Previous epidemiological studies have shown that the metabolic syndrome is very common with a population prevalence of ~30% in middle-aged Americans. The metabolic syndrome predisposes to coronary artery disease, the major cause of death in the U.S. Elevated plasma triglycerides (TGs) and low high-density lipoprotein cholesterol (HDL-C) are the key atherogenic lipid phenotypes ofthe metabolic syndrome. However, the genetic basis for the metabolic syndrome is not well understood. The major goal of project 2 is to systematically identify DNA sequence variants, genes and metabolic pathways contributing to the lipid traits, TGs and HDL-C, of the metabolic syndrome and to investigate the sequence variants for risk as well as for gene-gene and gene-environment interactions in the population.
Specific Aim 1 focuses on resequencing ofthe genes we identified during the previous cycle of this Project 2 (WWOX and LMFI) to identify the variants exhibiting the strongest phenotypic effects. These variants will be further investigated in functional studies. Our ultimate goal is to provide novel biomarkers and targets for clinical interventions.
Specific Aim 2 integrates genomic data obtained from mouse and human to systemically identify novel genes and pathways implicated at the DNA and RNA level in the metabolic syndrome related lipid traits in human. As an individual's risk to develop a complex cardiovascular phenotype is a combination of susceptibility variants, environmental factors, behavior and chance, we will investigate the DNA sequence variants supported by multiple lines of evidence for risk as well as for gene-gene and gene-environment interactions in a large population sample, the METabolic Syndrome In Men (METSIM) study, comprising currently 8,600 Finns, and ultimately 10,000 Finns in 2010. This study will be performed in collaboration with Dr. Markku Laakso, University of Kuopio, Finland who is collecting the METSIM sample. Utilizing this extensive population sample with refined phenotypes available for the study gives us a unique opportunity to explore the population risks and gene-environment interactions. The gene-environment interactions, critical for the expression of complex traits, have not been investigated in the recent genome-wide association studies, because there are very few large enough population samples such as the METSIM study with refined enough phenotypic information available for gene-environment interaction analyses. Elucidation of the unknown genetic factors and molecular mechanisms influencing the high susceptibility to the metabolic syndrome in human is of great relevance to the American healthcare system.

Public Health Relevance

.The metabolic syndrome is very common with a population prevalence of -30% in middle-aged Americans, and it predisposes these individuals to coronary artery disease. However, the genetic factors underlying this high susceptibility are poorly identified. The major goal of this proposal is to systemically identify novel genes and pathways contributing to the lipid traits ofthe metabolic syndrome in human and to determine population risks and gene-environment interactions related to the identified variants in a large population-based study.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL028481-29
Application #
8502726
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
29
Fiscal Year
2013
Total Cost
$414,731
Indirect Cost
$145,425
Name
University of California Los Angeles
Department
Type
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Tarling, Elizabeth J; Clifford, Bethan L; Cheng, Joan et al. (2017) RNA-binding protein ZFP36L1 maintains posttranscriptional regulation of bile acid metabolism. J Clin Invest 127:3741-3754
Nakano, Haruko; Minami, Itsunari; Braas, Daniel et al. (2017) Glucose inhibits cardiac muscle maturation through nucleotide biosynthesis. Elife 6:
Org, Elin; Blum, Yuna; Kasela, Silva et al. (2017) Relationships between gut microbiota, plasma metabolites, and metabolic syndrome traits in the METSIM cohort. Genome Biol 18:70
Pillai, Indulekha C L; Li, Shen; Romay, Milagros et al. (2017) Cardiac Fibroblasts Adopt Osteogenic Fates and Can Be Targeted to Attenuate Pathological Heart Calcification. Cell Stem Cell 20:218-232.e5
von Scheidt, Moritz; Zhao, Yuqi; Kurt, Zeyneb et al. (2017) Applications and Limitations of Mouse Models for Understanding Human Atherosclerosis. Cell Metab 25:248-261
Nikkola, Elina; Ko, Arthur; Alvarez, Marcus et al. (2017) Family-specific aggregation of lipid GWAS variants confers the susceptibility to familial hypercholesterolemia in a large Austrian family. Atherosclerosis 264:58-66
Schugar, Rebecca C; Shih, Diana M; Warrier, Manya et al. (2017) The TMAO-Producing Enzyme Flavin-Containing Monooxygenase 3 Regulates Obesity and the Beiging of White Adipose Tissue. Cell Rep 19:2451-2461
Rau, Christoph D; Romay, Milagros C; Tuteryan, Mary et al. (2017) Systems Genetics Approach Identifies Gene Pathways and Adamts2 as Drivers of Isoproterenol-Induced Cardiac Hypertrophy and Cardiomyopathy in Mice. Cell Syst 4:121-128.e4
Wang, Huan; Airola, Michael V; Reue, Karen (2017) How lipid droplets ""TAG"" along: Glycerolipid synthetic enzymes and lipid storage. Biochim Biophys Acta 1862:1131-1145
Kessler, Thorsten; Wobst, Jana; Wolf, Bernhard et al. (2017) Functional Characterization of the GUCY1A3 Coronary Artery Disease Risk Locus. Circulation 136:476-489

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