Contribution of apolipoprotein(a) size, pentanucleotide TTTTA repeat and C/T(+93) polymorphisms of the apo(a) gene to regulation of lipoprotein(a) plasma levels in a population of young European Caucasians.
Several studies indicate that the inter-individual variation in plasma concentrations of lipoprotein(a) (Lp(a)) is mainly under genetic control. To define the effect of three DNA polymorphisms on apolipoprotein(a) (apo(a)) expression, we have determined plasma Lp(a) concentrations, apo(a) isoform size, KpnI allele size, the TTTTA pentanucleotide repeat number in the 5' control region of the apo(a) gene and the +93 C/T polymorphism in a European Caucasian population. The simultaneous determination of the kringle 4 (K4) number by genotyping and by phenotyping revealed that the size distribution of non-expressed apo(a) alleles was markedly skewed towards alleles with greater than 25 K4 repeats. This is consistent with the inverse relationship frequently described between the kringle 4 number and the plasma Lp(a) level. Apportioning the Lp(a) concentration from the surface of the peaks on apo(a) phenotyping blots, we have observed that the Lp(a) plasma concentration associated with alleles having more than 25 K4 units does not exceed 400 mg/l, whereas the range of Lp(a) concentrations associated with smaller alleles was broad, from 0 to more than 1000 mg/l. It can thus be concluded that the number of K4 repeats is the main determinant of Lp(a) concentration when this number is more than 25, whereas other polymorphisms may be involved in the alleles with fewer than 26 K4. Analyses of the TTTTA repeat number and of the +93 C/T polymorphism were performed in subjects with KpnI alleles of the same length: low Lp(a) concentrations were shown to be preferentially associated with the presence of apo(a) alleles with more than eight pentanucleotide repeats while no association was revealed between Lp(a) plasma levels and the C/T polymorphism. These results demonstrate that the (TTTTA)(n) polymorphism affects the Lp(a) expression independently of apo(a) size polymorphism.
Valenti
K
K
Laboratoire de Biochimie A, CHU de Grenoble, 38043, Grenoble, France.
Aveynier
E
E
Leauté
S
S
Laporte
F
F
Hadjian
A J
AJ
D000293:Adolescent; D000328:Adult; D000483:Alleles; D001053:Apolipoproteins / Q000235:genetics* / Q000378:metabolism; D053241:Apoprotein(a); D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D017270:Lipoprotein(a) / Q000097:blood*; D008297:Male; D018895:Microsatellite Repeats; D010641:Phenotype; D011110:Polymorphism, Genetic; D020033:Protein Isoforms / Q000235:genetics; D044465:White People / Q000235:genetics*
D001053:Apolipoproteins; D017270:Lipoprotein(a); D020033:Protein Isoforms; D053241:Apoprotein(a)