Obesity has become a national epidemic. The health consequences are manifold including increases in the risk and prevalence of metabolic syndrome (MetS) and non- alcoholic fatty liver disease (NAFLD). The metabolic underpinnings of these conditions, both of which are influenced by obesity and, specifically, increased stores of abdominal visceral fat and insulin resistance, are highly intertwined and have both genetic and environmental determinants. Characterization of fatty liver (steatosis) in conjunction with liver enzymes and abdominal fat depots in a large family study will provide an unprecedented opportunity to study the genetic epidemiology of MetS and NAFLD. Using existing CT scans obtained in over 3,300 Caucasian and African-American subjects from families of the NHLBI Family Heart Study (FHS), we propose to obtain measures of four focal phenotypes: liver attenuation, and total, subcutaneous, and visceral abdominal fat. Combined with the wealth of phenotypic and genetic information available already in the FHS, we will carry out studies of the genetic epidemiology of these important phenotypes, with the goal of identifying risk factors for these diseases including both genetic and environmental factors. We will use standard epidemiological models to characterize the risk factors for NAFLD, specifically, dietary factors (as ascertained using the Willett questionnaire), habitual physical activity, and alcohol consumption. Using existing measures of coronary and aortic artery calcification on these subjects, we will also characterize the influence of steatosis and abdominal fat on the degree of subclinical atherosclerosis. While the genetic basis of abdominal fat is well-established exhibiting a heritability of 50-70%, a recent study has estimated the heritability of liver attenuation to be 34%, suggesting that mapping studies are warranted. Genetic scans will be carried out in both Caucasian and African-American families using a panel of over 400 microsatellite linkage markers that are already typed on these subjects, to identify regions harboring trait loci. Genomewide association scans are being currently conducted for 1,000 Caucasian cases and controls for atherosclerosis, and for all 622 African-American subjects. These genotypes also will be available to this project to enhance the power for gene discovery and localization. Finally, we are particularly interested in characterizing the systems biological multivariate relationships among our focal phenotypes with other aspects of the MetS including insulin and glucose levels, insulin resistance, blood pressure, and lipids and lipoproteins in order to identify determinants that explain the clustering in this adverse risk factor profile. The proposed studies will help localize genes involved in the metabolic diseases of obesity, help elucidate the role of environmental exposures in these pathways, and will be among the largest, most definitive studies to date on fatty liver disease. Obesity has become a national epidemic. The health consequences are manifold including increases in the risk and prevalence of diabetes, metabolic syndrome (MetS) and non-alcoholic fatty liver disease (NAFLD). The metabolic underpinnings of these conditions, all of which are influenced and exacerbated by obesity are highly intertwined and have both genetic and environmental determinants. The overall goal of this project is to study abdominal fat patterning and NAFLD, both of which are associated with insulin resistance, to identify their underlying genetic architecture using state of the art genome screening methods, evaluate the influence of diet and physical activity, and to understand their relationship to features of the MetS and coronary artery disease.

Public Health Relevance

Obesity has become a national epidemic. The health consequences are manifold including increases in the risk and prevalence of diabetes, metabolic syndrome (MetS) and non-alcoholic fatty liver disease (NAFLD). The metabolic underpinnings of these conditions, all of which are influenced and exacerbated by obesity are highly intertwined and have both genetic and environmental determinants. The overall goal of this project is to study abdominal fat patterning and NAFLD, both of which are associated with insulin resistance, to identify their underlying genetic architecture using state of the art genome screening methods, evaluate the influence of diet and physical activity, and to understand their relationship to features of the MetS and coronary artery disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK075681-02
Application #
7609134
Study Section
Kidney, Nutrition, Obesity and Diabetes (KNOD)
Program Officer
Karp, Robert W
Project Start
2008-05-01
Project End
2012-04-30
Budget Start
2009-05-01
Budget End
2010-04-30
Support Year
2
Fiscal Year
2009
Total Cost
$510,805
Indirect Cost
Name
Washington University
Department
Genetics
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Zillikens, M Carola; Demissie, Serkalem; Hsu, Yi-Hsiang et al. (2017) Large meta-analysis of genome-wide association studies identifies five loci for lean body mass. Nat Commun 8:80
Kilpeläinen, Tuomas O; Carli, Jayne F Martin; Skowronski, Alicja A et al. (2016) Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels. Nat Commun 7:10494
Manichaikul, Ani; Wang, Xin-Qun; Zhao, Wei et al. (2016) Genetic association of long-chain acyl-CoA synthetase 1 variants with fasting glucose, diabetes, and subclinical atherosclerosis. J Lipid Res 57:433-42
Wang, Shuai; Zhao, Jing Hua; An, Ping et al. (2016) General Framework for Meta-Analysis of Haplotype Association Tests. Genet Epidemiol 40:244-52
Rao, Goutham; Powell-Wiley, Tiffany M; Ancheta, Irma et al. (2015) Identification of Obesity and Cardiovascular Risk in Ethnically and Racially Diverse Populations: A Scientific Statement From the American Heart Association. Circulation 132:457-72
Nettleton, Jennifer A; Follis, Jack L; Ngwa, Julius S et al. (2015) Gene × dietary pattern interactions in obesity: analysis of up to 68 317 adults of European ancestry. Hum Mol Genet 24:4728-38
Wessel, Jennifer; Chu, Audrey Y; Willems, Sara M et al. (2015) Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility. Nat Commun 6:5897
Zhang, Qunyuan; Abel, Haley; Wells, Alan et al. (2015) Selection of models for the analysis of risk-factor trees: leveraging biological knowledge to mine large sets of risk factors with application to microbiome data. Bioinformatics 31:1607-13
Ma, Y; Tucker, K L; Smith, C E et al. (2014) Lipoprotein lipase variants interact with polyunsaturated fatty acids for obesity traits in women: replication in two populations. Nutr Metab Cardiovasc Dis 24:1323-9
Kraja, Aldi T; Chasman, Daniel I; North, Kari E et al. (2014) Pleiotropic genes for metabolic syndrome and inflammation. Mol Genet Metab 112:317-38

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