There is a fundamental gap in knowledge regarding host susceptibility and mechanisms of drug-induced liver injury (DILI) in humans. To date, the Drug Induced Liver Injury Network (DILIN) has succeeded in maintaining a prospective registry of well-defined cases with DILI to further research in this area. The long term-goal is to understand the genetic influence on mechanisms and clinical outcomes of DILI. Critical to the success for improved understanding of pathogenesis, the objective of this application is to further expand the registry by including additional patients with DILI from geographic areas not currently within the Network. In response to RFA-DK-07-712 (Continuation and Expansion of the Drug Induced Liver Injury Network), the Central Hypothesis of this application is to effectively contribute well-defined cases of DILI and propose novel mechanistic studies examining phenotype-genotype associations. The proposed research is relevant to that part of the NIH mission which pertains to developing fundamental knowledge to reduce the burden of disease. This hypothesis will be tested by pursuing two specific aims.
Specific Aim 1 will focus on the identification and enrollment of cases with bona fide DILI and matched controls within a diverse racial and ethnic geographic population of 7 million individuals. Based on recent clinical experience with DILI, this consortium anticipates the enrollment of 250 cases affected by DILI and 750 matched controls with appropriate biospecimen collections over a 5 year period.
Specific Aim 2 outlines a series of proposed experiments to determine whether differential activation of the unfolded protein response (UPR) from endoplasmic reticulum stress occurs in the pathogenesis of idiosyncratic DILI. The proposed work is innovative based on the coupling of advanced bioinformatics technology, extensive clinical experience, and recognized expertise in liver cell injury and genetic epidemiology. In turn, we are enthusiastic to work cooperatively with the Clinical Centers, the Data Coordinating Center, and sponsoring organizations in this expanded Network to oversee the implementation of and adherence to common protocols.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01DK082992-04
Application #
8132958
Study Section
Special Emphasis Panel (ZDK1-GRB-8 (O1))
Program Officer
Serrano, Jose
Project Start
2008-09-30
Project End
2013-06-30
Budget Start
2011-07-01
Budget End
2012-06-30
Support Year
4
Fiscal Year
2011
Total Cost
$233,579
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Chalasani, Naga; Reddy, K Rajender K; Fontana, Robert J et al. (2017) Idiosyncratic Drug Induced Liver Injury in African-Americans Is Associated With Greater Morbidity and Mortality Compared to Caucasians. Am J Gastroenterol 112:1382-1388
Bonkovsky, Herbert L; Kleiner, David E; Gu, Jiezhun et al. (2017) Clinical presentations and outcomes of bile duct loss caused by drugs and herbal and dietary supplements. Hepatology 65:1267-1277
Nicoletti, Paola; Aithal, Guruprasad P; Bjornsson, Einar S et al. (2017) Association of Liver Injury From Specific Drugs, or Groups of Drugs, With Polymorphisms in HLA and Other Genes in a Genome-Wide Association Study. Gastroenterology 152:1078-1089
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Urban, Thomas Jacob; Nicoletti, Paola; Chalasani, Naga et al. (2017) Minocycline hepatotoxicity: Clinical characterization and identification of HLA-B?35:02 as a risk factor. J Hepatol 67:137-144
Navarro, Victor J; Khan, Ikhlas; Björnsson, Einar et al. (2017) Liver injury from herbal and dietary supplements. Hepatology 65:363-373
Whritenour, Jessica; Ko, Mira; Zong, Qing et al. (2017) Development of a modified lymphocyte transformation test for diagnosing drug-induced liver injury associated with an adaptive immune response. J Immunotoxicol 14:31-38
Russo, Mark W; Steuerwald, Nury; Norton, Harry J et al. (2017) Profiles of miRNAs in serum in severe acute drug induced liver injury and their prognostic significance. Liver Int 37:757-764
Schmeltzer, Paul A; Kosinski, Andrzej S; Kleiner, David E et al. (2016) Liver injury from nonsteroidal anti-inflammatory drugs in the United States. Liver Int 36:603-9
Hayashi, Paul H; Fontana, Robert J; Chalasani, Naga P et al. (2015) Under-reporting and Poor Adherence to Monitoring Guidelines for Severe Cases of Isoniazid Hepatotoxicity. Clin Gastroenterol Hepatol 13:1676-82.e1

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