Gene:
PROC
protein C (inactivator of coagulation factors Va and VIIIa)

PharmGKB contains no dosing guidelines for this . To report known genotype-based dosing guidelines, or if you are interested in developing guidelines, click here.

PharmGKB gathers information regarding PGx on FDA drug labels from the FDA's "Table of Pharmacogenomic Biomarkers in Drug Labels", and from FDA-approved FDA and EMA-approved (European Medicines Agency) EMA labels brought to our attention. Excerpts from the label and downloadable highlighted label PDFs are manually curated by PharmGKB.

Please note that some drugs may have been removed from or added to the FDA's "Table of Pharmacogenomic Biomarkers in Drug Labels" without our knowledge. We periodically check the table for additions to this table and update PharmGKB accordingly.

There is currently no such list for European drug labels - we are working with the EMA to establish a list of European Public Assessment Reports (EPAR)s that contain PGx information. We are constructing this list by initially searching for drugs for which we have PGx-containing FDA drug labels - of these 44 EMA EPARs were identified and are being curated for pgx information.

We welcome any information regarding drug labels containing PGx information approved by the FDA, EMA or other Medicine Agencies around the world - please contact feedback.


last updated 07/14/2014

FDA Label for warfarin and CYP2C9, PROC, VKORC1

This label is on the FDA Biomarker List
Actionable PGx

Summary

Warfarin (Coumadin) is an anticoagulant used as a prophylaxis and to treat venous thrombosis, pulmonary embolism, thromboembolic complications from atrial fibrillationa and cardiac valve replacement, and to reduce the recurrence of myocardial infarction. The FDA recommends genetic testing for CYP2C9 and VKORC1 variants prior to initiating treatment with warfarin. The drug label notes that deficiency in protein C (PROC) has been associated with tissue necrosis following warfarin administration.

Annotation

The VKORC1:G-1639A polymorphism is associated with lower dose requirements for warfarin in Caucasian and Asian patients. Increased bleeding risk and lower initial warfarin dose requirements have been associated with the CYP2C9*2 and CYP2C9*3 alleles. Approximately 30% of the variance in warfarin dose could be attributed to genetic variation in VKORC1, and about 40% of dose variance could be explained taking into consideration both VKORC1 and CYP2C9 genetic polymorphisms. Accounting for genetic variation in both VKORC1 and CYP2C9, age, height, body weight, interacting drugs, and indication for warfarin therapy explained about 55% of the variability in warfarin dose. The drug label also notes that hereditary or acquired deficiency of protein C (encoded by the PROC gene) have been associated with tissue necrosis following administration of warfarin.

Excerpts from the warfarin drug label:

The patient's CYP2C9 and VKORC1 genotype information, when available, can assist in selection of the starting dose. Table 5 describes the range of stable maintenance doses observed in multiple patients having different combinations of CYP2C9 and VKORC1 gene variants. Consider these ranges in choosing the initial dose.

Known or suspected deficiency in protein C mediated anticoagulant response: Hereditary or acquired deficiencies of protein C or its cofactor, protein S, have been associated with tissue necrosis following warfarin administration.

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the warfarin drug label. Pharmacogenomics-related dosing information is found in Table 5 on page 27.

*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.

Full label available at DailyMed

Genes and/or phenotypes found in this label


PharmGKB contains no Clinical Variants that meet the highest level of criteria.

Disclaimer: The PharmGKB's clinical annotations reflect expert consensus based on clinical evidence and peer-reviewed literature available at the time they are written and are intended only to assist clinicians in decision-making and to identify questions for further research. New evidence may have emerged since the time an annotation was submitted to the PharmGKB. The annotations are limited in scope and are not applicable to interventions or diseases that are not specifically identified.

The annotations do not account for individual variations among patients, and cannot be considered inclusive of all proper methods of care or exclusive of other treatments. It remains the responsibility of the health-care provider to determine the best course of treatment for a patient. Adherence to any guideline is voluntary, with the ultimate determination regarding its application to be made solely by the clinician and the patient. PharmGKB assumes no responsibility for any injury or damage to persons or property arising out of or related to any use of the PharmGKB clinical annotations, or for any errors or omissions.

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This is a non-comprehensive list of genetic tests with pharmacogenetics relevance, typically submitted by the manufacturer and manually curated by PharmGKB. The information listed is provided for educational purposes only and does not constitute an endorsement of any listed test or manufacturer.

