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Table 1 Potential pharmacogenomic biomarkers and steps to discovery for drugs used clinically, drugs in development, and drugs that could be resurrected in sepsis

From: Genomics and pharmacogenomics of sepsis: so close and yet so far

Drugs in use clinically in sepsis and septic shock

Potential pharmacogenomic biomarkers

First step(s) to discovery/validation of PGx biomarkers

Norepinephrine (NE), epinephrine (EP), dobutamine

ARs:

ADBR1 and ADBR2 [7] SNPs

ADRA1A and B SNPs

G-protein subunits (α, β, and γ) of ADR2a

α2A N251K and α2C Δ322-325 (common AR SNPs)

ADRA2A, B and C SNPs

ADCY9 SNPs

Genotyping of patients in RCT

(e.g., Annane et al. [8])

Vasopressin

LNPEP SNPs [9],

AVPR1a, AVPR1b, and AVPR2 SNPs

Genotyping of patients in RCT

(e.g., Russell et al. [10])

Corticosteroids

CRF SNPs

GRs [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 SNPs

ABCB1 SNPs

IL-1β SNPs

NR3C1 SNPs

MR SNPs (e.g., TthIIII, MRI180V, and MR-2G/C)

NALP1 SNPs

NK2R SNPs

CTLA4 SNPs

Genotyping of patients in RCT

(e.g., Sprung et al. [12])

Examples of drugs used in sepsis that have FDA-approved companion diagnostics

Diazepam

CYP2C19 (poor metabolizers of diazepam)

FDA labela

Methylene blue

G6PD deficiency

FDA labela

Omeprazole, pantoprazole

CYP2C19 (poor metabolizers of Omeprazole and pantoprazole)

FDA labela

Resperidone

CYP2D6 (poor metabolizers of respiradone)

FDA labela

Drugs in or near development

  

Thrombomodulin (TM)

TM, EPCR [1], and

Genotyping of patients in RCTb

PROC SNPs

Selepressin

LNPEP SNPs [9],

AVPR1a SNPs

Genotyping of patients in RCTb

Angiotensin II (ANG II)

AGT SNPs

AGTRAP SNPs [13]

ACE SNPs and ID

AT1R and 2R SNPs

Genotyping of patients in RCTb

PCSK9 inhibitor

PCSK9 SNPs [5]

Genotyping of patients in RCTb

IL-7

IL-7, IL-7ra SNPs

Genotyping of patients in RCTb

Esmolol

ADBR1A and B SNPs [7]

Genotyping of patients in RCT

Resurrecting a drug

  

Activated protein C

TM, EPCR [1]

PROC SNPs [14]

Genotyping of patients in RCT

(e.g., Ranieri et al. [15])

  1. PGx pharmacogenomics, SNP single nucleotide polymorphism, RCT randomized controlled trial, AR adrenergic receptor
  2. ADRA adrenergic alpha receptor, ADBR1/2 β1/2-adrenergic receptor, LNPEP leucyl/cystinyl aminopeptidase (vasopressinase), AVPR1a/b gene name for V1a/b receptors, CRF corticotropin-releasing factor, ADCY9 adenylyl cyclase type 9, EPCR endothelial protein C receptor, PROC protein C, GR membrane-bound and cytosolic glucocorticoid receptor, GLCCI1 glucocorticoid-induced transcript 1 gene, ABCB1 gene codes for P-glycoprotein, NR3C1 glucocorticoid receptor gene, MR mineralocorticoid receptor, NALP1 NACHT leucine-rich-repeat protein 1, NK2R neurokinin receptor 2, CTLA4 anti-cytotoxic T lymphocyte-associated antigen-4, PCSK9 proprotein convertase subtilisin/kexin type 9, CYP2C19 cytochrome P450 2C19, G6PD glucose-6-phosphate dehydrogenase, AGT angiotensinogen gene, AGTRAP angiotensin II receptor-associated protein, ACE angiotensin-converting enzyme, ID insertion/deletion polymorphisms, AT1/ 2R angiotensin-II type 1 and 2 receptor gene, IL-7ra interleukin-7 receptor alpha chain
  3. aThese 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 the companion diagnostic strategy in practice
  4. bOverviews 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)
  5. angiotensin II, (https://clinicaltrials.gov/ct2/show/NCT01393782?term=angiotensin+II+in+septic+shock&rank=2), and IL-7 (https://clinicaltrials.gov/ct2/show/NCT02640807?term=il-7+in+sepsis&rank=1)
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