Shohet Ralph V, Vega Gloria L, Bersot Thomas P, Mahley Robert W, Grundy Scott M, Guerra Rudy, Cohen Jonathan C
Internal Medicine, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, USA.
Hum Mutat. 2002 May;19(5):536-42. doi: 10.1002/humu.10079.
Genetic association studies have been widely used to identify loci that influence plasma lipoprotein concentrations, but few of the associations reported have proved consistently reproducible across different study populations. This lack of consistency is a widely recognized limitation of association studies, and is often ascribed to inadequate statistical power, population substructure, and population-specific linkage disequilibrium. However, few studies have assessed the causes of variability underlying a given genotype-phenotype association. We have examined two possible sources of variability in the association between the -514 polymorphism in hepatic lipase (LIPC) and plasma HDL-C concentrations. First, we compared the association between this polymorphism and hepatic lipase activity in four populations. A single copy of the -514C allele was associated with a 10 mmol.hr(-1).l(-1) increase in hepatic lipase activity in white American and Turkish men but only approximately 5 mmol.hr(-1).l(-1) in Chinese and African-American men. Second, we tested the effects of a stanozolol-induced increase in hepatic lipase activity on plasma HDL-C concentrations in men with normal (< 150mg/dl) or elevated (150-300mg/dl) levels of plasma triglyceride. The increase in hepatic lipase activity was similar in the two groups, but the resulting decline in HDL-C levels was significantly greater in normolipidemic men. These data suggest that the effect of a polymorphism on gene expression can vary among individuals, and that the resulting phenotype may be further modified by interactions with other factors. Three novel LIPC polymorphisms were identified in the study (-1596insC, -2740A>G, and -2880G>C).
基因关联研究已被广泛用于识别影响血浆脂蛋白浓度的基因座，但所报道的关联中很少有在不同研究人群中被证明具有一致的可重复性。这种缺乏一致性是关联研究中一个广泛认可的局限性，通常归因于统计效力不足、人群亚结构以及人群特异性连锁不平衡。然而，很少有研究评估给定基因型 - 表型关联背后变异性的原因。我们研究了肝脂酶（LIPC）-514多态性与血浆高密度脂蛋白胆固醇（HDL-C）浓度之间关联变异性的两个可能来源。首先，我们比较了该多态性与四个群体中肝脂酶活性之间的关联。-514C等位基因的单拷贝与美国白人和土耳其男性肝脂酶活性增加10 mmol·hr⁻¹·L⁻¹相关，但在中国和非裔美国男性中仅约为5 mmol·hr⁻¹·L⁻¹。其次，我们测试了司坦唑醇诱导的肝脂酶活性增加对血浆甘油三酯水平正常（<150mg/dl）或升高（150 - 300mg/dl）男性血浆HDL-C浓度的影响。两组中肝脂酶活性的增加相似，但正常血脂男性中HDL-C水平的下降明显更大。这些数据表明，多态性对基因表达的影响在个体间可能有所不同，并且由此产生的表型可能会因与其他因素的相互作用而进一步改变。在该研究中鉴定出三个新的LIPC多态性（-1596insC、-2740A>G和-2880G>C）。