A more complete listing of genetic tests is found at the Genetic Testing Registry (GTR).

PGx Test Variants Assayed Related Drugs?

The table below contains information about pharmacogenomic variants on PharmGKB. Please follow the link in the "Variant" column for more information about a particular variant. Each link in the "Variant" column leads to the corresponding PharmGKB Variant Page. The Variant Page contains summary data, including PharmGKB manually curated information about variant-drug pairs based on individual PubMed publications. The PMIDs for these PubMed publications can be found on the Variant Page.

The tags in the first column of the table indicate what type of information can be found on the corresponding Variant Page on the appropriate tab.

Links in the "Drugs" column lead to PharmGKB Drug Pages.

Variant?
(138)
Alternate Names / Tag SNPs ? Drugs ? Alleles ?
(+ chr strand)
Function ? Amino Acid?
Translation
No VIP available No Clinical Annotations available VA
rs1799808 -228C>T, 128175862C>T, 17924525C>T, 4867C>T
C > T
5' Flanking
No VIP available No Clinical Annotations available VA
rs1799809 -215G>A, 128175875G>A, 17924538G>A, 4880G>A
G > A
5' Flanking
No VIP available No Clinical Annotations available VA
rs2069919 128179553G>A, 17928216G>A, 237+528G>A, 8558G>A, PROC, intron 3 G/A
G > A
Intronic
Alleles, Functions, and Amino Acid Translations are all sourced from dbSNP 138

Overview

Alternate Names:  prepro-protein C
Alternate Symbols:  None
PharmGKB Accession Id: PA33799

Details

Cytogenetic Location: chr2 : q13 - q14.3
GP mRNA Boundary: chr2 : 128175996 - 128186822
GP Gene Boundary: chr2 : 128165996 - 128189822
Strand: plus
The mRNA boundaries are calculated using the gene's default feature set from NCBI, mapped onto the UCSC Golden Path. PharmGKB sets gene boundaries by expanding the mRNA boundaries by no less than 10,000 bases upstream (5') and 3,000 bases downstream (3') to allow for potential regulatory regions.
No related genes are available

Curated Information ?

Evidence Drug
No Dosing Guideline available No Drug Label available No Clinical Annotation available VA No VIP available No VIP available
phenprocoumon
No Dosing Guideline available DL No Clinical Annotation available VA No VIP available No VIP available
warfarin
No related diseases are available

Publications related to PROC: 6

No Dosing Guideline available No Drug Label available No Clinical Annotation available VA No VIP available No VIP available
Prediction of phenprocoumon maintenance dose and phenprocoumon plasma concentration by genetic and non-genetic parameters. European journal of clinical pharmacology. 2011. Geisen Christof, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Systematic review of pharmacoeconomic studies of pharmacogenomic tests. Pharmacogenomics. 2010. Beaulieu Mathieu, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available VA No VIP available No VIP available
Genetic factors (VKORC1, CYP2C9, EPHX1, and CYP4F2) are predictor variables for warfarin response in very elderly, frail inpatients. Clinical pharmacology and therapeutics. 2010. Pautas E, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Genetic determinants of warfarin dosing in the Han-Chinese population. Pharmacogenomics. 2009. Lee M T Michael, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Association of warfarin dose with genes involved in its action and metabolism. Human genetics. 2007. Wadelius Mia, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Site-directed mutagenesis of coumarin-type anticoagulant-sensitive VKORC1: evidence that highly conserved amino acids define structural requirements for enzymatic activity and inhibition by warfarin. Thrombosis and haemostasis. 2005. Rost Simone, et al. PubMed

LinkOuts

Entrez Gene:
5624
OMIM:
176860
612283
612304
UCSC Genome Browser:
NM_000312
RefSeq RNA:
NM_000312
RefSeq Protein:
NP_000303
RefSeq DNA:
AC_000045
AC_000134
NC_000002
NG_016323
NT_022135
NW_001838849
NW_921507
UniProtKB:
PROC_HUMAN (P04070)
Ensembl:
ENSG00000115718
GenAtlas:
PROC
GeneCard:
PROC
MutDB:
PROC
ALFRED:
LO133899H
HuGE:
PROC
Comparative Toxicogenomics Database:
5624
ModBase:
P04070
HumanCyc Gene:
HS03931
HGNC:
9451

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