Homozygous familial hypercholesterolaemia nearly doubles Lp(a) compared to heterozygotes, showing a clear LDL receptor gene-dose effect, a study of 69 family members (Arterioscler Thromb Vasc Biol 2000)

Original title: Lipoprotein(a) in homozygous familial hypercholesterolemia

Arterioscler Thromb Vasc Biol · 1 February 2000 · 7

Kraft HG, Lingenhel A, Raal FJ, Hohenegger M, Utermann G

This study examined how LDL receptor (LDL-R) gene mutations affect Lp(a) levels in 69 members of 22 families with familial hypercholesterolaemia (FH), including 26 homozygotes and 43 heterozygotes for FH, genotyped for LDL-R mutations, apo(a) alleles and isoforms. Confirming prior findings, FH heterozygotes had significantly higher Lp(a) than non-FH individuals, and FH homozygotes with two nonfunctional LDL-R alleles had almost twice the Lp(a) levels of heterozygotes, a difference not explained by apo(a) allele frequency differences. Comparing 40 identical-by-descent apo(a) allele pairs, those from individuals with two defective LDL-R alleles had significantly higher Lp(a) than those with only one defective allele, consistent across the full range of apo(a) allele sizes. The findings demonstrate a clear gene-dosage effect of LDL-R mutations on Lp(a) plasma concentrations.

Original abstract

Lipoprotein(a) [Lp(a)] is a quantitative genetic trait that in the general population is largely controlled by 1 major locus-the locus for the apolipoprotein(a) [apo(a)] gene. Sibpair studies in families including familial defective apolipoprotein B or familial hypercholesterolemia (FH) heterozygotes have demonstrated that, in addition, mutations in apolipoprotein B and in the LDL receptor (LDL-R) gene may affect Lp(a) plasma concentrations, but this issue is controversial. Here, we have further investigated the influence of mutations in the LDL-R gene on Lp(a) levels by inclusion of FH homozygotes. Sixty-nine members of 22 families with FH were analyzed for mutations in the LDL-R as well as for apo(a) genotypes, apo(a) isoforms, and Lp(a) plasma levels. Twenty-six individuals were found to be homozygous for FH, and 43 were heterozygous for FH. As in our previous analysis, FH heterozygotes had significantly higher Lp(a) than did non-FH individuals from the same population. FH homozygotes with 2 nonfunctional LDL-R alleles had almost 2-fold higher Lp(a) levels than did FH heterozygotes. This increase was not explained by differences in apo(a) allele frequencies. Phenotyping of apo(a) and quantitative analysis of isoforms in family members allowed the assignment of Lp(a) levels to both isoforms in apo(a) heterozygous individuals. Thus, Lp(a) levels associated with apo(a) alleles that were identical by descent could be compared. In the resulting 40 allele pairs, significantly higher Lp(a) levels were detected in association with apo(a) alleles from individuals with 2 defective LDL-R alleles compared with those with only 1 defective allele. This difference of Lp(a) levels between allele pairs was present across the whole size range of apo(a) alleles. Hence, mutations in the LDL-R demonstrate a clear gene-dosage effect on Lp(a) plasma concentrations.

Summary written by lp-a.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.