当前位置： SCI文献检索 > NATURE MEDICINE期刊下所有文献 > Polygenic architecture informs potential vulnerability to drug-induced liver injury.

Polygenic architecture informs potential vulnerability to drug-induced liver injury.

Abstract：

:Drug-induced liver injury (DILI) is a leading cause of termination in drug development programs and removal of drugs from the market; this is partially due to the inability to identify patients who are at risk1. In this study, we developed a polygenic risk score (PRS) for DILI by aggregating effects of numerous genome-wide loci identified from previous large-scale genome-wide association studies2. The PRS predicted the susceptibility to DILI in patients treated with fasiglifam, amoxicillin-clavulanate or flucloxacillin and in primary hepatocytes and stem cell-derived organoids from multiple donors treated with over ten different drugs. Pathway analysis highlighted processes previously implicated in DILI, including unfolded protein responses and oxidative stress. In silico screening identified compounds that elicit transcriptomic signatures present in hepatocytes from individuals with elevated PRS, supporting mechanistic links and suggesting a novel screen for safety of new drug candidates. This genetic-, cellular-, organoid- and human-scale evidence underscored the polygenic architecture underlying DILI vulnerability at the level of hepatocytes, thus facilitating future mechanistic studies. Moreover, the proposed 'polygenicity-in-a-dish' strategy might potentially inform designs of safer, more efficient and robust clinical trials.

journal_name

Nat Med

journal_title

Nature medicine

authors

Koido M,Kawakami E,Fukumura J,Noguchi Y,Ohori M,Nio Y,Nicoletti P,Aithal GP,Daly AK,Watkins PB,Anayama H,Dragan Y,Shinozawa T,Takebe T

doi

10.1038/s41591-020-1023-0

subject

Has Abstract

pub_date

2020-10-01 00:00:00

pages

1541-1548

issue

10

eissn

1078-8956

issn

1546-170X

pii

10.1038/s41591-020-1023-0

journal_volume

26

pub_type

杂志文章

相关文献

NATURE MEDICINE文献大全
  • Transgenic plants expressing autoantigens fed to mice to induce oral immune tolerance.

    abstract：:Oral administration of protein can induce antigen-specific immune hyporesponsiveness. However, the utility of oral tolerance to autoantigens in the treatment of autoimmune diseases may be limited when candidate autoantigens cannot be produced by conventional systems in quantities sufficient for clinical studies. Plant...

    journal_title：Nature medicine

    pub_type： 杂志文章

    doi：10.1038/nm0797-793

    authors： Ma SW,Zhao DL,Yin ZQ,Mukherjee R,Singh B,Qin HY,Stiller CR,Jevnikar AM

    更新日期：1997-07-01 00:00:00

  • Genetic clues to the pathogenesis of Parkinson's disease.

    abstract：:Recent years have seen an explosion in the rate of discovery of genetic defects linked to Parkinson's disease. These breakthroughs have not provided a direct explanation for the disease process. Nevertheless, they have helped transform Parkinson's disease research by providing tangible clues to the neurobiology of the...

    journal_title：Nature medicine

    pub_type： 杂志文章,评审

    doi：10.1038/nm1068

    authors： Vila M,Przedborski S

    更新日期：2004-07-01 00:00:00

  • GABAergic excitation after febrile seizures induces ectopic granule cells and adult epilepsy.

    abstract：:Temporal lobe epilepsy (TLE) is accompanied by an abnormal location of granule cells in the dentate gyrus. Using a rat model of complex febrile seizures, which are thought to be a precipitating insult of TLE later in life, we report that aberrant migration of neonatal-generated granule cells results in granule cell ec...

    journal_title：Nature medicine

    pub_type： 杂志文章

    doi：10.1038/nm.2850

    authors： Koyama R,Tao K,Sasaki T,Ichikawa J,Miyamoto D,Muramatsu R,Matsuki N,Ikegaya Y

    更新日期：2012-08-01 00:00:00

  • A newly discovered human pneumovirus isolated from young children with respiratory tract disease.

