MCID: CMR002
MIFTS: 44

Coumarin Resistance

Categories: Genetic diseases, Rare diseases, Metabolic diseases

Aliases & Classifications for Coumarin Resistance

MalaCards integrated aliases for Coumarin Resistance:

Name: Coumarin Resistance 53 24 71 36 13 69
Warfarin Resistance 53 49 24 71 51
Warfarin Sensitivity 53 49 24 69
Poor Metabolism of Coumarin 24 71
Coumadin Sensitivity 49 24
Warfarin Response 24 28
Coumarin, Poor Metabolism of 53
Drug Resistance 41
Cmres 71

Characteristics:

OMIM:

53
Inheritance:
autosomal dominant


HPO:

31
coumarin resistance:
Inheritance autosomal dominant inheritance


Classifications:



External Ids:

OMIM 53 122700
MeSH 41 D004351
KEGG 36 H01205
SNOMED-CT via HPO 65 263681008 191124002 34093004

Summaries for Coumarin Resistance

NIH Rare Diseases : 49 Warfarin resistance is a condition that is characterized by a high tolerance for a "blood-thinning" medication called warfarin. Warfarin is an anticoagulant that is often prescribed to people who are at an increased risk for blood clots. Some people with a warfarin resistance do not respond to the drug at all, while others can achieve the benefits of warfarin treatment at a high dose. In either case, affected people will still be at an elevated risk for blood clots when given the standard dose of warfarin. The metabolism of warfarin and the drug's effects in the body are complex traits that are determined by several genes as well as environmental and lifestyle factors such as gender, age, weight, diet, and other medications. One specific genetic polymorphism in the VKORC1 gene accounts for approximately 20% of variation in the response to warfarin and can be passed on to future generations in an autosomal dominant manner. Last updated: 9/15/2015

MalaCards based summary : Coumarin Resistance, also known as warfarin resistance, is related to multidrug-resistant tuberculosis and mycobacterium abscessus, and has symptoms including abnormality of metabolism/homeostasis and abnormality of blood and blood-forming tissues. An important gene associated with Coumarin Resistance is VKORC1 (Vitamin K Epoxide Reductase Complex Subunit 1), and among its related pathways/superpathways are Drug metabolism - cytochrome P450 and Arachidonic acid metabolism. The drugs Warfarin and Phenprocoumon have been mentioned in the context of this disorder. Affiliated tissues include heart and liver, and related phenotypes are Increased shRNA abundance (Z-score > 2) and Increased shRNA abundance (Z-score > 2)

OMIM : 53 Warfarin is a widely prescribed anticoagulant for the prevention of thromboembolic diseases for subjects with deep vein thrombosis, atrial fibrillation, or mechanical heart valve replacement (Yuan et al., 2005). The dose requirement is highly variable, both interindividually and interethnically. Variation in the VKORC1 gene is believed to be the most important individual predictor of warfarin dose, accounting for about 30% of the variance observed in dosing (Ross et al., 2010). (122700)

UniProtKB/Swiss-Prot : 71 Coumarin resistance: A condition characterized by partial or complete resistance to warfarin or other 4-hydroxycoumarin derivatives. These drugs are used as anti-coagulants for the prevention of thromboembolic diseases in subjects with deep vein thrombosis, atrial fibrillation, or mechanical heart valve replacement.

CDC : 3 Antibiotics and similar drugs, together called antimicrobial agents, have been used for the last 70 years to treat patients who have infectious diseases. Since the 1940s, these drugs have greatly reduced illness and death from infectious diseases. However, these drugs have been used so widely and for so long that the infectious organisms the antibiotics are designed to kill have adapted to them, making the drugs less effective.

Genetics Home Reference : 24 Warfarin sensitivity is a condition in which individuals have a low tolerance for the drug warfarin. Warfarin is an anticoagulant, which means that it thins the blood, preventing blood clots from forming. Warfarin is often prescribed to prevent blood clots in people with heart valve disease who have replacement heart valves, people with an irregular heart beat (atrial fibrillation), or those with a history of heart attack, stroke, or a prior blood clot in the deep veins of the arms or legs (deep vein thrombosis).

