Lipoprotein(a) (Lp(a)) is a plasma complex that consists of a single apolipoprotein(a) (Apo(a)) molecule covalently linked through a disulfide bond to a single apolipoprotein B-100 molecule together with cholesterol-rich lipid (Marcovina et al. in Handbook of lipoprotein testing Rifai et al. Eds.: AACC Press, Washington, D.C., 2000; p. 819). While the biological functions of Lp(a) in normal physiology remain uncertain, high levels of Lp(a) have been associated with increased cardiovascular risk and cardiovascular events such as myocardial infarction and stroke, particularly when LDL-C is also elevated (Berglund et al., Arterioscler Thromb Vasc Biol 24, 2219 (2004); Hobbs et al., Curr Opin Lipidol 10, 225 (1999); Danesh et al., Circulation 102, 1082 (2000); Ridker et al., JAMA 297, 611 (2007); Danik et al., JAMA 296, 1363 (2006)).
The apolipoprotein(a) locus is among the most polymorphic in the human genome. Apo(a) genetic variation has been associated with the wide range of Lp(a) levels and largely accounts for the heritability of Lp(a) (Broeckel et al., Nat Genet 30, 210 (2002); Boerwinkle et al., J Clin Invest 90, 52 (1992); Mooser et al., Am J Hum Genet 61, 402 (1997); Schmidt et al., Eur J Hum Genet 14 190 (2006)). Recently, several single nucleotide polymorphisms (SNPs) in the Apo(a) gene were identified and have been associated with cardiovascular disorders such as myocardial infarction and stroke and/or drug response such as response to statins (See U.S. Patent Application Publication US2005/0272054A1).
Subjects at increased risk of future cardiovascular events are often prescribed acetylsalicylic acid (aspirin) to reduce the risk of a cardiovascular event. However, acetylsalicylic acid is not effective in all subjects and the use of acetylsalicylic acid (aspirin) as primary prevention against cardiovascular events has been controversial, particularly in women, for whom there have been few data (Ridker et al., N Engl J Med 352, 1293; 2005).
Thus, there is a continuing need to improve pharmaceutical agent selection design and therapy. In that regard, SNPs can be used to identify patients most suited to treatment with particular pharmaceutical agents such as acetylsalicylic acid and/or other anti-platelet and/or antithrombotic agents (this is often termed “pharmacogenetics”). Similarly, SNPs can be used to exclude patients from certain treatments due to the patient's increased likelihood of developing toxic side effects or their likelihood of not responding to the treatment. By doing so, such SNPs could be useful in defining the benefit to risk ratio of a given intervention for individual subjects. Pharmacogenetics can also be used in pharmaceutical research to assist the drug development and selection process. (Linder et al., Clinical Chemistry, 43, 254 (1997); Marshall, Nature Biotechnology, 15, 1249 (1997); International Patent Application WO 97/40462, Spectra Biomedical; and Schafer et al., Nature Biotechnology, 16, 3 (1998)).