    abstract：:From 28 young children in the Netherlands, we isolated a paramyxovirus that was identified as a tentative new member of the Metapneumovirus genus based on virological data, sequence homology and gene constellation. Previously, avian pneumovirus was the sole member of this recently assigned genus, hence the provisional...

    journal_title：Nature medicine

    pub_type： 杂志文章

    doi：10.1038/89098

    authors： van den Hoogen BG,de Jong JC,Groen J,Kuiken T,de Groot R,Fouchier RA,Osterhaus AD

    更新日期：2001-06-01 00:00:00

  • HRDetect is a predictor of BRCA1 and BRCA2 deficiency based on mutational signatures.

    abstract：:Approximately 1-5% of breast cancers are attributed to inherited mutations in BRCA1 or BRCA2 and are selectively sensitive to poly(ADP-ribose) polymerase (PARP) inhibitors. In other cancer types, germline and/or somatic mutations in BRCA1 and/or BRCA2 (BRCA1/BRCA2) also confer selective sensitivity to PARP inhibitors....

    journal_title：Nature medicine

    pub_type： 杂志文章

    doi：10.1038/nm.4292

    authors： Davies H,Glodzik D,Morganella S,Yates LR,Staaf J,Zou X,Ramakrishna M,Martin S,Boyault S,Sieuwerts AM,Simpson PT,King TA,Raine K,Eyfjord JE,Kong G,Borg Å,Birney E,Stunnenberg HG,van de Vijver MJ,Børresen-Dale AL,Ma

    更新日期：2017-04-01 00:00:00

  • Restoration of cytomegalovirus-specific CD4+ T-lymphocyte responses after ganciclovir and highly active antiretroviral therapy in individuals infected with HIV-1.

    abstract：:Recent studies of subjects infected with human immunodeficiency virus (HIV-1) have produced conflicting results about the extent of reconstitution possible in the CD4+ lymphocyte repertoire after highly active antiretroviral therapy (HAART). The effect of HAART on the incidence of opportunistic infections will probabl...

    journal_title：Nature medicine

    pub_type： 杂志文章

    doi：10.1038/nm0898-953

    authors： Komanduri KV,Viswanathan MN,Wieder ED,Schmidt DK,Bredt BM,Jacobson MA,McCune JM

    更新日期：1998-08-01 00:00:00

  • Immunosuppression in acutely decompensated cirrhosis is mediated by prostaglandin E2.

    abstract：:Liver disease is one of the leading causes of death worldwide. Patients with cirrhosis display an increased predisposition to and mortality from infection due to multimodal defects in the innate immune system; however, the causative mechanism has remained elusive. We present evidence that the cyclooxygenase (COX)-deri...

    journal_title：Nature medicine

    pub_type： 杂志文章

    doi：10.1038/nm.3516

    authors： O'Brien AJ,Fullerton JN,Massey KA,Auld G,Sewell G,James S,Newson J,Karra E,Winstanley A,Alazawi W,Garcia-Martinez R,Cordoba J,Nicolaou A,Gilroy DW

    更新日期：2014-05-01 00:00:00

  • Neoadjuvant immunotherapy leads to pathological responses in MMR-proficient and MMR-deficient early-stage colon cancers.

    abstract：:PD-1 plus CTLA-4 blockade is highly effective in advanced-stage, mismatch repair (MMR)-deficient (dMMR) colorectal cancers, yet not in MMR-proficient (pMMR) tumors. We postulated a higher efficacy of neoadjuvant immunotherapy in early-stage colon cancers. In the exploratory NICHE study (ClinicalTrials.gov: NCT03026140...

    journal_title：Nature medicine

    pub_type： 杂志文章,随机对照试验

    doi：10.1038/s41591-020-0805-8

    authors： Chalabi M,Fanchi LF,Dijkstra KK,Van den Berg JG,Aalbers AG,Sikorska K,Lopez-Yurda M,Grootscholten C,Beets GL,Snaebjornsson P,Maas M,Mertz M,Veninga V,Bounova G,Broeks A,Beets-Tan RG,de Wijkerslooth TR,van Lent AU,Mars

    更新日期：2020-04-01 00:00:00

  • Negative feedback-defective PRPS1 mutants drive thiopurine resistance in relapsed childhood ALL.

