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Associations of Genetic Variants in ATP-Binding Cassette A1 and Cholesteryl Ester Transfer Protein and Differences in Lipoprotein Subclasses in the Multi-Ethnic Study of Atherosclerosis

¹ Laboratory Medicine & Pathology, University of Minnesota, Minneapolis, MN; ² Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, MN; ³ Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD; ⁴ Departments of Medicine and Epidemiology, Schools of Medicine and Public Health, Columbia University, New York, NY; ⁵ Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, MN, and Department of Nutrition, University of Oslo, Oslo, Norway; ⁶ Laboratory for Clinical Biochemistry Research, Departments of Pathology and Biochemistry, College of Medicine, University of Vermont, Burlington, VT; ⁷ Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL; ⁸ Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, MD.

^aAddress correspondence to this author at 420 Delaware St. SE, Mayo Mail Code 609, Minneapolis, MN 55455-0392. Fax 612-625-1121; e-mail tsaix001{at}umn.edu.

Background: ATP-binding cassette A1 (ABCA1) and cholesteryl ester transfer protein (CETP) play important roles in the reverse cholesterol transport pathway. The associations of ABCA1 and CETP polymorphisms with lipoprotein subclasses have not been extensively studied.

Methods: We genotyped 2 ABCA1 and 5 CETP polymorphisms in 999 participants of the Multi-Ethnic Study of Atherosclerosis (MESA) and studied their associations with HDL and LDL subclass particle concentrations, measured by nuclear magnetic resonance spectroscopy.

Results: ABCA1 and CETP polymorphisms were associated with different and distinct changes in lipoprotein subclass concentrations. The ABCA1 1051G/A AA genotype, previously found to be associated with cardioprotective effects in this cohort, was associated with a 5.5% higher concentration of small HDL particles (P = 0.024). The CETP TaqIB B2B2, –2505C/A AA, and –629C/A AA genotypes, previously demonstrated to lack cardioprotective effects, were associated with 15.2%, 15.4%, and 11.7% higher HDL cholesterol concentrations, respectively, and 36.5%, 40.7%, and 25.4% higher large HDL particle concentrations (P < 0.0001). The minor alleles of the A373P and R451Q polymorphisms were associated with lower large HDL particle concentrations.

Conclusions: Our study of the influence of ABCA1 and CETP genetic variants on lipoprotein subclasses demonstrates the importance of interpreting lipoprotein subclasses within the context of the biochemical processes involved in the alterations. In the case of HDL, the study of subclass particle numbers and sizes may not be sufficiently informative. Assays for HDL function may be needed to supplement quantification of HDL cholesterol and HDL particle numbers and sizes.