlA2 in those younger than 50 years of
age.5 In these subjects, we have also found a
significant association of the HPA-3 polymorphism of
glycoprotein IIb with poststroke mortality (A.M. Carter,
A.J. Catto, and P.J. Grant, unpublished observation, 1998). These
findings serve to highlight the potential role of polymorphisms of
glycoprotein IIb/IIIa in atherothrombosis, as well as the
importance of considering gene-environment interactions. Additional
knowledge of these interactions will help to target subjects most at
risk in whom more aggressive antiplatelet treatments could be
initiated.
© 1998 American Heart Association, Inc.
References
1.
Weiss EJ, Bray PF, Tayback M, Schulman SP, Kickler TS,
Becker LC, Weiss JL, Gerstenblith G, Goldschmidt-Clermont PJ. A
polymorphism of a platelet glycoprotein receptor as
an inherited risk factor for coronary thrombosis. N
Engl J Med. 1996;334:1090–1094.
2.
Carter AM, Ossei-Gerning N, Wilson IJ, Grant PJ.
Association of the platelet PlA polymorphism of
glycoprotein IIb/IIIa and the fibrinogen Bß 448
polymorphism with myocardial infarction and extent of
coronary artery disease. Circulation. 1997;96:1424–1431.
3.
Walter DH, Schachinger V, Elsner M, Dimmeter S, Zeiner
AM. Platelet glycoprotein IIIa polymorphism and
risk of coronary stent thrombosis. Lancet. 1997;350:1217–1219.[Medline]
[Order article via Infotrieve]
4.
Bray PF, Weiss EJ, Tayback M, Goldschmidt-Clermont PJ.
PlA1/A2 polymorphism of platelet
glycoprotein IIIa and risk of
cardiovascular disease. Lancet. 1997;349:1100–1101.
5.
Carter AM, Catto AJ, Bamford JM, Grant PJ.
Platelet GPIIIa PlA and GPIb variable number tandem
repeat (VNTR) polymorphisms and markers of platelet activation
in acute stroke. Arterioscler Thromb Vasc Biol. In
press.
© 1998 American Heart Association, Inc.
Correspondence
Platelet PlA Polymorphism, Myocardial Infarction, and Extent of Coronary Artery Disease
Response
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