Rohit Loomba, MD, MHSc (PI) is a hepatologist and Assistant Professor of Medicine at the University of California-San Diego. Dr. Loomba's long-term goal is to develop an independent research career in the genetic epidemiology of nonalcoholic fatty liver disease (NAFLD) by combining patient- centered research with clinical epidemiology. He is interested in underpinning genetic and environmental risk factors that are associated with NAFLD and identify novel mechanistic pathways that are linked with progressive form of NAFLD, which is termed as nonalcoholic steatohepatitis (NASH). NAFLD is the most common liver disease in the United States. It is associated with metabolic syndrome traits including hypertension (HTN), insulin resistance (IR), and hypertriglyceridemia. These metabolic traits predict increased risk of NASH, which can lead to cirrhosis. A critical barrier to progress in the field and to management of patients with NAFLD is that the mechanism underlying the association between metabolic traits and NAFLD, and those associated with progression of NAFLD, are not well understood. In order to fill this gap in knowledge, Dr. Loomba, under the mentorship of Drs. Daniel O'Connor, Elizabeth Barrett-Connor, and David Brenner, proposes to measure liver fat, quantitatively, by a novel magnetic resonance imaging (MRI) technique, in a large, previously well-characterized, existing, twin-pair cohort in humans: (specific aim 1) To examine genetic co-variance between NAFLD and metabolic risk factors including hypertension (HTN), insulin resistance (IR), and elevated triglycerides (TG), which would be assessed by using multivariate generalized estimating equations after adjustment for age and sex. Previous studies suggest that adrenergic system has a strong genetic association with HTN, IR &TG;and in-vitro and in-vivo studies suggest that norepinephrine (increased adrenergic activity) activates hepatic stellate cells &induces fibrogenesis in mice model of diet-induced fibrosis and NAFLD. Therefore, we hypothesize that adrenergic genes are associated with human NAFLD and may be responsible for the shared gene effects between NAFLD and HTN, IR, &TG. (specific aim 2) To examine if the genes in the adrenergic system (already genotyped: preliminary data suggests 2-2 adrenergic gene effect with serum gamma-glutamyl transpeptidase (GGT), a marker of NAFLD, in this twin cohort) are associated with NAFLD. This twin-pair study, which includes both mono-zygotic and di-zygotic twins, allows us to tease out the genetic versus environmental co-variance between the metabolic traits and NAFLD. Furthermore, we will be utilizing a cutting-edge MRI technique to quantify the liver fat fraction as a non-invasive biomarker of hepatic triglyceride content. These innovations would advance the knowledge in the field. In order to gain expertise in genetic epidemiology and twin studies, a rigorous career development plan is proposed that benefits from a multi-disciplinary approach designed to provide a closely mentored, patient-oriented research experience in association with a comprehensively structured didactic curriculum in genetic and advanced epidemiology. This unique twin study design would shed light on shared gene effects between NAFLD and these metabolic syndrome traits and help in identifying novel genetic variations in adrenergic genes that may explain this shared gene effect. These findings may be exploited in assessing liver disease progression and development of novel targets for treatment of NAFLD and associated metabolic complications. The long- term goal of the proposed research program is to reduce the burden of NAFLD and halt progression of NAFLD to NASH.

Public Health Relevance

NAFLD affects one out of every three Americans. The proposed twin study will improve our understanding of disease progression in NAFLD. This study would lead to discovery of specific adrenergic genotypes that are associated with NAFLD, which may be exploited to develop new prognostic models for predicting disease progression and develop newer targets of therapy.

Agency
National Institute of Health (NIH)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23DK090303-04
Application #
8721400
Study Section
Special Emphasis Panel (ZDK1)
Program Officer
Podskalny, Judith M,
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of California San Diego
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Lin, Steven C; Heba, Elhamy; Wolfson, Tanya et al. (2015) Noninvasive Diagnosis of Nonalcoholic Fatty Liver Disease and Quantification of Liver Fat Using a New Quantitative Ultrasound Technique. Clin Gastroenterol Hepatol 13:1337-1345.e6
Singh, Siddharth; Allen, Alina M; Wang, Zhen et al. (2015) Fibrosis progression in nonalcoholic fatty liver vs nonalcoholic steatohepatitis: a systematic review and meta-analysis of paired-biopsy studies. Clin Gastroenterol Hepatol 13:643-54.e1-9; quiz e39-40
Patel, Niraj S; Doycheva, Iliana; Peterson, Michael R et al. (2015) Effect of weight loss on magnetic resonance imaging estimation of liver fat and volume in patients with nonalcoholic steatohepatitis. Clin Gastroenterol Hepatol 13:561-568.e1
Boland, Brigid S; Dong, Mamie H; Bettencourt, Ricki et al. (2014) Association of serum bilirubin with aging and mortality. J Clin Exp Hepatol 4:1-7
Stinton, L M; Loomba, R (2014) Recommendations for liver biopsy evaluation in non-alcoholic fatty liver disease. Minerva Gastroenterol Dietol 60:5-13
Loomba, Rohit; Wolfson, Tanya; Ang, Brandon et al. (2014) Magnetic resonance elastography predicts advanced fibrosis in patients with nonalcoholic fatty liver disease: a prospective study. Hepatology 60:1920-8
Loomba, Rohit (2014) Serum alanine aminotransferase as a biomarker of treatment response in nonalcoholic steatohepatitis. Clin Gastroenterol Hepatol 12:1731-2
Johnson, Benjamin L; Schroeder, Michael E; Wolfson, Tanya et al. (2014) Effect of flip angle on the accuracy and repeatability of hepatic proton density fat fraction estimation by complex data-based, T1-independent, T2*-corrected, spectrum-modeled MRI. J Magn Reson Imaging 39:440-7
Pearlman, Michelle; Loomba, Rohit (2014) State of the art: treatment of nonalcoholic steatohepatitis. Curr Opin Gastroenterol 30:223-37
Levin, Yakir S; Yokoo, Takeshi; Wolfson, Tanya et al. (2014) Effect of echo-sampling strategy on the accuracy of out-of-phase and in-phase multiecho gradient-echo MRI hepatic fat fraction estimation. J Magn Reson Imaging 39:567-75

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