Whereas treatment of low-density lipoprotein cholesterol (LDL-C) with statins reduces risk for coronary heart disease (CHD), a significant residual risk remains. This observation raises the following fundamental question: beyond LDL-C, which lipid pathway(s) affects risk for CHD in humans? We have accrued preliminary evidence showing that the lipoprotein lipase (LPL) pathway contributes to the development of CHD in humans. Common, low-frequency, and/or rare DNA sequence variants in lipoprotein lipase (LPL) and two genes encoding LPL regulating proteins (APOA5, APOC3) are associated with risk of CHD as well as plasma triglycerides (TG). For example, through exome sequencing, we discovered that 1 in 150 individuals carried one of four rare apolipoprotein C-III (APOC3) mutations, each leading to loss-of-function (LoF) (Crosby*, Peloso*, N Engl J Med, in press). Carriers of APOC3 LoF mutations had lower plasma TG and apoC-III protein level as well as 40% lower risk for CHD (P = 4 x 10-6). These findings indicate that beyond LDL-C, the LPL pathway is a key route to CHD and suggest several questions: (1) what is the full suite of genes that regulate/interact with LPL and comprise the LPL pathway?; (2) are there other genes in the LPL pathway with rare, cardio-protective alleles?; and (3) can we study physiology in APOC3 protective allele carriers to understand mechanisms behind the protection? To address these questions, we propose the following specific aims:
Aim 1 : To test the hypothesis that additional genes in the LPL pathway can be discovered using computational approaches and coding variation in these new genes will associate with plasma TG;
Aim 2 : To test the hypothesis that LPL pathway genes (beyond APOC3) harbor rare, LoF alleles that protect against CHD;
and Aim 3 : To test the hypothesis that APOC3 LoF mutation carriers have increased lipolysis of TG-rich lipoproteins and improved insulin sensitivity. Furthermore, the PI has assembled a mentoring committee who will provide the necessary training and support to accomplish the proposed research, as well as facilitate the growth of the PI. The proposed research will train a young investigator in 3 key areas: (1). To expand her knowledge of lipoprotein metabolism; (2). To develop skills for performing and interpreting pathway analysis; and (3) To perform hypothesis-driven human physiology experiments. Successful completion of the training plan and the proposed research should propel the PI to independence as a biomedical investigator.

Public Health Relevance

We recently discovered human genetic evidence that the lipoprotein lipase (LPL) pathway represents a key route to coronary heart disease (CHD). For example, about 1 in 150 individuals in the US carries a mutation that disrupts function of APOC3, a key regulator of LPL, and these individuals are naturally protected from risk for CHD. This proposal seeks to define the full set of genes that comprise the LPL pathway and test if genetic variation at each of these genes relates to plasma triglycerides and/or CHD risk. In addition, we propose to recruit carriers of protective mutations at APOC3 and matched non-carriers and perform intensive metabolic studies in order to understand how these individuals are protected and if carrying these mutations has effects on blood glucose.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01HL125751-04
Application #
9389003
Study Section
Special Emphasis Panel (ZHL1)
Program Officer
Reis, Jared P
Project Start
2014-12-01
Project End
2019-11-30
Budget Start
2017-12-01
Budget End
2019-11-30
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Boston University
Department
Biostatistics & Other Math Sci
Type
Schools of Public Health
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
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
Peloso, Gina M; Natarajan, Pradeep (2018) Insights from population-based analyses of plasma lipids across the allele frequency spectrum. Curr Opin Genet Dev 50:1-6
Klarin, Derek; Damrauer, Scott M; Cho, Kelly et al. (2018) Genetics of blood lipids among ~300,000 multi-ethnic participants of the Million Veteran Program. Nat Genet 50:1514-1523
Liu, Dajiang J (see original citation for additional authors) (2017) Exome-wide association study of plasma lipids in >300,000 individuals. Nat Genet 49:1758-1766
Lu, Xiangfeng; Peloso, Gina M; Liu, Dajiang J et al. (2017) Exome chip meta-analysis identifies novel loci and East Asian-specific coding variants that contribute to lipid levels and coronary artery disease. Nat Genet 49:1722-1730
Khera, Amit V; Won, Hong-Hee; Peloso, Gina M et al. (2017) Association of Rare and Common Variation in the Lipoprotein Lipase Gene With Coronary Artery Disease. JAMA 317:937-946
Khetarpal, Sumeet A; Zeng, Xuemei; Millar, John S et al. (2017) A human APOC3 missense variant and monoclonal antibody accelerate apoC-III clearance and lower triglyceride-rich lipoprotein levels. Nat Med 23:1086-1094
Nomura, Akihiro; Won, Hong-Hee; Khera, Amit V et al. (2017) Protein-Truncating Variants at the Cholesteryl Ester Transfer Protein Gene and Risk for Coronary Heart Disease. Circ Res 121:81-88
Emdin, Connor A; Khera, Amit V; Natarajan, Pradeep et al. (2016) Phenotypic Characterization of Genetically Lowered Human Lipoprotein(a) Levels. J Am Coll Cardiol 68:2761-2772
Clapham, Katharine R; Chu, Audrey Y; Wessel, Jennifer et al. (2016) A null mutation in ANGPTL8 does not associate with either plasma glucose or type 2 diabetes in humans. BMC Endocr Disord 16:7

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