Project 3 Recent epidemiological studies demonstrate that the metabolic syndrome and its clinical components, obesity, hypertension, dyslipidemia, and impaired glucose tolerance, are common and strongly associated with cardiovascular disease (CVD), diabetes, and other diseases. It would be clinically significant to elucidate genetic factors that contribute to their high prevalence and population-specific differences. Large scale genome-wide association studies (GWAS) have successfully identified common and rare variants for the metabolic syndrome traits, however, the identified variants do not explain a majority of variance in these traits. Furthermore, most of the previous GWAS of CVD have been performed in Europeans, and less is known about the genomic architecture of the metabolic CVD traits in the rapidly growing Hispanic minority of the U.S. who display a high predisposition. We propose two Specific Aims that will utilize comprehensive genomic approaches and refined clinical data available in the Finnish and Mexican cohorts combined with the established synergic, interdisciplinary genomics and functional expertise of lipids and CVD that the PIs and investigators of this PPG grant possess to tackle the key challenge and scientific knowledge gap of human genetics: the slow conversion of the genome-wide associations into mechanistic insights and ethnicity-aware clinical applications. Project 3 puts heavy emphasis on investigation of human adipose transcriptome, because adipose is an accessible key tissue for obesity and other metabolic syndrome traits.
In Specific Aim 1, to identify genetic regulators of the metabolic syndrome and its component traits in human adipose tissue, we propose a targeted design, focusing on the investigation of 1) the Kruppel-like factor 14 (KLF14) gene as a replicated master regulator of multiple critical metabolic genes; 2) variant-specific regulation of the lipid and obesity GWAS loci; and 3) context-specific genomic regulation of the metabolic syndrome and its obesogenic component traits.
In Specific Aim 2, we aim to identify genetic and epigenetic mechanisms underlying two-way conversions between weight loss and gain in both Europeans and Latinos. Personalized medicine cannot be implemented successfully without taking into account ethnicity, making the discovery of population-specific genetic differences critically important in assessing CVD susceptibility. Accomplishing these Specific Aims will shed light on the genetic and epigenetic mechanisms underlying key risk factors of CVD in Mexicans and Europeans.

Public Health Relevance

Project 3 The metabolic syndrome and its clinical components, obesity, hypertension, dyslipidemia, and impaired glucose tolerance, are common and strongly associated with cardiovascular disease. They also differ significantly in frequencies among populations, suggesting that there are population-specific genetic risk factors underlying them. We propose two approaches, one investigating genetic regulators of the metabolic syndrome and its component traits in human adipose tissue, and another one investigating genetic and epigenetic mechanisms underlying weight loss and gain in Europeans and Latinos to shed light on the genetic and epigenetic processes underlying key risk factors of cardiovascular disease in Mexicans and Europeans.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL028481-35
Application #
9689510
Study Section
Special Emphasis Panel (ZHL1)
Program Officer
Liu, Lijuan
Project Start
Project End
Budget Start
2019-05-01
Budget End
2020-04-30
Support Year
35
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Type
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Lang, Jennifer M; Pan, Calvin; Cantor, Rita M et al. (2018) Impact of Individual Traits, Saturated Fat, and Protein Source on the Gut Microbiome. MBio 9:
Cherlin, Svetlana; Wang, Maggie Haitian; Bickeböller, Heike et al. (2018) Detecting responses to treatment with fenofibrate in pedigrees. BMC Genet 19:64
Park, Shuin; Ranjbarvaziri, Sara; Lay, Fides D et al. (2018) Genetic Regulation of Fibroblast Activation and Proliferation in Cardiac Fibrosis. Circulation 138:1224-1235
Roberts, Adam B; Gu, Xiaodong; Buffa, Jennifer A et al. (2018) Development of a gut microbe-targeted nonlethal therapeutic to inhibit thrombosis potential. Nat Med 24:1407-1417
Zhu, W; Buffa, J A; Wang, Z et al. (2018) Flavin monooxygenase 3, the host hepatic enzyme in the metaorganismal trimethylamine N-oxide-generating pathway, modulates platelet responsiveness and thrombosis risk. J Thromb Haemost 16:1857-1872
Lee, Jessica M; Ong, Jessica R; Vergnes, Laurent et al. (2018) Diet1, bile acid diarrhea, and FGF15/19: mouse model and human genetic variants. J Lipid Res 59:429-438
Miao, Zong; Alvarez, Marcus; Pajukanta, Päivi et al. (2018) ASElux: an ultra-fast and accurate allelic reads counter. Bioinformatics 34:1313-1320
Kurt, Zeyneb; Barrere-Cain, Rio; LaGuardia, Jonnby et al. (2018) Tissue-specific pathways and networks underlying sexual dimorphism in non-alcoholic fatty liver disease. Biol Sex Differ 9:46
Orozco, Luz D; Farrell, Colin; Hale, Christopher et al. (2018) Epigenome-wide association in adipose tissue from the METSIM cohort. Hum Mol Genet 27:1830-1846
Chella Krishnan, Karthickeyan; Kurt, Zeyneb; Barrere-Cain, Rio et al. (2018) Integration of Multi-omics Data from Mouse Diversity Panel Highlights Mitochondrial Dysfunction in Non-alcoholic Fatty Liver Disease. Cell Syst 6:103-115.e7

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