Lipoprotein(a) in renal disease

Kronenberg, Florian; Utermann, Gerd; Dieplinger, Hans

doi:10.1016/s0272-6386(96)90026-8

Cited by 219 publications

(143 citation statements)

References 165 publications

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“…1 -4 There are few nongenetic influences on Lp(a) concentrations, 5 one of which is kidney disease. 6 We demonstrate in the present study that the effect of kidney disease and apo(a) genotype on Lp(a) plasma concentrations is not additive but multiplicative and hence fulfills the criteria for an interaction, which may be called a disease -gene interaction (Figure 4). Since the disease under study (endstage kidney disease) may have primary environmental (eg toxic) or genetic (eg polycystic kidney disease) causes, we conclude that a gene -environmental interaction or a gene -gene interaction may underlie the observed interaction with the kidney disease.…”

Section: Discussionmentioning

confidence: 53%

Apolipoprotein(a) isoform-specific changes of lipoprotein(a) after kidney transplantation

et al. 2003

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The atherogenic lipoprotein(a) (Lp(a)) is significantly increased in patients with kidney disease. Some studies in hemodialysis patients described this increase to be dependent on the genetic apolipoprotein(a) (apo(a)) isoforms. Only patients who express high molecular weight (HMW) apo(a) isoforms but not those with low molecular weight (LMW) isoforms show a relative increase of Lp(a) when compared to healthy controls matched for apo(a) isoforms. However, this was not confirmed by all studies. We therefore prospectively investigated the changes of Lp(a) deriving from each apo(a) isoform in heterozygotes following kidney transplantation. Lp(a) concentrations were measured by ELISA. To calculate the isoformspecific concentrations and the changes of Lp(a) deriving from each isoform, we densitometrically scanned the apo(a) bands from immunoblots before and after transplantation in 20 patients expressing two apo(a) isoforms. Of these, 10 patients expressed both an LMW and an HMW apo(a) isoform. The other 10 patients expressed only HMW isoforms. Densitometric scanning of apo(a) bands and calculation of isoform-derived Lp(a) concentrations clearly demonstrated that the decrease of Lp(a) following kidney transplantation is caused by changes in the expression of HMW apo(a) isoforms. In some patients, we observed an almost complete disappearance of the HMW apo(a) isoform after transplantation. This study clearly demonstrates that the changes of Lp(a) plasma concentrations in kidney disease depend on the genetically determined size of apo(a). This provides evidence for an interaction of apo(a) genetic variability and kidney function on Lp(a) concentrations.

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Section: Discussionmentioning

confidence: 53%

Apolipoprotein(a) isoform-specific changes of lipoprotein(a) after kidney transplantation

et al. 2003

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“…This not only confirmed our conclusions from the analysis of FH heterozygotes but also demonstrated a significant gene-dosage effect. Not only were Lp(a) concentrations higher in the combined FH homozygotes from the 20 families analyzed in the present study than in almost any other sample of the white population [only patients with nephrotic syndrome have been reported to have higher Lp(a) 28 ], but average Lp(a) concentrations were also significantly higher in the FH homozygotes (mean 49.9 mg/dL) than in the FH heterozygotes (mean 29.9 mg/dL) from the same families.…”

Section: Discussionmentioning

confidence: 57%

Lipoprotein(a) in Homozygous Familial Hypercholesterolemia

Kraft

Lingenhel

Raal

et al. 2000

ATVB

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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) ] plasma levels has been addressed in several studies in the past. 1-9 Because Lp(a) contains, in addition to apolipoprotein(a) [apo(a)], LDL (the principal ligand of the LDL-R), it was suggested that Lp(a) might be internalized and degraded via the LDL-R pathway. Consequently, it was postulated that Lp(a) concentrations should be increased in patients with familial hypercholesterolemia (FH), a condition caused by mutations in the LDL-R. 10 Several studies have focused on this theme, but conflicting results have been produced. One major reason for this dilemma might be the unique genetic control of Lp(a) levels.Unlike all other lipoproteins, Lp(a) levels show an extreme interindividual variability and are largely controlled by variation in 1 major gene, which is the structural gene for apo(a). 11,12 The apo(a) gene is highly polymorphic. One of the polymorphisms, the kringle IV (K-IV) polymorphism, which gives rise to the size polymorphism of the apo(a) protein, is responsible for a large part of the variation in Lp(a) plasma levels. In white populations, Ϸ50% of the variation in the Lp(a) concentration is explained by the number of K-IV repeats in the apo(a) allele. 11 The category of this effect is the same in every population studied to date, but the size of the ef...

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“…This should not be misinterpreted to mean that other genes and/or environmental factors may not have a significant impact on Lp(a) concentrations in certain subsets of the population. Examples for non-genetic effects are kidney failure 45 and for genetic effects disorders of lipoprotein metabolism including Abetalipoproteinaemia, familial LCAT deficiency, and familial defective apolipoprotein B. [46][47][48] The present analysis describes the situation in apparently healthy families/individuals.…”

Section: Discussionmentioning

confidence: 99%

Genetic control of lipoprotein(a) concentrations is different in Africans and Caucasians

et al. 1999

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Lipoprotein(a) (Lp(a)) represents a quantitative trait in human plasma associated with atherothrombotic disease. Large variation in the distribution of Lp(a) concentrations exists across populations which is at present unexplained. Sib-pair linkage analysis has suggested that the apo(a) gene on chromosome 6q27 is the major determinant of Lp(a) levels in Caucasians. We have here dissected the genetic architecture of the Lp(a) trait in Africans (Khoi San, South African Blacks) and Caucasians (Austrians) by family/sib-pair analysis. Heritability estimates ranged from h 2 = 51% in Blacks, h 2 = 61% in Khoi San, to h 2 = 71% in Caucasians. Analysis by a variance components model also demonstrated that the proportion of the total phenotypic variance explained by genetic factors is smaller in Africans (65%) than in Caucasians (74%). Importantly the sib-pair analysis clearly identified the apo(a) gene as the major locus in Caucasians which explained the total genetic variance. In the African samples the apo(a) gene accounted for only half the genetic variance. Together with previous results from population studies our data indicate that genetic control of Lp(a) levels seems to be distinctly different between Africans and Caucasians. In the former genetic factors distinct from the apo(a) locus and also non-genetic factors may play a major role.

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Lipoprotein(a) in renal disease

Cited by 219 publications

References 165 publications

Apolipoprotein(a) isoform-specific changes of lipoprotein(a) after kidney transplantation

Apolipoprotein(a) isoform-specific changes of lipoprotein(a) after kidney transplantation

Lipoprotein(a) in Homozygous Familial Hypercholesterolemia

Genetic control of lipoprotein(a) concentrations is different in Africans and Caucasians

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