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Genome-Wide Association Studies for Idiosyncratic Drug-Induced Hepatotoxicity: Looking Back-Looking Forward to Next-Generation Innovation.

ABSTRACT: Idiosyncratic drug-induced hepatotoxicity is a formidable challenge for rational drug discovery and development, as well as the science of personalized medicine. There is evidence that hereditary factors, in part, contribute to drug toxicity. This expert analysis and review offer the insights gained, and the challenges ahead, for genome-wide association studies (GWASs) of idiosyncratic drug-induced hepatotoxicity. Published articles on genome-wide and subsequent replication studies were systematically searched in the PubMed electronic database. We found that the genetic risk variants that were identified genome-wide, and replication confirmed, are mainly related to polymorphisms in the human leukocyte antigen (HLA) region that include HLA-DQB1*06:02 for amoxicillin-clavulanate, HLA-B*57:01 for flucloxacillin, HLA-DRB1*15:01 for lumiracoxib, and HLA-DRB1*07:01 for lapatinib and ximelagatran-induced hepatotoxicity. Additionally, polymorphisms in ST6 ?-galactosamide ?-2, 6-sialyltranferase-1 (ST6GAL1), which plays a role in systemic inflammatory response, and variants in intron of family with sequence similarity-65 member-B (FAM65B) that play roles in liver inflammation displayed association with flucloxacillin and antituberculosis drug-induced hepatotoxicity, respectively. Taken together, these GWAS findings offer molecular leads on the central role that the immune system plays in idiosyncratic drug-induced hepatotoxicity. We conclude the expert review with a brief discussion of the salient challenges ahead. These include, for example, the need for discursive discovery paradigms that incorporate alternating GWASs and candidate gene studies, as well as the study of the environtome, the entire complement of environmental factors, including science and innovation policies that enact on global society and the human host, and by extension, on susceptibility for idiosyncratic drug-induced hepatotoxicity.

SUBMITTER: Petros Z

PROVIDER: S-EPMC5346905 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Genome-Wide Association Studies for Idiosyncratic Drug-Induced Hepatotoxicity: Looking Back-Looking Forward to Next-Generation Innovation.

Petros Zelalem Z Makonnen Eyasu E Aklillu Eleni E

Omics : a journal of integrative biology 20170216 3

Idiosyncratic drug-induced hepatotoxicity is a formidable challenge for rational drug discovery and development, as well as the science of personalized medicine. There is evidence that hereditary factors, in part, contribute to drug toxicity. This expert analysis and review offer the insights gained, and the challenges ahead, for genome-wide association studies (GWASs) of idiosyncratic drug-induced hepatotoxicity. Published articles on genome-wide and subsequent replication studies were systemat ...[more]

PMID: 28253087

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Project description:Recent studies have found substantial variation in hospital resource use by expired Medicare beneficiaries with chronic illnesses. By analyzing only expired patients, these studies cannot identify differences across hospitals in health outcomes like mortality. This study examines the association between mortality and resource use at the hospital level, when all Medicare beneficiaries hospitalized for heart failure are examined.A total of 3999 individuals hospitalized with a principal diagnosis of heart failure at 6 California teaching hospitals between January 1, 2001, and June 30, 2005, were analyzed with multivariate risk-adjustment models for total hospital days, total hospital direct costs, and mortality within 180-days after initial admission ("Looking Forward"). A subset of 1639 individuals who died during the study period were analyzed with multivariate risk-adjustment models for total hospital days and total hospital direct costs within 180-days before death ("Looking Back"). "Looking Forward" risk-adjusted hospital means ranged from 17.0% to 26.0% for mortality, 7.8 to 14.9 days for total hospital days, and 0.66 to 1.30 times the mean value for indexed total direct costs. Spearman rank correlation coefficients were -0.68 between mortality and hospital days, and -0.93 between mortality and indexed total direct costs. "Looking Back" risk-adjusted hospital means ranged from 9.1 to 21.7 days for total hospital days and 0.91 to 1.79 times the mean value for indexed total direct costs. Variation in resource use site ranks between expired and all individuals were attributable to insignificant differences.California teaching hospitals that used more resources caring for patients hospitalized for heart failure had lower mortality rates. Focusing only on expired individuals may overlook mortality variation as well as associations between greater resource use and lower mortality. Reporting values without identifying significant differences may result in incorrect assumption of true differences.

Dataset Information

Genome-Wide Association Studies for Idiosyncratic Drug-Induced Hepatotoxicity: Looking Back-Looking Forward to Next-Generation Innovation.

Publications

Genome-Wide Association Studies for Idiosyncratic Drug-Induced Hepatotoxicity: Looking Back-Looking Forward to Next-Generation Innovation.

Similar Datasets

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