Common Variants in 6 Lipid-Related Genes Discovered by High-Resolution DNA Melting Analysis and Their Association with Plasma Lipids
|John F. Carlquist1,2*, Jason T. McKinney3, Benjamin D. Horne1,2, Nicola J. Camp2, Lisa Cannon-Albright2, Joseph B. Muhlestein1,2,
Paul Hopkins2, Jessica L. Clarke1, Chrissa P. Mower1, James J. Park1, Zachary P. Nicholas1, John A. Huntinghouse1 and
Jeffrey L. Anderson1,2
|1Cardiovascular Department, Intermountain Healthcare, USA|
|2Department of Internal Medicine, University of Utah School of Medicine, USA|
|3Idaho Technology, Inc., Salt Lake City, UT, USA|
|Corresponding Author :||Dr. John F. Carlquist
Intermountain Healthcare Cardiovascular ResearchLaboratory
LDS Hospital, 8th Avenue & C Street, Salt Lake City, UT 84132, USA
E-mail: [email protected]
|Received May 02, 2011; Accepted July 06, 2011; Published July 10, 2011|
|Citation: Carlquist JF, McKinney JT, Horne BD, Camp NJ, Cannon-Albright L, et al. (2011) Common Variants in 6 Lipid-Related Genes Discovered by High-Resolution DNA Melting Analysis and Their Association with Plasma Lipids. J Clinic Experiment Cardiol 2:138. doi: 10.4172/2155-9880.1000138|
|Copyright: © 2011 Carlquist JF, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.|
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Background: Total cholesterol was among the earliest identified risk factors for coronary heart disease (CHD). We sought to identify genetic variants in six genes associated with lipid metabolism and estimate their respective contribution to risk for CHD.
Methods: For 6 lipid-associated genes ( LCAT, CETP , LIPC , LPL , SCARB1 , and ApoF ) we scanned exons, 5’ and 3’ untranslated regions, and donor and acceptor splice sites for variants using Hi-Res Melting® curve analysis (HRMCA) with confirmation by cycle sequencing. Healthy subjects were used for SNP discovery (n=64), haplotype determination/tagging SNP discovery (n=339), and lipid association testing (n=786).
Results: In 17,840 bases of interrogated sequence, 90 variant SNPs were identified; 19 (21.1%) previously unreported. Thirty-four variants (37.8%) were exonic(16 non-synonymous), 28 (31.1%) in intron-exon boundaries, and 28 (31.1%) in the 5’ and 3’ untranslated regions. Compared to cycle sequencing, HRMCA had sensitivity of 99.4% and specificity of 97.7%. Tagging SNPs (n=38) explained >90% of the variation in the 6 genes and identified linkage disequilibrium (LD) groups. Significant beneficial lipid profiles were observed for CETP LD group 2, LIPC LD groups 1 and 7, and SCARB1 LD groups 1, 3 and 4. Risk profiles worsened for CETP LD group 3, LPL LD group 4.
Conclusions: These findings demonstrate the feasibility, sensitivity, and specificity of HRMCA for SNP discovery. Variants identified in these genes may be used to predict lipid-associated risk and reclassification of clinical CHD risk.