High levels of LDL cholesterol (LDL-c) and low levels of HDL cholesterol (HDL-c) are independent risk factors for coronary artery disease (CAD). During the mentored phase of this award, we have identified 59 novel regions associated with lipid levels (Teslovich et al., 2010). We are continuing our research to identify novel genes and genetic regions associated with lipid levels through several strategies, several of which are extensions to successful aims from the Mentored Phase of this award. We will continue to test for association in a GWAS framework by testing the most promising 5,000 genetic variants in 100,000 additional samples. We are also involved in the analysis ofthe Exome Sequencing Project of NHLBI which has completed whole exome sequencing of 417 samples, all from the upper or lower 1% tails ofthe LDL-c distribution. Identification of novel, highly disruptive genetic mutations may provide valuable clues about which gene in a potentially large region may be involved in lipid metabolism, a reversal of the typical paradigm to identify common variants in genes that contain rare disruptive mutations for related Mendelian disorders. For the independent phase of this award, experiments designed to understand the functional basis of previously identified genetic signals will be undertaken, including aligning genetic variants that play a role in lipid levels with position of known transcription factor binding sites from publicly-available Chip-Seq data.
The final aim for the independent phase ofthe award is to use information from the 1000 Genomes Project to impute and test ~10 million SNPs for association with lipid levels, catalog associated variants in associated regions and refine signatures of long-range regulatory elements.

Public Health Relevance

The identification of novel genes and functional elements associated with HDL-cholesterol, LDL-cholesterol and triglyceride levels is likely to have a significant impact on our understanding of the mechanisms of heart disease and has the potential to lead to new treatments.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Transition Award (R00)
Project #
5R00HL094535-04
Application #
8309055
Study Section
Special Emphasis Panel (NSS)
Program Officer
Papanicolaou, George
Project Start
2011-08-01
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
4
Fiscal Year
2012
Total Cost
$243,514
Indirect Cost
$73,352
Name
University of Michigan Ann Arbor
Department
Biostatistics & Other Math Sci
Type
Schools of Public Health
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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Lange, Leslie A; Hu, Youna; Zhang, He et al. (2014) Whole-exome sequencing identifies rare and low-frequency coding variants associated with LDL cholesterol. Am J Hum Genet 94:233-45
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(2013) Identification of heart rate-associated loci and their effects on cardiac conduction and rhythm disorders. Nat Genet 45:621-31
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