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Genomics and pharmacogenomics of sepsis: so close and yet so far Russell, James A Jul 7, 2016

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COMMENTARY Open AccessGenomics and pharmacogenomics ofsepsis: so close and yet so farJames A. Russell1,2AbstractSapru et al. show in this issue of Critical Care thatvariants of thrombomodulin and the endothelialprotein C receptor, but not protein C, are associatedwith mortality and organ dysfunction (ventilation-freeand organ failure-free days) in ARDS. Hundreds ofgene variants have been found prognostic in sepsis.However, none of these prognostic genomicbiomarkers are used clinically. Predictive biomarkerdiscovery (pharmacogenomics) usually follows acandidate gene approach, utilizing knowledge of drugpathways. Pharmacogenomics could be applied toenhance efficacy and safety of drugs used fortreatment of sepsis (e.g., norepinephrine, epinephrine,vasopressin, and corticosteroids). Pharmacogenomicscan enhance drug development in sepsis, which isvery important because there is no approved drug forsepsis. Pharmacogenomics biomarkers must pass threemilestones: scientific, regulatory, and commercial. Hugechallenges remain but great opportunities forpharmacogenomics of sepsis are on the horizon.This issue of Critical Care presents a novel human gen-omics study showing that variants of thrombomodulin(TM) and the endothelial protein C receptor (EPCR),but not protein C, are associated with mortality and organdysfunction (ventilation-free and organ failure-free days) inARDS—that is, they are prognostic biomarkers [1].Strengths include the cohort, gene, and variant selections,Hardy–Weinberg equilibrium, correlation of variants withplasma protein levels, correction for multiple comparisons,a haplotype model, a multivariant approach, and a priorisample size calculation. A relative weakness was theCorrespondence: Jim.Russell@hli.ubc.ca1Centre for Heart Lung Innovation, St. Paul’s Hospital, 1081 Burrard Street,Vancouver, BC V6Z 1Y6, Canada2Division of Critical Care Medicine, St. Paul’s Hospital, University of BritishColumbia, 1081 Burrard Street, Vancouver, BC V6Z 1Y6, CanadaSee related research by Sapru et al., https://ccforum.biomedcentral.com/articles/10.1186/s13054-016-1330-5reliance on literature for biological plausibility of the“significant” variants. These innovative insights could leadto “predictive biomarkers” for response to recombinanthuman TM and even activated protein C (APC) in sepsis.Genomics and pharmacogenomics (PGx) are pivotal tofields such as cancer and cardiovascular medicine. Incancer, PGx biomarker(s) include trastuzumab (Hercep-tin, HER2), irenotecan (UGT1A1*28), azothioprine and6-mercaptopurine (TPMT), capecitabine (dihydropyri-midine dehydrogenase), and cetuximab/panitumumab(KRAS)—these drugs are very frequently given accordingto the specific PGx biomarker. In cardiovascular medicine,clopidogrel (CYP2C19) and warfarin (VKORC1) are well-documented PGx biomarkers that indicate altered efficacyand safety respectively. PGx biomarkers are used increas-ingly in clinical practice.Sepsis has gone through 15 years of discovery of manygenomic biomarkers [2, 3]. A PubMed search for “sepsisand polymorphism” yields 1199 publications. Let us de-fine some terminology: a prognostic biomarker identifiesprognosis (e.g., increased risk of death); a diagnostic bio-marker diagnoses condition (e.g., sepsis diagnostic); anda predictive biomarker (companion diagnostic) usesgenomics to define response to a drug (see http://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/InVi-troDiagnostics/ucm407297.htm). Over 100 drugs have ap-proved predictive biomarkers on the drug label (http://www.fda.gov/drugs/scienceresearch/researchareas/pharma-cogenetics/ucm083378.htm)!About one quarter of the human genome changes ex-pression in sepsis [4], so it is not surprising that hun-dreds of variants are described in sepsis [3]. However,none of these prognostic genomic biomarkers are usedclinically, probably because of lack of clinical utility (i.e.,the test result would not change a clinician’s behavior).Nonetheless, genomics of sepsis studies have identifiedkey pathways associated with specific organ dysfunctionsand mortality, and have identified drug targets in sepsis(e.g., proprotein convertase subtilisin/kexin type 9 (PCSK9)© 2016 The Author(s). Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Russell Critical Care  (2016) 20:185 DOI 10.1186/s13054-016-1374-6Table 1 Potential pharmacogenomic biomarkers and steps to discovery for drugs used clinically, drugs in development, and drugsthat could be resurrected in sepsisDrugs in use clinically in sepsis and septic shock Potential pharmacogenomic biomarkers First step(s) to discovery/validation of PGx biomarkersNorepinephrine (NE), epinephrine (EP),dobutamineARs:ADBR1 and ADBR2 [7] SNPsADRA1A and B SNPsG-protein subunits (α, β, and γ) of ADR2aα2A N251K and α2C Δ322-325 (common AR SNPs)ADRA2A, B and C SNPsADCY9 SNPsGenotyping of patients in RCT(e.g., Annane et al. [8])Vasopressin LNPEP SNPs [9],AVPR1a, AVPR1b, and AVPR2 SNPsGenotyping of patients in RCT(e.g., Russell et al. [10])Corticosteroids CRF SNPsGRs [11]GR heterocomplex gene STIP1 SNPs:ER22/23EK (common GR SNP)GR: N363S (common GR SNP)GR: 9β A/G (common GR SNP)Bcll (common GR SNP)GLCC1 SNPsABCB1 SNPsIL-1β SNPsNR3C1 SNPsMR SNPs (e.g., TthIIII, MRI180V, and MR-2G/C)NALP1 SNPsNK2R SNPsCTLA4 SNPsGenotyping of patients in RCT(e.g., Sprung et al. [12])Examples of drugs used in sepsis thathave FDA-approved companion diagnosticsDiazepam CYP2C19 (poor metabolizers of diazepam) FDA labelaMethylene blue G6PD deficiency FDA labelaOmeprazole, pantoprazole CYP2C19 (poor metabolizers of Omeprazole andpantoprazole)FDA labelaResperidone CYP2D6 (poor metabolizers of respiradone) FDA labelaDrugs in or near developmentThrombomodulin (TM) TM, EPCR [1], and Genotyping of patients in RCTbPROC SNPsSelepressin LNPEP SNPs [9],AVPR1a SNPsGenotyping of patients in RCTbAngiotensin II (ANG II) AGT SNPsAGTRAP SNPs [13]ACE SNPs and IDAT1R and 2R SNPsGenotyping of patients in RCTbPCSK9 inhibitor PCSK9 SNPs [5] Genotyping of patients in RCTbIL-7 IL-7, IL-7ra SNPs Genotyping of patients in RCTbEsmolol ADBR1A and B SNPs [7] Genotyping of patients in RCTResurrecting a drugActivated protein C TM, EPCR [1]PROC SNPs [14]Genotyping of patients in RCT(e.g., Ranieri et al. [15])PGx pharmacogenomics, SNP single nucleotide polymorphism, RCT randomized controlled trial, AR adrenergic receptorADRA adrenergic alpha receptor, ADBR1/2 β1/2-adrenergic receptor, LNPEP leucyl/cystinyl aminopeptidase (vasopressinase), AVPR1a/b gene name for V1a/breceptors, CRF corticotropin-releasing factor, ADCY9 adenylyl cyclase type 9, EPCR endothelial protein C receptor, PROC protein C, GR membrane-bound andcytosolic glucocorticoid receptor, GLCCI1 glucocorticoid-induced transcript 1 gene, ABCB1 gene codes for P-glycoprotein, NR3C1 glucocorticoid receptor gene, MRmineralocorticoid receptor, NALP1 NACHT leucine-rich-repeat protein 1, NK2R neurokinin receptor 2, CTLA4 anti-cytotoxic T lymphocyte-associated antigen-4, PCSK9proprotein convertase subtilisin/kexin type 9, CYP2C19 cytochrome P450 2C19, G6PD glucose-6-phosphate dehydrogenase, AGT angiotensinogen gene, AGTRAPangiotensin II receptor-associated protein, ACE angiotensin-converting enzyme, ID insertion/deletion polymorphisms, AT1/ 2R angiotensin-II type 1 and 2 receptorgene, IL-7ra interleukin-7 receptor alpha chainaThese markers are already approved for clinical use with shown drugs on the drug FDA label. No further RCTs are required for “on label” clinical use of thecompanion diagnostic strategy in practicebOverviews of RCTs of: thrombomodulin (https://clinicaltrials.gov/ct2/show/NCT01598831?term=thrombomodulin+in+sepsis&rank=2),selepressin (https://clinicaltrials.gov/ct2/show/NCT02508649?term=selepressin+in+shock&rank=1)angiotensin II, (https://clinicaltrials.gov/ct2/show/NCT01393782?term=angiotensin+II+in+septic+shock&rank=2), andIL-7 (https://clinicaltrials.gov/ct2/show/NCT02640807?term=il-7+in+sepsis&rank=1)Russell Critical Care  (2016) 20:185 Page 2 of 4[5]). Variants of PCSK9 were associated with outcomes ofsepsis, and post treatment of cecal ligation and perforationmodel mice with PCSK9 inhibitors decreased inflamma-tion, cardiovascular dysfunction, and mortality; thus,PCSK9 inhibition could be effective in sepsis [5]. This ex-ample could be expanded to other genes and novel drugs.Predictive biomarker discovery often follows a candi-date gene approach, utilizing knowledge of drug recep-tors, transporters, enzymes that metabolize a drug, anddrug target pathways. Predictive biomarkers often havehigh clinical utility. FDA-approved drug labels have ahierarchy of recommendations for companion diagnos-tics: (1) for information (i.e., descriptions of publishedstudies of PGx related to the drug); (2) recommended—-physicians are encouraged to measure the biomarker;and (3) required—physicians MUST use the companiondiagnostic to prescribe the drug. The required companiondiagnostic relates to trastuzumab: HER2 must test positivefor identifying good responders to order trastuzumab.The PGx biomarker discovery pathway is arduous, time-consuming, and expensive. A successful PGx biomarkermust pass three milestones: scientific, regulatory, andcommercial. Scientific steps include: a decision regardinga nonhypothesis-driven (genome-wide) vs a candidategene approach, RCTs, significant drug/PGx biomarkerinteraction, validation often in a separate RCT, and valid-ation of a rapid turnaround time (TAT) kit in real time.The regulatory node includes many submissions and visitsto regulators before and after each study. Regulators haveapproved PGx biomarkers in cancer that were assessed atthe end of pivotal RCTs provided that the biomarker hy-pothesis was logged before locking the RCT dataset. Thus,selection of PGx biomarkers may occur in parallel withRCT execution. Finally, the commercial node includescosts of kits, reimbursement methods and amounts,FDA-approved and EMEA-approved manufacturing,and distribution of a rapid TAT kit (and sometimes aunique “box” for measuring the biomarker) to hospitals(laboratories and/or ICUs or EDs).PGx could be applied to enhance efficacy and safety ofdrugs in use for sepsis and septic shock including nor-epinephrine, epinephrine, vasopressin, and corticoste-roids (CS) (Table 1); known genomic variants intersectwith these drugs. Genomics of the CS and vasopressin(AVP) axes have been well studied for prediction of re-sponse to CS (and less so vasopressin), because CS andAVP variants are widely studied in many conditions andbecause CS are used in so many conditions (Table 1).PGx can also enhance drug development, very importantsince there is no approved drug for sepsis. PGx could in-crease chances of drug development success in sepsis; thatis, precision medicine to enrich the heterogeneous sepsiscohorts [2, 6]. Potential predictive biomarkers/companiondiagnostics could be used with recombinant human TM,selepressin, angiotensin II, PCSK9 inhibitor, IL-7, andesmolol (Table 1). Studies of PGx of ACE inhibitors in car-diovascular disease and IL-7 in cancer could inform angio-tensin II and IL-7 PGx in sepsis (Table 1). Several drugsused clinically in sepsis have proven companion diagnostics(Table 1).Finally, PGx could resurrect “dead” drugs by increasingefficacy. APC could be resurrected by using genetic vari-ants such as those discovered by Sapru et al. [1] that mightmark patients who have an enhanced response to APC toenrich patient selection in a future RCT (Table 1).In summary, there remain huge challenges but greatopportunities for genomics, and I think more import-antly for PGx of sepsis. We are close—but yet so far be-cause there are many complex steps and milestones tobring a novel PGx biomarker to septic patients and theircaregivers. I remain very optimistic that researchers suchas Sapru et al. [1] and other scientists in the field are