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Platelet Glycoprotein lb a HPA-2 Met/VNTR B Haplotype as a Genetic Predictor of Myocardial Infarction and Sudden Cardiac Death

October 2, 2001

Reviewed by:

Andrea E. Cassidy and Patricia A. Peyser
Department of Epidemiology, School of Public Health
University of Michigan

The Health Outcome

Coronary heart disease (CHD) is one of the leading causes of morbidity and mortality in the developed world.  This disease often strikes without warning.  One-half of sudden coronary deaths (SCDs) and one- half of first myocardial infarctions (MIs) occur in people who have had no previous symptoms (1).  Atherosclerosis is the major cause of CHD and is influenced by the complex interplay of numerous environmental and genetic factors (2). Individual gene effects are thought to be relatively small, with many depending on environmental and genetic contexts. Several CHD risk factors, including measures of lipid metabolism, obesity, and blood pressure, have a genetic basis.  Such known risk factors for CHD, however, fail to identify a large proportion of SCDs and MIs (3).  Since the increased risk of CHD associated with family history of disease persists even after controlling for these risk factors, there are additional genetic mechanisms for susceptibility to CHD yet to be identified.


The Finding

Platelet glycoprotein Ib alpha (GP Ib alpha) forms a complex with GP Ib beta, GP IX, and GPV. GP Ib alpha is the primary receptor for von Willebrand factor and contains a high-affinity binding site for thrombin.  GP Ib alpha also plays a role in platelet adhesion and platelet aggregation.  Two polymorphisms of GP Ib alpha exist that affect the structure of the protein.  The first polymorphism, the HPA-2 system, is determined by a C-to-T substitution at position 3550, which results in an amino acid switch of threonine to methionine.  The second polymorphism is a variable number of tandem repeats of 13 amino acids that alter the molecular weight of the protein; there are four possible repeat lengths (A, B, C, and D, with each differing by 39 bases pairs).  The largest repeat length is the A form and the smallest is the D form.  Previous studies have demonstrated that the VNTR and HPA-2 polymorphisms are in nearly complete linkage disequilibrium (4).  This linkage disequilibrium makes it impossible to identify which polymorphism is responsible for an increased risk of disease. Previous studies present inconsistencies in the relation between GP Ib alpha polymorphisms and various manifestations of cardiovascular disease.  Several studies have reported an association between the HPA polymorphism and cerebrovascular disease (5,6), CHD (6), and ischemic stroke (7).  These studies have also reported that the VNTR polymorphism is associated with an increased risk of cerebrovascular disease and CHD (6).  Other studies have found no association between the VNTR polymorphism and acute stroke (8) or between the HPA polymorphism and MI (9).

Mikkelsson et al. (10) report an association between the HPA-2 Met/VNTR B haplotype of GP Ib alpha and SCD, acute MI, and coronary thrombosis among middle-aged men younger than 55 years of age.  The study consisted of 700 men who were part of two series of the Helsinki Sudden-Death Study. The men underwent a medicolegal autopsy at the Department of Forensic Medicine, University of Helsinki , in the years 1981 to 1982 (n=400) and 1991 to 1992 (n=300). The frequency of the Met allele was found to be higher in men younger than 55 years of age with SCD (odds ratio [OR] 2.2; 95% confidence interval [CI] 1.3 to 3.7), coronary thrombosis (OR 9.2; 95% CI 2.4 to 35.0), and acute MI (OR 5.6; 95% CI 1.8 to 17.3) compared to controls younger than 55 years of age.  The frequency of this allele was not significantly higher in men older than 55 years of age with these outcomes compared to controls of the same age. Thus, a significant age-genotype interaction for SCD, coronary thrombosis, and acute MI was also found.


Public Health Implications

As the authors state, one of the most important risk factors of CHD is having a relative with CHD.  The association of the HPA-2 Met/VNTR B haplotype of GP Ib alpha to SCD, acute MI, and coronary thrombosis in early middle-aged men may be a potential marker for inherited risk of CHD among such men.  If the first presentation of CHD for many individuals is SCD, identification of a gene that places individuals at higher risk for SCD, especially in the context of family history of disease, may enable physicians to direct more rigorous preventive therapies at higher-risk individuals.  It is important to replicate these findings in prospective studies of diverse populations, especially given the fact that the allele frequencies of the VNTR polymorphism vary among populations (4).

References

  1. Devereux RB, Alderman MH. Role of preclinical cardiovascular disease in the evolution from risk factor exposure to development of morbid events. Circulation 1993;88:1444-5.
  2. Peyser PA. Genetic epidemiology of coronary artery disease. Epidemiol Rev 1997;19:80-90.
  3. Grover SA, Coupal L, Hu XP. Identifying adults at increased risk of coronary disease. How well do the current cholesterol guidelines work? JAMA 1995;274:801-6.
  4. Corral J, Gonzalez-Conejero R, Lozano ML, Rivera J, Vicente V. New alleles of the platelet glycoprotein Ib alpha gene. Br J Haematol 1998;103:997-1003.
  5. Sonoda A, Murata M, Ito D, Tanahashi N, Ohta A, Tada Y, Takeshita E, Yoshida T, Saito I, Yamamoto M, Ikeda Y, Fukuuchi Y, Watanabe K. Association between platelet glycoprotein Ib alpha genotype and ischemic cerebrovascular disease. Stroke 2000;31:493-7.
  6. Gonzalez-Conejero R, Lozano ML, Rivera J, Corral J, Iniesta JA, Moraleda JM, Vicente V. Polymorphisms of platelet membrane glycoprotein Ib alpha associated with arterial thrombotic disease. Blood 1998;92:2771-6.
  7. Baker RI, Eikelboom J, Lofthouse E, Staples N, Afshar-Kharghan V, Lopez JA, Shen Y, Berndt MC, Hankey G. Platelet glycoprotein Ib alpha Kozak polymorphism is associated with an increased risk of ischemic stroke. Blood 98:36-40.
  8. Carter AM, Catto AJ, Bamford JM, Grant PJ. Platelet GP III Pl A and GP Ib variable number tandem repeat polymorphisms and markers of platelet activation in acute stroke. Arterioscler Thrombosis Vasc Biol 1998;18:1124-31.
  9. Ardissino D, Mannucci PM, Merlini PA, Duca F, Fetiveau R, Tagliabue L, Tubaro M, Galvani M, Ottani F, Ferrario M, Corral J, Margaglione M. Prothrombotic genetic risk factors in young survivors of myocardial infarction. Blood 94:46-51.
  10. Mikkelsson J, Perola M, Penttila A, Karhunen PJ. Platelet glycoprotein Ib alpha " HPA-2 Met/VNTR B haplotype as a genetic predictor of myocardial infarction and sudden cardiac death. Circulation 2001;104:876-80.
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