Related Diseases for Coumarin Resistance

Graphical network of the top 20 diseases related to Coumarin Resistance:



Diseases related to Coumarin Resistance

Symptoms & Phenotypes for Coumarin Resistance

Symptoms via clinical synopsis from OMIM:

53
Heme:
warfarin resistance

Lab:
decreased affinity of liver receptors for coumarin


Clinical features from OMIM:

122700

Human phenotypes related to Coumarin Resistance:

31
# Description HPO Frequency HPO Source Accession
1 abnormality of metabolism/homeostasis 31 HP:0001939
2 abnormality of blood and blood-forming tissues 31 HP:0001871

GenomeRNAi Phenotypes related to Coumarin Resistance according to GeneCards Suite gene sharing:

25 (show all 14)
# Description GenomeRNAi Source Accession Score Top Affiliating Genes
1 Increased shRNA abundance (Z-score > 2) GR00366-A-157 9.5 F9
2 Increased shRNA abundance (Z-score > 2) GR00366-A-164 9.5 F9
3 Increased shRNA abundance (Z-score > 2) GR00366-A-169 9.5 CYP2C9
4 Increased shRNA abundance (Z-score > 2) GR00366-A-176 9.5 F9
5 Increased shRNA abundance (Z-score > 2) GR00366-A-183 9.5 CYP2C9 F9
6 Increased shRNA abundance (Z-score > 2) GR00366-A-199 9.5 CYP2C9
7 Increased shRNA abundance (Z-score > 2) GR00366-A-207 9.5 CYP2C9
8 Increased shRNA abundance (Z-score > 2) GR00366-A-208 9.5 F9
9 Increased shRNA abundance (Z-score > 2) GR00366-A-41 9.5 F9
10 Increased shRNA abundance (Z-score > 2) GR00366-A-44 9.5 F9
11 Increased shRNA abundance (Z-score > 2) GR00366-A-50 9.5 CYP2C9
12 Increased shRNA abundance (Z-score > 2) GR00366-A-73 9.5 CYP2C9
13 Increased shRNA abundance (Z-score > 2) GR00366-A-81 9.5 F9
14 Increased shRNA abundance (Z-score > 2) GR00366-A-88 9.5 F9

Drugs & Therapeutics for Coumarin Resistance

Drugs for Coumarin Resistance (from DrugBank, HMDB, Dgidb, PharmGKB, IUPHAR, NovoSeek, BitterDB):


# Name Status Phase Clinical Trials Cas Number PubChem Id
1
Warfarin Approved Phase 4 81-81-2 54678486 6691
2
Phenprocoumon Approved, Investigational Phase 4 435-97-2 54680692 9908
3
Acenocoumarol Approved, Investigational Phase 4 152-72-7 54676537 9052
4 Anticoagulants Phase 4

Interventional clinical trials:


# Name Status NCT ID Phase Drugs
1 EUropean Pharmacogenetics of AntiCoagulant Therapy - Warfarin Completed NCT01119300 Phase 4
2 EUropean Pharmacogenetics of AntiCoagulant Therapy - Phenprocoumon Completed NCT01119274 Phase 4
3 EUropean Pharmacogenetics of AntiCoagulant Therapy - Acenocoumarol Completed NCT01119261 Phase 4

Search NIH Clinical Center for Coumarin Resistance

Cochrane evidence based reviews: drug resistance

Genetic Tests for Coumarin Resistance

Genetic tests related to Coumarin Resistance:

# Genetic test Affiliating Genes
1 Warfarin Response 28 CYP2A6 CYP2C9 F9 VKORC1

Anatomical Context for Coumarin Resistance

MalaCards organs/tissues related to Coumarin Resistance:

38
Heart, Liver

Publications for Coumarin Resistance

Articles related to Coumarin Resistance:

# Title Authors Year
1
gyrB mutations which confer coumarin resistance also affect DNA supercoiling and ATP hydrolysis by Escherichia coli DNA gyrase. ( 1323022 )
1992
2
Coumarin resistance: a diagnostic and therapeutic approach. ( 910171 )
1977
3
Coumarin resistance in a Negro woman. ( 4123117 )
1973

Variations for Coumarin Resistance

UniProtKB/Swiss-Prot genetic disease variations for Coumarin Resistance:

