The identification and significance of a Thr-->Pro polymorphism in kringle IV type 8 of apolipoprotein(a).
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).
Prins
J
J
Department of Clinical Chemistry, University Hospital Utrecht, The Netherlands. j.prins@lab.azu.nl
Leus
F R
FR
van der Hoek
Y Y
YY
Kastelein
J J
JJ
Bouma
B N
BN
van Rijn
H J
HJ
D000328:Adult; D001161:Arteriosclerosis / Q000097:blood / Q000453:epidemiology / Q000235:genetics*; D016022:Case-Control Studies; D017931:DNA Primers; D005260:Female; D006801:Humans; D018082:Kringles; D017270:Lipoprotein(a) / Q000097:blood / Q000737:chemistry / Q000235:genetics*; D008297:Male; D010641:Phenotype; D010958:Plasminogen / Q000737:chemistry / Q000235:genetics; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D011392:Proline; D017433:Protein Structure, Secondary; D012016:Reference Values; D012091:Repetitive Sequences, Nucleic Acid; D012307:Risk Factors; D012689:Sequence Homology, Nucleic Acid; D013912:Threonine
D017931:DNA Primers; D017270:Lipoprotein(a); D013912:Threonine; D010958:Plasminogen; D011392:Proline