    abstract：:Relapse is the leading cause of mortality in children with acute lymphoblastic leukemia (ALL). Among chemotherapeutics, thiopurines are key drugs in ALL combination therapy. Using whole-exome sequencing, we identified relapse-specific mutations in the phosphoribosyl pyrophosphate synthetase 1 gene (PRPS1), which encod...

    journal_title：Nature medicine

    pub_type： 杂志文章

    doi：10.1038/nm.3840

    authors： Li B,Li H,Bai Y,Kirschner-Schwabe R,Yang JJ,Chen Y,Lu G,Tzoneva G,Ma X,Wu T,Li W,Lu H,Ding L,Liang H,Huang X,Yang M,Jin L,Kang H,Chen S,Du A,Shen S,Ding J,Chen H,Chen J,von Stackelberg A,Gu L,Zhang J,

    更新日期：2015-06-01 00:00:00

  • Successful transduction of liver in hemophilia by AAV-Factor IX and limitations imposed by the host immune response.

    abstract：:We have previously shown that a single portal vein infusion of a recombinant adeno-associated viral vector (rAAV) expressing canine Factor IX (F.IX) resulted in long-term expression of therapeutic levels of F.IX in dogs with severe hemophilia B. We carried out a phase 1/2 dose-escalation clinical study to extend this ...

    journal_title：Nature medicine

    pub_type： 杂志文章

    doi：10.1038/nm1358

    authors： Manno CS,Pierce GF,Arruda VR,Glader B,Ragni M,Rasko JJ,Ozelo MC,Hoots K,Blatt P,Konkle B,Dake M,Kaye R,Razavi M,Zajko A,Zehnder J,Rustagi PK,Nakai H,Chew A,Leonard D,Wright JF,Lessard RR,Sommer JM,Tigges M,S

    更新日期：2006-03-01 00:00:00

  • Peroxiredoxin family proteins are key initiators of post-ischemic inflammation in the brain.

    abstract：:Post-ischemic inflammation is an essential step in the progression of brain ischemia-reperfusion injury. However, the mechanism that activates infiltrating macrophages in the ischemic brain remains to be clarified. Here we demonstrate that peroxiredoxin (Prx) family proteins released extracellularly from necrotic brai...

    journal_title：Nature medicine

    pub_type： 杂志文章

    doi：10.1038/nm.2749

    authors： Shichita T,Hasegawa E,Kimura A,Morita R,Sakaguchi R,Takada I,Sekiya T,Ooboshi H,Kitazono T,Yanagawa T,Ishii T,Takahashi H,Mori S,Nishibori M,Kuroda K,Akira S,Miyake K,Yoshimura A

    更新日期：2012-06-01 00:00:00

  • Restoration of immunity in lymphopenic individuals with cancer by vaccination and adoptive T-cell transfer.

    abstract：:Immunodeficiency is a barrier to successful vaccination in individuals with cancer and chronic infection. We performed a randomized phase 1/2 study in lymphopenic individuals after high-dose chemotherapy and autologous hematopoietic stem cell transplantation for myeloma. Combination immunotherapy consisting of a singl...

    journal_title：Nature medicine

    pub_type： 杂志文章,随机对照试验

    doi：10.1038/nm1310

    authors： Rapoport AP,Stadtmauer EA,Aqui N,Badros A,Cotte J,Chrisley L,Veloso E,Zheng Z,Westphal S,Mair R,Chi N,Ratterree B,Pochran MF,Natt S,Hinkle J,Sickles C,Sohal A,Ruehle K,Lynch C,Zhang L,Porter DL,Luger S,Guo C,

    更新日期：2005-11-01 00:00:00

  • AIDS restriction HLA allotypes target distinct intervals of HIV-1 pathogenesis.

    abstract：:An effective acquired immune response to infectious agents mediated by HLA-restricted T-cell recognition can target different stages of disease pathogenesis. We show here that three distinct HLA alleles known to alter the overall rate of AIDS progression act during distinct intervals after HIV-1 infection. The discret...

