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.
.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.
|Rau, Christoph D; Wang, Jessica; Avetisyan, Rozeta et al. (2015) Mapping genetic contributions to cardiac pathology induced by Beta-adrenergic stimulation in mice. Circ Cardiovasc Genet 8:40-9|
|Iatan, Iulia; Choi, Hong Y; Ruel, Isabelle et al. (2014) The WWOX gene modulates high-density lipoprotein and lipid metabolism. Circ Cardiovasc Genet 7:491-504|
|Aguilar-Salinas, Carlos A; Tusie-Luna, Teresa; Pajukanta, Päivi (2014) Genetic and environmental determinants of the susceptibility of Amerindian derived populations for having hypertriglyceridemia. Metabolism 63:887-94|
|Mao, Hui Z; Ehrhardt, Nicole; Bedoya, Candy et al. (2014) Lipase maturation factor 1 (lmf1) is induced by endoplasmic reticulum stress through activating transcription factor 6? (Atf6?) signaling. J Biol Chem 289:24417-27|
|Hartiala, Jaana; Bennett, Brian J; Tang, W H Wilson et al. (2014) Comparative genome-wide association studies in mice and humans for trimethylamine N-oxide, a proatherogenic metabolite of choline and L-carnitine. Arterioscler Thromb Vasc Biol 34:1307-13|
|He, Dan; Furlotte, Nicholas A; Hormozdiari, Farhad et al. (2014) Identifying genetic relatives without compromising privacy. Genome Res 24:664-72|
|Reue, Karen; Lee, Jessica M; Vergnes, Laurent (2014) Regulation of bile acid homeostasis by the intestinal Diet1-FGF15/19 axis. Curr Opin Lipidol 25:140-7|
|Mangul, Serghei; Wu, Nicholas C; Mancuso, Nicholas et al. (2014) Accurate viral population assembly from ultra-deep sequencing data. Bioinformatics 30:i329-37|
|Sha, Haibo; Sun, Shengyi; Francisco, Adam B et al. (2014) The ER-associated degradation adaptor protein Sel1L regulates LPL secretion and lipid metabolism. Cell Metab 20:458-70|
|Vergnes, Laurent; Reue, Karen (2014) Adaptive thermogenesis in white adipose tissue: is lactate the new brown(ing)? Diabetes 63:3175-6|
Showing the most recent 10 out of 367 publications