Guerra R, Wang J, Grundy S M, Cohen J C
Department of Statistical Science, Southern Methodist University, Dallas, TX 75275-0332, USA.
Proc Natl Acad Sci U S A. 1997 Apr 29;94(9):4532-7. doi: 10.1073/pnas.94.9.4532.
Genetic factors strongly influence interindividual variation in plasma high density lipoprotein cholesterol (HDL-C) levels, but the specific genetic polymorphisms that confer heritable variation in HDL-C levels have not been identified. In this study we examined the relationship between polymorphism in LIPC, the gene encoding hepatic lipase, and plasma HDL-C concentrations using a sequential approach comprising linkage analysis, DNA sequencing, and association studies. Linkage studies in 1465 American white subjects from 218 nuclear families indicated that allelic variation at, or closely linked to, the hepatic lipase gene accounts for a significant fraction ( approximately 25%) of the variation in plasma HDL-C concentrations. The hepatic lipase gene was then sequenced in selected individuals, and four novel polymorphisms were identified in the 5' flanking region of the gene. These polymorphisms were in complete linkage disequilibrium and thus identified a single novel allele. Association studies indicated that heterozygosity for the rare allele was associated with modestly increased concentrations of plasma HDL-C (41 +/- 11 vs. 37 +/- 10 mg/dl, P < 0.05) and apolipoprotein AI in men (131 +/- 23 vs. 122 +/- 21 mg/dl, P < 0.05) but not in women. Homozygosity for the rare allele was associated with markedly higher plasma HDL-C (63 +/- 3 mg/dl) and apolipoprotein AI (153 +/- 9 mg/dl) concentrations in men. The results of the association study were replicated in a second, independently ascertained sample. Taken together, the results of the linkage and association studies provide strong evidence that genetic variation in hepatic lipase activity is a major determinant of plasma HDL-C levels.
遗传因素强烈影响血浆高密度脂蛋白胆固醇（HDL-C）水平的个体间差异，但尚未确定导致HDL-C水平遗传变异的具体基因多态性。在本研究中，我们采用连锁分析、DNA测序和关联研究的序贯方法，研究了编码肝脂酶的基因LIPC中的多态性与血浆HDL-C浓度之间的关系。对来自218个核心家庭的1465名美国白人受试者进行的连锁研究表明，肝脂酶基因处或与之紧密连锁的等位基因变异占血浆HDL-C浓度变异的很大一部分（约25%）。然后对选定个体的肝脂酶基因进行测序，在该基因的5'侧翼区域鉴定出四个新的多态性。这些多态性处于完全连锁不平衡状态，因此确定了一个单一的新等位基因。关联研究表明，罕见等位基因的杂合性与男性血浆HDL-C浓度适度升高（41±11 vs. 37±10 mg/dl，P<0.05）和载脂蛋白AI升高有关（131±23 vs. 122±21 mg/dl，P<0.05），而在女性中则不然。罕见等位基因的纯合性与男性血浆HDL-C（63±3 mg/dl）和载脂蛋白AI（153±9 mg/dl）浓度显著升高有关。关联研究的结果在第二个独立确定的样本中得到了重复。综合来看，连锁和关联研究的结果提供了强有力的证据，表明肝脂酶活性的遗传变异是血浆HDL-C水平的主要决定因素。