    journal_title：Nature medicine

    pub_type： 杂志文章

    doi：10.1038/nm1333

    authors： Gao X,Bashirova A,Iversen AK,Phair J,Goedert JJ,Buchbinder S,Hoots K,Vlahov D,Altfeld M,O'Brien SJ,Carrington M

    更新日期：2005-12-01 00:00:00

  • Serum insulin-like growth factor I regulates brain amyloid-beta levels.

    abstract：:Levels of insulin-like growth factor I (IGF-I), a neuroprotective hormone, decrease in serum during aging, whereas amyloid-beta (Abeta), which is involved in the pathogenesis of Alzheimer disease, accumulates in the brain. High brain Abeta levels are found at an early age in mutant mice with low circulating IGF-I, and...

    journal_title：Nature medicine

    pub_type： 杂志文章

    doi：10.1038/nm1202-793

    authors： Carro E,Trejo JL,Gomez-Isla T,LeRoith D,Torres-Aleman I

    更新日期：2002-12-01 00:00:00

  • Intravenous immunoglobulin ameliorates ITP via activating Fc gamma receptors on dendritic cells.

    abstract：:Despite a more than 20-year experience of therapeutic benefit, the relevant molecular and cellular targets of intravenous immunoglobulin (IVIg) in autoimmune disease remain unclear. Contrary to the prevailing theories of IVIg action in autoimmunity, we show that IVIg drives signaling through activating Fc gamma recept...

    journal_title：Nature medicine

    pub_type： 杂志文章

    doi：10.1038/nm1416

    authors： Siragam V,Crow AR,Brinc D,Song S,Freedman J,Lazarus AH

    更新日期：2006-06-01 00:00:00

  • Interleukin-6-deficient mice develop mature-onset obesity.

    abstract：:The immune-modulating cytokine interleukin-6 (IL-6) is expressed both in adipose tissue and centrally in hypothalamic nuclei that regulate body composition. We investigated the impact of loss of IL-6 on body composition in mice lacking the gene encoding IL-6 (Il6-/- mice) and found that they developed mature-onset obe...

    journal_title：Nature medicine

    pub_type： 杂志文章

    doi：10.1038/nm0102-75

    authors： Wallenius V,Wallenius K,Ahrén B,Rudling M,Carlsten H,Dickson SL,Ohlsson C,Jansson JO

    更新日期：2002-01-01 00:00:00

  • Immune complement and coagulation dysfunction in adverse outcomes of SARS-CoV-2 infection.

    abstract：:Understanding the pathophysiology of SARS-CoV-2 infection is critical for therapeutic and public health strategies. Viral-host interactions can guide discovery of disease regulators, and protein structure function analysis points to several immune pathways, including complement and coagulation, as targets of coronavir...

    journal_title：Nature medicine

    pub_type： 杂志文章

    doi：10.1038/s41591-020-1021-2

    authors： Ramlall V,Thangaraj PM,Meydan C,Foox J,Butler D,Kim J,May B,De Freitas JK,Glicksberg BS,Mason CE,Tatonetti NP,Shapira SD

    更新日期：2020-10-01 00:00:00

  • Suppressing aberrant GluN3A expression rescues synaptic and behavioral impairments in Huntington's disease models.

    abstract：:Huntington's disease is caused by an expanded polyglutamine repeat in the huntingtin protein (HTT), but the pathophysiological sequence of events that trigger synaptic failure and neuronal loss are not fully understood. Alterations in N-methyl-D-aspartate (NMDA)-type glutamate receptors (NMDARs) have been implicated. ...

    journal_title：Nature medicine

    pub_type： 杂志文章

    doi：10.1038/nm.3246

    authors： Marco S,Giralt A,Petrovic MM,Pouladi MA,Martínez-Turrillas R,Martínez-Hernández J,Kaltenbach LS,Torres-Peraza J,Graham RK,Watanabe M,Luján R,Nakanishi N,Lipton SA,Lo DC,Hayden MR,Alberch J,Wesseling JF,Pérez-Otaño I

    更新日期：2013-08-01 00:00:00

  • Mice deficient in tumor necrosis factor-alpha are resistant to skin carcinogenesis.