upto the challenge!AbbreviationsAPC, activated protein C; CS, corticosteroids; EPCR, endothelial protein Creceptor; PCSK9, proprotein convertase subtilisin/kexin type 9; PGx,pharmacogenomics; RCT, randomized controlled trial; TAT, turnaround time;TM, thrombomodulinAuthors’ contributionsJAR conceived, designed, researched, and wrote the submission. The authorread and approved the final manuscript.Competing interestsJAR reports patents owned by the University of British Columbia (UBC)that are related to PCSK9 inhibitor(s) and sepsis and related to the use ofvasopressin in septic shock. JAR is an inventor on these patents. JAR is afounder, director, and shareholder in Cyon Therapeutics Inc. (developing asepsis therapy); has share options in Leading Biosciences Inc.; and is ashareholder in Molecular You Corp. JAR reports receiving consulting feesfrom Cubist Pharmaceuticals (now owned by Merck, formerly was TriusPharmaceuticals; developing antibiotics), Leading Biosciences (developinga sepsis therapeutic), Ferring Pharmaceuticals (manufacturing vasopressinand developing selepressin), Grifols (selling albumin), and La JollaPharmaceuticals (developing angiotensin II); chairs the DSMB of a trial ofangiotensin II), CytoVale Inc. (developing a sepsis diagnostic), and Asahi KesaiPharmaceuticals of America (AKPA; developing recombinant thrombomodulin);and reports having received grant support from Ferring Pharmaceuticals andfrom Grifols that was provided to and administered by UBC.References1. Sapru A, Liu KD, Wiemels J, et al. Association of common genetic variationin the protein C pathway genes with clinical outcomes in acute respiratorydistress syndrome. Crit Care. 2016;20:151.2. Vincent JL. Individual gene expression and personalised medicine in sepsis.Lancet Respir Med. 2016;4(4):242–43.3. Christaki E, Giamarellos-Bourboulis EJ. The beginning of personalizedmedicine in sepsis: small steps to a bright future. Clin Genet. 2014;86(1):56–61.4. Calvano SE, Xiao W, Richards DR, et al. A network-based analysis of systemicinflammation in humans. Nature. 2005;437(7061):1032–7.5. Walley KR, Thain KR, Russell JA, et al. PCSK9 is a critical regulator of theinnate immune response and septic shock outcome. Sci Transl Med. 2014;6(258):258ra143.6. Mebazaa A, Laterre PF, Russell JA, et al. Designing phase 3 sepsis trials:application of learned experiences from critical care trials in acute heartfailure. J Int Care. 2016;4:24.Russell Critical Care  (2016) 20:185 Page 3 of 47. Nakada TA, Russell JA, Boyd JH, et al. beta2-Adrenergic receptor genepolymorphism is associated with mortality in septic shock. Am J Respir CritCare Med. 2010;181(2):143–9.8. Annane D, Vignon P, Renault A, et al. Norepinephrine plus dobutamineversus epinephrine alone for management of septic shock: a randomisedtrial. Lancet. 2007;370(9588):676–84.9. Nakada TA, Russell JA, Wellman H, et al. Leucyl/cystinyl aminopeptidasegene variants in septic shock. Chest. 2011;139(5):1042–9.10. Russell JA, Walley KR, Singer J, et al. Vasopressin versus norepinephrineinfusion in patients with septic shock. N Engl J Med. 2008;358(9):877–87.11. Lasker MV, Leventhal SM, Lim D, et al. Hyperactive human glucocorticoidreceptor isoforms and their implications for the stress response. Shock.2015;43(3):228–32.12. Sprung CL, Annane D, Keh D, et al. Hydrocortisone therapy for patients withseptic shock. N Engl J Med. 2008;358(2):111–24.13. Nakada TA, Russell JA, Boyd JH, et al. Association of angiotensin II type 1receptor-associated protein gene polymorphism with increased mortality inseptic shock. Crit Care Med. 2011;39(7):1641–8.14. Walley KR, Russell JA. Protein C −1641 AA is associated with decreasedsurvival and more organ dysfunction in severe sepsis. Crit Care Med.2007;35(1):12–7.15. Ranieri VM, Thompson BT, Barie PS, et al. Drotrecogin alfa (activated) inadults with septic shock. N Engl J Med. 2012;366(22):2055–64.Russell Critical Care  (2016) 20:185 Page 4 of 4

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