Apo(a) isoforms predict risk for coronary heart disease. A study in six populations.

Abstract

Elevated concentrations of lipoprotein(a) (Lp[a]) in plasma are associated with premature coronary heart disease (CHD). Lp(a) levels are largely determined by alleles at the hypervariable apolipoprotein(a) (apo[a]) gene locus, but other genetic and environmental factors as well as diseases also affect plasma Lp(a) concentrations. It is therefore unclear whether Lp(a) is a primary genetic risk factor or whether Lp(a) levels are elevated secondary to disease in CHD patients. We have analyzed apo(a) phenotypes that represent a stable genetic trait in subjects with CHD and control subjects from different populations representing a variety of ethnic groups (Tyrol, Germany, Wales, Israel, Singapore Chinese, and Singapore Indian). Despite differences in sampling design and disease definition in this multipopulation case-control study, those apo(a) isoforms associated with high Lp(a) plasma concentrations (B, S1, and S2) were more frequent in the CHD patients in each ethnic group. These differences were significant in three of the studied populations and highly significant (p < 0.001) in the pooled (total) group. Lp(a) concentrations were also measured in all groups except Germans and were found to be consistently higher in cases than in control subjects in each ethnic group. For all but one population (Israeli) the differences were significant. The effects of the apo(a) size polymorphism on Lp(a) levels were similar in CHD patients and control subjects from different populations. The data demonstrate that alleles at the apo(a) locus determine the risk for CHD through their effects on Lp(a) concentrations across multiple populations with large differences in CHD frequency and risk factor profiles.

High Levels of Lp(a) With a Small Apo(a) Isoform Are Associated With Coronary Artery Disease in African American and White Men

“…26 Elevated Lp(a) levels were defined as Ն30 mg/dL (Ն72 nmol/L). [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][17][18][19][20][21][22][23][24] …”

“…The possibility that size variation of apo(a) could be associated with cardiovascular disease has been raised in previous studies, although the results have been inconsistent. 7,[17][18][19][20][21][22][23][24][31][32][33] In several of these studies, only a limited number of apo(a) size isoforms were resolved. 22,23,32 Subsequently, a high-resolution technique allowing separation of Ͼ34 differently sized apo(a) isoforms was introduced.…”

“…27 Apo(a) isoforms were classified as being either of small size (Ͻ22 K4 repeats) or large size (Ն22 K4 repeats). [17][18][19][20][21][22][23][24] To validate the apo(a) isoform size determination, we performed genotyping of apo(a) allele sizes by pulsed field electrophoresis. 28 Overall, there was an excellent agreement between the phenotyping and genotyping procedures (rϭ0.997).…”

“…[17][18][19][20][21][22][23][24] In the majority of studies using high-resolution sizing techniques, small apo(a) size has been defined as Ͻ22 kringle 4 (K4) repeats. 17,18,24 The majority of whites with high Lp(a) levels possesses at least 1 small apo(a) isoform; however, the majority of African Americans with high Lp(a) levels has no small apo(a) isoform. 25 The high degree of correlation between elevated levels of Lp(a) and small apo(a) isoforms in whites makes it difficult to ascertain whether one is a confounder for the other regarding CAD.…”

Is apolipoprotein(a) a susceptibility gene for Type I diabetes mellitus and related to long-term survival?

“…Since phenotypes with 11±16 or more than 34 K±IV repeats in the smaller apo(a) isoform were underrepresented, we formed one group by combining 11±19 and one by combining more than 31 K±IV repeats. In a further step, we divided apo(a) phenotypes in two subgroups according to the molecular weight of the smaller apo(a) iso-forms, as done in all of our and some of others previous works [3,4,8,30,32,33]. The low molecular weight group (LMW) included all subjects with at least one apo(a) isoform with 11 to 22 K±IV repeats [29]; the high molecular weight (HMW) group comprised all subjects who had only isoforms with more than 22 K±IV repeats.…”