Determinants de la concentració plasmàtica de la Lipoproteïna (a)en la malaltia cardiovascular.
Lipoprotein (a) is a class of lipoprotein particles resembling low density lipoprotein (LDL) in which apo B100 is covalently linked to a high polymorphic glycoprotein apolipoprotein termed apo(a).
Although the physiological function of Lp(a) is unknown, numerous epidemiological studies have shown that a high plasma concentration of Lp(a) represent an independent risk factor for the development of coronary heart disease, however some confusing results in some of this studies has been reported.
Apo(a) shares a high structural homology with plasminogen As plasminogen, apo(a) kringle domains contain Lysine Binding Site(s) (LBS) that interact with residues of lysine. Kringle IV10 of apo(a) is the primary LBS of Lp(a) and is associated with lesion formation on transgenic mice .
The purpose of this study was
· To examine de association of Lp(a) concentration, apo(a) size and Lp(a) lysine-binding site in patients with early onset heart diseases and age matched controls.
· Search for mutations in the apo(a) kringle IV10 which could alter the LBS activity of Lp(a)
· to investigate the decrease in Lp(a) values in samples from controls and patients with established cardiovascular disease that had been frozen for 5 years and to analyze the relationship between such decrease and the number of kringle IV repeats in the smallest and largest isoforms.
Blood was obtained from survivors of premature myocardial infarction and age matched controls, plasma was measured by immunoturbidimetry , apo(a) genotype was determined by pulsed-field gel electrophoresis, apo(a) phenotype by gel electrophoresis and immunoblotting, LBS activity was measured by a quantitative LBS-Lp(a) immunoassay as previously described. Detection of mutations and polymorphisms in kringle IV10 was revealed by PCR amplification and applying SSCP analysis to the product
Simo JM, Camps J, Vilella E, Gomez F, Paul A, Joven J. Instability of lipoprotein(a) in plasma stored at -70 degrees C: effects of concentration, apolipoprotein(a) genotype, and donor cardiovascular disease. Clin Chem. 2001 Sep;47(9):1673-8.
Simo JM, Joven J, Vilella E, Ribas M, Figuera L, Virgos C, Sundaram IM, Hoover-Plow J. Polymorphisms in human apolipoprotein(a) kringle IV-10 and coronary artery disease: relationship to allele size, plasma lipoprotein(a) concentration, and lysine binding site activity. J Mol Med. 2001 Jun;79(5-6):294-9.
Simo JM, Joven J, Vilella E, Ribas M, Pujana MA, Sundaram IM, Hammel JP, Hoover-Plow JL. Impact of apolipoprotein(a) isoform size heterogeneity on the lysine binding function of lipoprotein(a) in early onset coronary artery disease. Thromb Haemost. 2001 Mar;85(3):412-7.
· In the patients, Lp(a) concentration was higher, apo(a) size was smaller, and LBS activity higher in the small isoforms compared to the controls.
· We identified a novel mutation in a patient heterozygous for the mutation The mutation W81R previously identified in humans was not found in our sample, but the M75T mutation was frequent.. The genotype TT conferred a significant risk for myocardial infarction but was not associated with the LBS function of apo(a).
· During storage, mean Lp(a) decreased significantly in samples from patients but not in samples from controls This was not related to the kringle number and was limited to samples with initial plasma Lp(a) concentrations between 41 and 345 mg/L.
· This study suggests an association of high LBS activity in small isoforms of Lp(a) with disease in humans.
· W81R mutation if present is infrequent in Spanish population
· Plasma Lp(a) from patients is less stable than Lp(a) from controls, and the difference is not related to distribution of apo(a) genotypes but may be concentration-dependent. Differential sample stability may complicate the interpretation of several studies.
Advisor:Joven Maried, Jorge
School:Universitat Rovira i Virgili
Source Type:Master's Thesis
Keywords:departament de bioquímica i biotecnologia
Date of Publication:06/25/2003