Goodarzi Mark O, Wong Howard, Quiñones Manuel J, Taylor Kent D, Guo Xiuqing, Castellani Lawrence W, Antoine Heath J, Yang Huiying, Hsueh Willa A, Rotter Jerome I
Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Cedars-Sinai Medical Center, 8700 Beverly Boulevard., Becker B-128, Los Angeles, California 90048, USA.
J Clin Endocrinol Metab. 2005 Aug;90(8):4816-23. doi: 10.1210/jc.2005-0389. Epub 2005 May 31.
Haplotypes comprising six single nucleotide polymorphisms (SNPs) (intron 7 to intron 9) of the lipoprotein lipase (LPL) gene appear to influence risk for atherosclerosis and insulin resistance in Mexican-Americans.
Based on rodent studies, we hypothesized that these haplotypes are in linkage disequilibrium with functional variants in the 3' untranslated region of LPL, which is encoded by exon 10, and that these variants influence phenotype by altering LPL expression.
We sequenced exon 10 in subjects with divergent insulin sensitivity and divergent haplotypes. We also sequenced the other common LPL haplotypes. Variants identified by sequencing were genotyped in a large, family-based population along with the six SNPs spanning intron 7 to intron 9. We tested the potential functional significance of variation in exon 10 by evaluating association of haplotypes with post-heparin plasma LPL activity.
The study took place within the general community, with the Mexican-American Coronary Artery Disease Project cohort.
Participants included 847 subjects from 163 families.
We determined LPL haplogenotype and post-heparin plasma LPL activity.
Exon 10 sequencing identified 15 variants. Thirteen of these variants were genotyped in large-scale along with the six SNPs spanning intron 7 to intron 9. LPL haplotypes and their relative frequencies in Mexican-Americans were determined. The fourth most common haplotype based on 19 SNPs (haplotype 19-4) was associated with increased LPL activity as well as multiple phenotypes related to the metabolic syndrome.
These results support the possibility that variation in the 3' untranslated region of LPL affects LPL expression and activity, consequently influencing risk of atherosclerosis and insulin resistance, and provides important tools for further dissection of LPL regulation.
脂蛋白脂肪酶（LPL）基因包含六个单核苷酸多态性（SNP）（内含子7至内含子9）的单倍型似乎会影响墨西哥裔美国人患动脉粥样硬化和胰岛素抵抗的风险。
基于啮齿动物研究，我们推测这些单倍型与LPL 3'非翻译区的功能变异处于连锁不平衡状态，该区域由外显子10编码，并且这些变异通过改变LPL表达来影响表型。
我们对胰岛素敏感性不同和单倍型不同的受试者的外显子10进行了测序。我们还对其他常见的LPL单倍型进行了测序。通过测序鉴定出的变异与跨越内含子7至内含子9的六个SNP一起在一个大型的、基于家系的人群中进行基因分型。我们通过评估单倍型与肝素后血浆LPL活性的关联来测试外显子10变异的潜在功能意义。
该研究在普通社区内的墨西哥裔美国人冠状动脉疾病项目队列中进行。
参与者包括来自163个家庭的847名受试者。
我们确定了LPL单倍型和肝素后血浆LPL活性。
外显子10测序鉴定出15个变异。其中13个变异与跨越内含子7至内含子9的六个SNP一起进行了大规模基因分型。确定了墨西哥裔美国人中LPL单倍型及其相对频率。基于19个SNP的第四常见单倍型（单倍型19-4）与LPL活性增加以及与代谢综合征相关的多种表型有关。
这些结果支持LPL 3'非翻译区的变异影响LPL表达和活性，从而影响动脉粥样硬化和胰岛素抵抗风险的可能性，并为进一步剖析LPL调控提供了重要工具。
