Tsai Michael Y, Johnson Craig, Kao W H Linda, Sharrett A Richey, Arends Valerie L, Kronmal Richard, Jenny Nancy Swords, Jacobs David R, Arnett Donna, O'Leary Daniel, Post Wendy
Laboratory Medicine & Pathology, University of Minnesota, Minneapolis, MN 55455, United States.
Atherosclerosis. 2008 Oct;200(2):359-67. doi: 10.1016/j.atherosclerosis.2007.12.038. Epub 2008 Feb 20.
The cholesteryl ester transfer protein (CETP) plays a key role in high-density lipoprotein (HDL) metabolism. Genetic variants that alter CETP activity and concentration may cause significant alterations in HDL-cholesterol (HDL-C) concentration; however, controversies remain about whether these genetic variants are associated with atherosclerosis. We genotyped the CETP R451Q, A373P, -629C/A, Taq1B, and -2505C/A polymorphisms in a cohort of Caucasian, Chinese, African-American, and Hispanic individuals within the Multi-Ethnic Study of Atherosclerosis. Genotypes were examined in relationship to HDL-C, CETP activity, CETP concentration, and three measures of subclinical cardiovascular disease (CVD): coronary artery calcium (CAC) measured by fast CT scanning, carotid intimal-medial thickness (IMT), and carotid artery plaque measured by ultrasonography. Carriers of the 451Q and 373P alleles have a significantly higher CETP concentration (22.4% and 19.5%, respectively; p<0.001) and activity (13.1% and 9.4%, respectively; p<0.01) and lower HDL-C (5.6% and 6.0%, respectively; p<0.05). The minor alleles of the R451Q and A373P polymorphisms are associated with the presence of CAC, even after adjusting for CVD risk factors and HDL-C (p=0.006 and p=0.01, respectively). The R451Q polymorphism is also associated with presence of carotid artery plaque (p=0.036). Polymorphism is associated with neither common nor internal carotid IMT. We confirmed that the -629A, Taq1B B2, and -2505A alleles are significantly associated with lower CETP concentration (20.8%, 25.0%, and 23.7%, respectively; p<0.001) and activity (14.8%, 19.8%, and 18.4%, respectively; p<0.001) and higher HDL-C concentration (9.7%, 11.5%, and 10.4%, respectively; p<0.01). However, we did not find any associations between these non-coding polymorphisms and subclinical CVD.
胆固醇酯转运蛋白(CETP)在高密度脂蛋白(HDL)代谢中起关键作用。改变CETP活性和浓度的基因变异可能会导致HDL胆固醇(HDL-C)浓度发生显著变化;然而,这些基因变异是否与动脉粥样硬化相关仍存在争议。我们在动脉粥样硬化多民族研究中,对一组白种人、中国人、非裔美国人和西班牙裔个体的CETP R451Q、A373P、-629C/A、Taq1B和-2505C/A多态性进行了基因分型。研究了这些基因型与HDL-C、CETP活性、CETP浓度以及亚临床心血管疾病(CVD)的三项指标之间的关系:通过快速CT扫描测量的冠状动脉钙化(CAC)、颈动脉内膜中层厚度(IMT)以及通过超声检查测量的颈动脉斑块。451Q和373P等位基因的携带者具有显著更高的CETP浓度(分别为22.4%和19.5%;p<0.001)和活性(分别为13.1%和9.4%;p<0.01),以及更低的HDL-C(分别为5.6%和6.0%;p<0.05)。即使在调整了CVD危险因素和HDL-C之后,R451Q和A373P多态性的次要等位基因仍与CAC的存在相关(分别为p=0.006和p=0.01)。R451Q多态性也与颈动脉斑块的存在相关(p=0.036)。多态性与颈总动脉或颈内动脉IMT均无关。我们证实,-629A、Taq1B B2和-2505A等位基因与显著更低的CETP浓度(分别为20.8%、25.0%和23.7%;p<0.001)和活性(分别为14.8%、19.8%和18.4%;p<0.001)以及更高的HDL-C浓度(分别为9.7%、11.5%和10.4%;p<0.01)相关。然而,我们未发现这些非编码多态性与亚临床CVD之间存在任何关联。