    abstract：:Given the associations between chronic inflammation and epithelial cancer, we studied susceptibility to skin carcinogenesis in mice deficient for the pro-inflammatory cytokine TNF-alpha (refs. 5,6). TNF-alpha(-/-) mice were resistant to development of benign and malignant skin tumors, whether induced by initiation wit...

    journal_title：Nature medicine

    pub_type： 杂志文章

    doi：10.1038/10552

    authors： Moore RJ,Owens DM,Stamp G,Arnott C,Burke F,East N,Holdsworth H,Turner L,Rollins B,Pasparakis M,Kollias G,Balkwill F

    更新日期：1999-07-01 00:00:00

  • Effects of underfeeding and oral vancomycin on gut microbiome and nutrient absorption in humans.

    abstract：:Direct evidence in humans for the impact of the microbiome on nutrient absorption is lacking. We conducted an extended inpatient study using two interventions that we hypothesized would alter the gut microbiome and nutrient absorption. In each, stool calorie loss, a direct proxy of nutrient absorption, was measured. T...

    journal_title：Nature medicine

    pub_type： 杂志文章,随机对照试验

    doi：10.1038/s41591-020-0801-z

    authors： Basolo A,Hohenadel M,Ang QY,Piaggi P,Heinitz S,Walter M,Walter P,Parrington S,Trinidad DD,von Schwartzenberg RJ,Turnbaugh PJ,Krakoff J

    更新日期：2020-04-01 00:00:00

  • Direct-to-stomach delivery.

    abstract：: ...

    journal_title：Nature medicine

    pub_type： 评论,杂志文章

    doi：10.1038/s41591-019-0397-3

    authors： Stower H

    更新日期：2019-03-01 00:00:00

  • Alternate replication in B cells and epithelial cells switches tropism of Epstein-Barr virus.

    abstract：:Epstein-Barr virus is ubiquitous and is causally implicated in lymphoid and epithelial malignancies. Virus invades oropharyngeal mucosa and establishes latency in B lymphocytes. Reactivating lymphocytes shed virus into saliva for spread to new hosts. A complex of three virus glycoproteins, gH, gL and gp42, is essentia...

    journal_title：Nature medicine

    pub_type： 杂志文章

    doi：10.1038/nm0602-594

    authors： Borza CM,Hutt-Fletcher LM

    更新日期：2002-06-01 00:00:00

  • Publisher Correction: Neuromodulation of lumbosacral spinal networks enables independent stepping after complete paraplegia.

    abstract：:In the version of this article originally published, Dimitry G. Sayenko's affiliations were not correct. The following affiliation for this author was missing: Department of Neurosurgery, Center for Neuroregeneration, Houston Methodist Research Institute, Houston, TX, USA. This affiliation has been added for the autho...

    journal_title：Nature medicine

    pub_type： 已发布勘误

    doi：10.1038/s41591-018-0248-7

    authors： Gill ML,Grahn PJ,Calvert JS,Linde MB,Lavrov IA,Strommen JA,Beck LA,Sayenko DG,Van Straaten MG,Drubach DI,Veith DD,Thoreson AR,Lopez C,Gerasimenko YP,Edgerton VR,Lee KH,Zhao KD

    更新日期：2018-12-01 00:00:00

  • TLR4 enhances TGF-beta signaling and hepatic fibrosis.

    abstract：:Hepatic injury is associated with a defective intestinal barrier and increased hepatic exposure to bacterial products. Here we report that the intestinal bacterial microflora and a functional Toll-like receptor 4 (TLR4), but not TLR2, are required for hepatic fibrogenesis. Using Tlr4-chimeric mice and in vivo lipopoly...

    journal_title：Nature medicine

    pub_type： 杂志文章

    doi：10.1038/nm1663

    authors： Seki E,De Minicis S,Osterreicher CH,Kluwe J,Osawa Y,Brenner DA,Schwabe RF

    更新日期：2007-11-01 00:00:00

  • Racioethnic diversity in the dynamics of the vaginal microbiome during pregnancy.

    abstract：:The microbiome of the female reproductive tract has implications for women's reproductive health. We examined the vaginal microbiome in two cohorts of women who experienced normal term births: a cross-sectionally sampled cohort of 613 pregnant and 1,969 non-pregnant women, focusing on 300 pregnant and 300 non-pregnant...

