As a consequence of the epidemic worldwide increase in obesity, many people have fat deposited in their liver that can lead to liver cirrhosis and liver failure;nevertheless, little is known about the genetic epidemiology or metabolic consequences of fatty liver. Dr. Speliotes is a fellow in gastroenterology at the Massachusetts General Hospital and a post doctoral fellow at the Broad Institute with an interest in obesity. She has a strong background in basic science research and now aims to expand her analytic skills to include human genetic epidemiology. Her long term goals are to be able to evaluate, apply, and create new information to treat obesity and associated illnesses in humans. The proposed career development plan includes a well defined mentored patient-oriented research proposal in concert with a structured didactic curriculum in statistics, epidemiology and genetics. She will elucidate the epidemiologic and genetic correlates of fatty liver in the population based Framingham Heart study cohort by carrying out the following aims:
Aim 1. Determine the prevalence and clinical correlates of fatty liver. A. She will analyze the over 3500 CT scans available in this sample for the presence of fatty liver and determine the prevalence of this condition in a cross-sectionally designed study. She will test whether metabolic diseases correlate with fatty liver independent of other measures of adiposity. B. Furthermore, she will test whether subclinical and clinical cardiovascular disease correlate with fatty liver independently of the other measures of adiposity and metabolic risk factors noted above.
Aim 2. Determine the heritability and linkage of fatty liver. She will take advantage of the family-based component of the cohort to estimate the A. heritability and B. linkage of fatty liver using variance-components likelihood methods.
Aim 3. Test genetic variants for association with fatty liver. A. She will test whether obesity- or diabetes-associated single nucleotide polymorphisms (SNPs) in the genes INSIG2, KCNJ11, PPARG, and TCF7L2 are independently associated with fatty liver using multivariable regression techniques. B. She will test whether the 1QOK/ 500K SNP markers that have been and will be genotyped in the cohort associate with fatty liver using multivariable regression techniques. She will attempt to replicate any SNPs associated with fatty liver in a sample of 1124 individuals that have had liver biopsies while undergoing gastric bypass surgery and have fatty liver by histology. An understanding of the best independent clinical and genetic correlates of fatty liver in a large community based sample will help us to better understand the biology and clinical significance of fat in the liver which will help us to better identify, manage and treat the many individuals that have fatty liver. Through the proposed research and educational training Dr. Speliotes will acquire the skills to become an independent scientist in human genetic epidemiology.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23DK080145-05
Application #
8286196
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Podskalny, Judith M,
Project Start
2008-03-01
Project End
2013-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
5
Fiscal Year
2012
Total Cost
$180,360
Indirect Cost
$13,360
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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Gorden, Alexis; Yang, Rongze; Yerges-Armstrong, Laura M et al. (2013) Genetic variation at NCAN locus is associated with inflammation and fibrosis in non-alcoholic fatty liver disease in morbid obesity. Hum Hered 75:34-43
Hernaez, Ruben; McLean, Jody; Lazo, Mariana et al. (2013) Association between variants in or near PNPLA3, GCKR, and PPP1R3B with ultrasound-defined steatosis based on data from the third National Health and Nutrition Examination Survey. Clin Gastroenterol Hepatol 11:1183-1190.e2
Therkelsen, Kate E; Pedley, Alison; Speliotes, Elizabeth K et al. (2013) Intramuscular fat and associations with metabolic risk factors in the Framingham Heart Study. Arterioscler Thromb Vasc Biol 33:863-70
Kilpeläinen, Tuomas O; Zillikens, M Carola; Stan?ákova, Alena et al. (2011) Genetic variation near IRS1 associates with reduced adiposity and an impaired metabolic profile. Nat Genet 43:753-60
Speliotes, Elizabeth K; Yerges-Armstrong, Laura M; Wu, Jun et al. (2011) Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits. PLoS Genet 7:e1001324
(2010) Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution. Nat Genet 42:949-60
Speliotes, Elizabeth K; Butler, Johannah L; Palmer, Cameron D et al. (2010) PNPLA3 variants specifically confer increased risk for histologic nonalcoholic fatty liver disease but not metabolic disease. Hepatology 52:904-12
Speliotes, Elizabeth K; Massaro, Joseph M; Hoffmann, Udo et al. (2010) Fatty liver is associated with dyslipidemia and dysglycemia independent of visceral fat: the Framingham Heart Study. Hepatology 51:1979-87
(2010) Hundreds of variants clustered in genomic loci and biological pathways affect human height. Nature 467:832-8

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