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The identification and significance of a Thr-->Pro polymorphism in kringle IV type 8 of apolipoprotein(a).
- Source :
-
Thrombosis and haemostasis [Thromb Haemost] 1997 May; Vol. 77 (5), pp. 949-54. - Publication Year :
- 1997
-
Abstract
- Elevated plasma levels of lipoprotein(a) [Lp(a)] represent a significant independent risk factor for the development of atherosclerosis. Interindividual levels of apo(a) vary over 1000-fold and are mainly due to inheritance that is linked to the locus of the apolipoprotein(a) [apo(a)] gene. The apo(a) gene encodes multiple repeats of a sequence exhibiting up to 85% DNA sequence homology with plasminogen kringle IV (K.IV), a lysine binding domain. In our search for sequence polymorphisms in the K.IV coding domain, we identified a polymorphism predicting a Thr-->Pro substitution located at amino acid position 12 of kringle IV type 8 of apo(a). The functional and clinical significance of this polymorphism was analysed in a case-control study and by comparing the in vitro lysine binding characteristics of the two Lp(a) subtypes. The case-control study (involving 153 subjects having symptomatic atherosclerosis and 153 age and gender matched normolipidemic controls) revealed a overall allele frequency for the Thr12-->Pro substitution in kringle IV type 8 of 14% and a negative association between presence of the Pro12-subtype and symptomatic atherosclerosis (p < 0.03). The in vitro lysine binding studies, using Lp(a) isolated from subjects homozygous for either Thr12 or Pro12 in K.IV type 8, revealed comparable lysine-Sepharose binding fractions for the two subtypes. The binding affinity (Kd) for immobilised plasmin degraded des-AA-fibrin (Desafib-X) was also comparable for the two subtypes, however a decreased maximal attainable binding (Bmax) for immobilised desafib-X was observed for the Pro12-subtype Lp(a).
- Subjects :
- Adult
Arteriosclerosis blood
Arteriosclerosis epidemiology
Case-Control Studies
DNA Primers
Female
Humans
Lipoprotein(a) blood
Lipoprotein(a) chemistry
Male
Phenotype
Plasminogen chemistry
Plasminogen genetics
Polymerase Chain Reaction
Protein Structure, Secondary
Reference Values
Repetitive Sequences, Nucleic Acid
Risk Factors
Sequence Homology, Nucleic Acid
Arteriosclerosis genetics
Kringles
Lipoprotein(a) genetics
Polymorphism, Genetic
Proline
Threonine
Subjects
Details
- Language :
- English
- ISSN :
- 0340-6245
- Volume :
- 77
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Thrombosis and haemostasis
- Publication Type :
- Academic Journal
- Accession number :
- 9184408