    journal_title：Nature medicine

    pub_type： 杂志文章

    doi：10.1038/s41591-019-0465-8

    authors： Serrano MG,Parikh HI,Brooks JP,Edwards DJ,Arodz TJ,Edupuganti L,Huang B,Girerd PH,Bokhari YA,Bradley SP,Brooks JL,Dickinson MR,Drake JI,Duckworth RA 3rd,Fong SS,Glascock AL,Jean S,Jimenez NR,Khoury J,Koparde VN,La

    更新日期：2019-06-01 00:00:00

  • Impaired flow-dependent control of vascular tone and remodeling in P2X4-deficient mice.

    abstract：:The structure and function of blood vessels adapt to environmental changes such as physical development and exercise. This phenomenon is based on the ability of the endothelial cells to sense and respond to blood flow; however, the underlying mechanisms remain unclear. Here we show that the ATP-gated P2X4 ion channel,...

    journal_title：Nature medicine

    pub_type： 杂志文章

    doi：10.1038/nm1338

    authors： Yamamoto K,Sokabe T,Matsumoto T,Yoshimura K,Shibata M,Ohura N,Fukuda T,Sato T,Sekine K,Kato S,Isshiki M,Fujita T,Kobayashi M,Kawamura K,Masuda H,Kamiya A,Ando J

    更新日期：2006-01-01 00:00:00

  • Deciphering the genomic, epigenomic, and transcriptomic landscapes of pre-invasive lung cancer lesions.

    abstract：:The molecular alterations that occur in cells before cancer is manifest are largely uncharted. Lung carcinoma in situ (CIS) lesions are the pre-invasive precursor to squamous cell carcinoma. Although microscopically identical, their future is in equipoise, with half progressing to invasive cancer and half regressing o...

    journal_title：Nature medicine

    pub_type： 杂志文章

    doi：10.1038/s41591-018-0323-0

    authors： Teixeira VH,Pipinikas CP,Pennycuick A,Lee-Six H,Chandrasekharan D,Beane J,Morris TJ,Karpathakis A,Feber A,Breeze CE,Ntolios P,Hynds RE,Falzon M,Capitanio A,Carroll B,Durrenberger PF,Hardavella G,Brown JM,Lynch AG,Fa

    更新日期：2019-03-01 00:00:00

  • Author Correction: China's response to a novel coronavirus stands in stark contrast to the 2002 SARS outbreak response.

    abstract：:An amendment to this paper has been published and can be accessed via a link at the top of the paper. ...

    journal_title：Nature medicine

    pub_type： 杂志文章,已发布勘误

    doi：10.1038/s41591-020-0816-5

    authors： Nkengasong J

    更新日期：2020-03-01 00:00:00

  • In vivo site-directed mutagenesis of the factor IX gene by chimeric RNA/DNA oligonucleotides.

    abstract：:A chimeric RNA/DNA oligonucleotide was constructed to induce a sequence mutation in the rat factor IX gene, resulting in prolonged coagulation. Oligonucleotides were targeted to hepatocytes in cell culture or in vivo by intravenous injection. Nucleotide conversion was both site-specific and dose-dependent. The mutated...

    journal_title：Nature medicine

    pub_type： 杂志文章

    doi：10.1038/nm0398-285

    authors： Kren BT,Bandyopadhyay P,Steer CJ

    更新日期：1998-03-01 00:00:00

  • Peroxisome proliferator-activated receptor-delta attenuates colon carcinogenesis.

    abstract：:Peroxisome proliferator-activated receptor-delta (PPAR-delta; also known as PPAR-beta) is expressed at high levels in colon tumors, but its contribution to colon cancer is unclear. We examined the role of PPAR-delta in colon carcinogenesis using PPAR-delta-deficient (Ppard(-/-)) mice. In both the Min mutant and chemic...

    journal_title：Nature medicine

    pub_type： 杂志文章

    doi：10.1038/nm1026

    authors： Harman FS,Nicol CJ,Marin HE,Ward JM,Gonzalez FJ,Peters JM

    更新日期：2004-05-01 00:00:00