Mooser V, Mancini F P, Bopp S, Pethö-Schramm A, Guerra R, Boerwinkle E, Müller H J, Hobbs H H
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, 75235, USA.
Hum Mol Genet. 1995 Feb;4(2):173-81. doi: 10.1093/hmg/4.2.173.
Most of the interindividual variations in plasma levels of lipoprotein(a) [Lp(a)] can be attributed to sequence differences linked to the apolipoprotein(a) [apo(a)] locus. Plasma levels of Lp(a) tend to be inversely related to the number of kringle 4 (K4)-encoding sequences in the apo(a) gene, but there are several exceptions to this general trend. Other aspects of the apo(a) gene, in addition to the number of K4 repeats, affect plasma levels of Lp(a). To identify sequences in the apo(a) gene that contribute to plasma Lp(a) levels, we characterized the relationship between a length polymorphism [(TTTTA)n] located 1.3 kb 5' of the first exon of the apo(a) gene, the number of K4 repeats in the gene, and the plasma levels of Lp(a). There was significant linkage disequilibrium between the number of TTTTA repeats and the number of K4 repeats. All of the apo(a) alleles with 11 TTTTA repeats contained fewer than 24 K4 repeats and were paradoxically associated with low plasma Lp(a) levels (< or = mg/dl). To determine whether this association was due to the effect of the 11 TTTTA copies on apo(a) gene transcription, we measured the ability of fragments containing 11 or eight TTTTA repeats to promote transcription when introduced into cultured human hepatocarcinoma cells. No difference was found in the transcriptional activity of the two fragments. The TTTTA repeat constitutes the first sequence polymorphism at the apo(a) locus, other than the number of K4 repeats, which is associated with plasma concentrations of Lp(a).
脂蛋白(a)[Lp(a)]血浆水平的个体间差异大多可归因于与载脂蛋白(a)[apo(a)]基因座相关的序列差异。Lp(a)的血浆水平往往与apo(a)基因中kringle 4(K4)编码序列的数量呈负相关，但这一普遍趋势存在一些例外。除了K4重复序列的数量外，apo(a)基因的其他方面也会影响Lp(a)的血浆水平。为了确定apo(a)基因中有助于血浆Lp(a)水平的序列，我们对位于apo(a)基因第一个外显子5'端1.3 kb处的长度多态性[(TTTTA)n]、该基因中K4重复序列的数量与Lp(a)的血浆水平之间的关系进行了表征。TTTTA重复序列的数量与K4重复序列的数量之间存在显著的连锁不平衡。所有具有11个TTTTA重复序列的apo(a)等位基因所含K4重复序列均少于24个，并且反常地与低血浆Lp(a)水平(<或=mg/dl)相关。为了确定这种关联是否是由于11个TTTTA拷贝对apo(a)基因转录的影响，我们在将含有11个或8个TTTTA重复序列的片段导入培养的人肝癌细胞时，测量了它们促进转录的能力。未发现这两个片段的转录活性有差异。TTTTA重复序列是apo(a)基因座上除K4重复序列数量之外的第一个与Lp(a)血浆浓度相关的序列多态性。
