Elevated low density lipoprotein cholesterol (LDL-C) levels are associated with the development of cardiovascular disease (CVD), and management of LDL-C levels is a mainstay of CVD prevention. Attainment of LDL-C target goals through either lifestyle of pharmacologic means can be challenging. There is a need for the development of cheaper and better drugs. Through our genetic studies of cardiovascular health in the Amish, we recently identified a SNP that is strongly associated with LDL-C levels in a genomic region (chr 5q33, P=3.8 ? 10-11) that does not contain established cholesterol metabolism genes. Each copy of the risk allele is associated with a 16 mg/dl increase in LDL-C levels. We have established that the risk allele is carried on a single 300 kb haplotype and that all carriers of the associated allele share this same haplotype identical by descent, presumably through its introduction into the Amish population many generations ago by a single Amish founder. Although the putative defect is likely to be rare in non-Amish, identifying and characterizing it is expected to be of high significance because it will illuminate new lipid biology. The goal of the proposed study is to identify and characterize the functional variant and gene responsible for elevated LDL-C levels. We have already sequenced the entire 300 kb region and identified a small set of candidate SNPs. We propose in this application to: (1) genotype these SNPs in a non-Amish population and test each for association with LDL-C;(2) evaluate the function of the 7 genes in the associated region using zebrafish and cell-based models;and (3) establish the effects of the candidate SNPs already identified on gene function. Successful completion of these studies is expected to lead to the identification of a novel cholesterol metabolism gene and uncover new biology that may have translational appeal for the development of novel therapies to prevent and/or treat atherosclerosis.

Public Health Relevance

The overall goal of the proposed research is to identify a novel gene on chromosome 5q that has a marked influence on LDL cholesterol levels. Identifying and characterizing this gene could not only increase our understanding of the development of atherosclerosis, but point to a new therapeutic target to prevent and/or treat heart disease.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Cardiovascular and Sleep Epidemiology (CASE)
Program Officer
Liu, Lijuan
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Maryland Baltimore
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Geng, Xin; Irvin, Marguerite R; Hidalgo, Bertha et al. (2018) An exome-wide sequencing study of lipid response to high-fat meal and fenofibrate in Caucasians from the GOLDN cohort. J Lipid Res 59:722-729
Natarajan, Pradeep; Peloso, Gina M; Zekavat, Seyedeh Maryam et al. (2018) Deep-coverage whole genome sequences and blood lipids among 16,324 individuals. Nat Commun 9:3391
Montasser, May E; O'Hare, Elizabeth A; Wang, Xiaochun et al. (2018) An APOO Pseudogene on Chromosome 5q Is Associated With Low-Density Lipoprotein Cholesterol Levels. Circulation 138:1343-1355
Brody, Jennifer A; Morrison, Alanna C; Bis, Joshua C et al. (2017) Analysis commons, a team approach to discovery in a big-data environment for genetic epidemiology. Nat Genet 49:1560-1563
O'Hare, Elizabeth A; Yang, Rongze; Yerges-Armstrong, Laura M et al. (2017) TM6SF2 rs58542926 impacts lipid processing in liver and small intestine. Hepatology 65:1526-1542
O'Hare, Elizabeth A; Wang, Xiaochun; Montasser, May E et al. (2014) Disruption of ldlr causes increased LDL-c and vascular lipid accumulation in a zebrafish model of hypercholesterolemia. J Lipid Res 55:2242-53