Lipoprotein(a) in homozygous familial hypercholesterolemia
Lipoprotein(a) in homozygous familial hypercholesterolemia
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DOI：
10.1161/01.atv.20.2.522
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发表时间：
2000-02-01
影响因子：
8.7
通讯作者：
Utermann, G
中科院分区：
文献类型：
--
作者：
Kraft, HG;Lingenhel, A;Utermann, G
脂蛋白（a）[Lp（a）]是一种数量遗传性状，在一般人群中主要由1个主要位点控制-载脂蛋白（a）[apo（a）]基因位点。在包括家族性载脂蛋白B缺陷或家族性高胆固醇血症（FH）杂合子的家族中进行的同胞对研究表明，此外，载脂蛋白B和LDL受体（LDL-R）基因的突变可能会影响Lp（a）血浆浓度，但这一问题存在争议。在此，我们通过纳入FH纯合子进一步研究了LDL-R基因突变对Lp（a）水平的影响。分析了22个FH家族的69名成员的LDL-R突变以及载脂蛋白（a）基因型、载脂蛋白（a）亚型和Lp（a）血浆水平。26个个体被发现是FH纯合子，43个是FH杂合子。正如我们以前的分析，FH杂合子有显着较高的Lp（a）比非FH个人从同一人群。具有2个非功能性LDL-R等位基因的FH纯合子的Lp（a）水平几乎是FH杂合子的2倍。这种增加不能用apo（a）等位基因频率的差异来解释。apo（a）表型分析和家族成员亚型的定量分析允许将Lp（a）水平分配给apo（a）杂合子个体中的两种亚型。因此，可以比较与血统相同的apo（a）等位基因相关的Lp（a）水平。在得到的40个等位基因对中，与仅具有1个缺陷等位基因的个体相比，检测到与来自具有2个缺陷LDL-R等位基因的个体的apo（a）等位基因相关的Lp（a）水平显著更高。等位基因对之间Lp（a）水平的这种差异存在于apo（a）等位基因的整个大小范围内。因此，LDL-R突变对Lp（a）血浆浓度有明显的基因剂量效应。
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.