APOLIPOPROTEIN(A) GENE ACCOUNTS FOR GREATER THAN 90-PERCENT OF THE VARIATION IN PLASMA LIPOPROTEIN(A) CONCENTRATIONS
APOLIPOPROTEIN(A) GENE ACCOUNTS FOR GREATER THAN 90-PERCENT OF THE VARIATION IN PLASMA LIPOPROTEIN(A) CONCENTRATIONS
复制标题
DOI：
10.1172/jci115855
复制
发表时间：
1992-07-01
影响因子：
15.9
通讯作者：
HOBBS, HH
中科院分区：
文献类型：
--
作者：
BOERWINKLE, E;LEFFERT, CC;HOBBS, HH
血浆脂蛋白（a）[Lp（a）]是一种附着载脂蛋白（a）[apo（a）]的低密度脂蛋白颗粒，个体之间的浓度差异很大。这些浓度差异是可遗传的，与载脂蛋白（a）基因中kringle 4重复序列的数量呈负相关。为明确血浆Lp（a）水平的遗传决定因素，检测了48个核心白种人家系的血浆Lp（a）水平和载脂蛋白（a）基因型。采用脉冲场凝胶电泳法对19种不同基因型的载脂蛋白（a）基因进行了分型。发现载脂蛋白（a）基因本身几乎可以解释血浆Lp（a）水平的所有遗传变异性。这一结论是通过分析血浆Lp（a）水平在兄弟姐妹共享零，一个，或两个载脂蛋白（a）基因是相同的血统（ibd）。携带两种apo（a）等位基因ibd的患者（n = 72）的血浆Lp（a）水平显著相似（r = 0.95），而不携带apo（a）等位基因的患者（n = 52）的血浆Lp（a）水平则不同（r = -0.23）。血浆Lp（a）浓度变异的91%与apo（a）基因有关。载脂蛋白（a）基因中kringle 4重复序列的数量占血浆Lp（a）水平个体间变异的69%，载脂蛋白（a）基因座上尚未确定的顺式作用序列占其余22%。在这些研究过程中，我们观察到一个新的apo（a）等位基因的重新产生，这一事件在376次减数分裂中发生一次。
Plasma lipoprotein(a) [Lp(a)], a low density lipoprotein particle with an attached apolipoprotein(a) [apo(a)], varies widely in concentration between individuals. These concentration differences are heritable and inversely related to the number of kringle 4 repeats in the apo(a) gene. To define the genetic determinants of plasma Lp(a) levels, plasma Lp(a) concentrations and apo(a) genotypes were examined in 48 nuclear Caucasian families. Apo(a) genotypes were determined using a newly developed pulsed-field gel electrophoresis method which distinguished 19 different genotypes at the apo(a) locus. The apo(a) gene itself was found to account for virtually all the genetic variability in plasma Lp(a) levels. This conclusion was reached by analyzing plasma Lp(a) levels in siblings who shared zero, one, or two apo(a) genes that were identical by descent (ibd). Siblings with both apo(a) alleles ibd (n = 72) have strikingly similar plasma Lp(a) levels (r = 0.95), whereas those who shared no apo(a) alleles (n = 52), had dissimilar concentrations (r = -0.23). The apo(a) gene was estimated to be responsible for 91% of the variance of plasma Lp(a) concentration. The number of kringle 4 repeats in the apo(a) gene accounted for 69% of the variation, and yet to be defined cis-acting sequences at the apo(a) locus accounted for the remaining 22% of the inter-individual variation in plasma Lp(a) levels. During the course of these studies we observed the de novo generation of a new apo(a) allele, an event that occurred once in 376 meioses.