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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)