High degree of genetic polymorphism in apolipoprotein(a) associated with plasma lipoprotein(a) levels in Japanese and Chinese populations

Abstract

We have developed a sensitive, high-resolutin method for the analysis of the apolipoprotein(a) [apo(a)] isoforms using sodium dodecyl sulfate (SDS)-agarose/gradient polyacrylamide gel electrophoresis. In an analysis of the genetic polymorphism of apo(a) isoforms and their relationship with plasma lipoprotein(a) [Lp(a)] levels in Japanese and Chinese, this method identified 25 different apo(a) isoforms and detected one or two apo(a) isoforms in more than 99.5% of the individuals tested. The apparent molecular weights of the apo(a) isoforms ranged from 370 kDa to 950 kDa, and 22 of the 25 different apo(a) isoforms had a higher molecular weight than of apo B-100. Studies on Japanese families confirmed the autosomal codominant segregation of apo(a) isoforms and the existence of a null allele at the apo(a) locus. The observed frequency distribution of apo(a) isoform phenotypes fit the expectations of the Hardy-Weinberg equilibrium in both the Japanese and Chinese populations. Our data indicate the existence of at least 26 alleles, including a null allele, at the apo(a) locus. The frequency distribution patterns of the apo(a) isoform alleles in Japanese and Chinese were similar to each other and also similar to that of apo(a) gene sizes reported in Caucasian American individuals. The average heterozygosity at the apo(a) locus was 92% in Japanese and 93% in Chinese. A highly significant inverse correlation was observed between plasma Lp(a) levels and the size of apo(a) isoforms in both the Japanese (r = 0.677, P = 0.0001) and the Chinese (r = -0.703, P = 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)

Associations Among Serum Lipoprotein(a) Levels, Apolipoprotein(a) Phenotypes, and Myocardial Infarction in Patients With Extremely Low and High Levels of Serum Lipoprotein(a)

“…Our finding that Lp(a) is an independent predictor for MI agrees with the results of most other recent studies, [14][15][16][17] except for 2 prospective studies. 18,19 Our finding that subjects with extremely high Lp(a) levels had small apo(a) isoforms and those with extremely low Lp(a) levels had large apo(a) isoforms confirms the findings of both our previous studies 11,12,32 and other studies 8,9,33 that an inverse relationship exists between apo(a) isoform size and plasma Lp(a) levels. Furthermore, this inverse relationship has been reported to be due to a difference in the rate of production, but not in the rate of catabolism, of Lp(a).…”

“…Apo(a) phenotyping was performed by the method of Kikuchi et al, 11 as we described previously. 12,13 …”

“…11 Approximately 75% of the subjects had a double band of apo(a), and the remaining subjects had a single band. An inverse relationship has been demonstrated between plasma Lp(a) concentrations and the size of apo(a), 8,11 and a smaller Lp(a) band was well correlated with Lp(a) levels in double-banded phenotypes. [11][12][13] High plasma levels of Lp(a) have been shown to be associated with myocardial infarction (MI), 14-17 although this association was not confirmed by 2 prospective studies.…”

“…An inverse relationship has been demonstrated between plasma Lp(a) concentrations and the size of apo(a), 8,11 and a smaller Lp(a) band was well correlated with Lp(a) levels in double-banded phenotypes. [11][12][13] High plasma levels of Lp(a) have been shown to be associated with myocardial infarction (MI), 14-17 although this association was not confirmed by 2 prospective studies. 18,19 Apo(a) size polymorphism has been shown to be inversely associated with the risk of coronary heart disease (CHD) in Jpn Circ J 1999; 63: 659 -665 (Received April 2, 1999; revised manuscript received May 24, 1999; accepted May 27, 1999 , age: 62±10 y) and control subjects (n=92, M/F: 53/39, age: 58±14 y) were classified into quintile groups (Groups I to V) according to Lp(a) levels.…”

“…13 However, the relation between apo(a) isoform size polymorphism and MI has rarely been studied, 23 and it would be interesting to determine whether, and how much, apo(a) isoform size polymorphism contributes to the increased serum Lp(a) levels in MI, because an inverse relation does exist between plasma Lp(a) levels and apo(a) size. 8,11 In the present study, we studied the associations among serum Lp(a) levels, apo(a) phenotyps, and MI. Because large differences in Lp(a) levels can be used to predict important associations, we initially targeted patients with MI as well as normal controls, and then selected the subjects with extremely low or high serum Lp(a) levels from among these.…”