71 (show all 18)
# Symbol AA change Variation ID SNP ID
1 VKORC1 p.Val29Leu VAR_021821 rs104894539
2 VKORC1 p.Val45Ala VAR_021822 rs104894540
3 VKORC1 p.Arg58Gly VAR_021823 rs104894541
4 VKORC1 p.Leu128Arg VAR_021825 rs104894542
5 VKORC1 p.Ala26Thr VAR_065785
6 VKORC1 p.Asp36Gly VAR_065786
7 VKORC1 p.Asp36Tyr VAR_065787 rs61742245
8 VKORC1 p.Ser52Trp VAR_065788
9 VKORC1 p.Ser56Phe VAR_065789
10 VKORC1 p.Trp59Cys VAR_065790
11 VKORC1 p.Trp59Leu VAR_065791
12 VKORC1 p.Val66Gly VAR_065792
13 VKORC1 p.Val66Met VAR_065793 rs72547529
14 VKORC1 p.Gly71Ala VAR_065794
15 VKORC1 p.Asn77Ser VAR_065795
16 VKORC1 p.Asn77Tyr VAR_065796 rs755767348
17 VKORC1 p.Ile123Asn VAR_065797
18 VKORC1 p.Tyr139His VAR_065798

ClinVar genetic disease variations for Coumarin Resistance:

6 (show all 16)
# Gene Variation Type Significance SNP ID Assembly Location
1 CYP2C9 NM_000771.3(CYP2C9): c.1075A> C (p.Ile359Leu) single nucleotide variant drug response rs1057910 GRCh37 Chromosome 10, 96741053: 96741053
2 CYP2C9 NM_000771.3(CYP2C9): c.430C> T (p.Arg144Cys) single nucleotide variant drug response rs1799853 GRCh37 Chromosome 10, 96702047: 96702047
3 CYP2C9 NM_000771.3(CYP2C9): c.622T> G (p.Leu208Val) single nucleotide variant Pathogenic rs72558191 GRCh37 Chromosome 10, 96707676: 96707676
4 F9 F9, ALA-10THR single nucleotide variant Pathogenic
5 F9 F9, ALA-10VAL undetermined variant Pathogenic
6 CYP2A6 NM_000762.5(CYP2A6): c.479T> A (p.Leu160His) single nucleotide variant drug response rs1801272 GRCh37 Chromosome 19, 41354533: 41354533
7 CYP2A6 CYP2A6*12A deletion drug response GRCh38 Chromosome 19, 40848764: 40881588
8 VKORC1 NM_024006.5(VKORC1): c.174-136C> T single nucleotide variant drug response rs9934438 GRCh37 Chromosome 16, 31104878: 31104878
9 VKORC1 NM_024006.5(VKORC1): c.-226-1362dupG insertion drug response rs397509427 GRCh37 Chromosome 16, 31107638: 31107638
10 VKORC1 NM_024006.5(VKORC1): c.-1639G= single nucleotide variant drug response rs9923231 GRCh37 Chromosome 16, 31107689: 31107689
11 VKORC1 NM_024006.5(VKORC1): c.85G> T (p.Val29Leu) single nucleotide variant Pathogenic rs104894539 GRCh37 Chromosome 16, 31105966: 31105966
12 VKORC1 NM_024006.5(VKORC1): c.134T> C (p.Val45Ala) single nucleotide variant Pathogenic rs104894540 GRCh37 Chromosome 16, 31105917: 31105917
13 VKORC1 NM_024006.5(VKORC1): c.172A> G (p.Arg58Gly) single nucleotide variant Pathogenic rs104894541 GRCh37 Chromosome 16, 31105879: 31105879
14 VKORC1 NM_024006.5(VKORC1): c.383T> G (p.Leu128Arg) single nucleotide variant drug response rs104894542 GRCh37 Chromosome 16, 31102564: 31102564
15 VKORC1 NM_024006.4(VKORC1): c.-1639G> A single nucleotide variant drug response rs9923231 GRCh37 Chromosome 16, 31107689: 31107689
16 VKORC1 NM_024006.5(VKORC1): c.106G> T (p.Asp36Tyr) single nucleotide variant drug response rs61742245 GRCh37 Chromosome 16, 31105945: 31105945

Expression for Coumarin Resistance

Search GEO for disease gene expression data for Coumarin Resistance.

Pathways for Coumarin Resistance

Pathways related to Coumarin Resistance according to KEGG:

36
# Name Kegg Source Accession
1 Drug metabolism - cytochrome P450 hsa00982

Pathways related to Coumarin Resistance according to GeneCards Suite gene sharing:

(show all 12)
# Super pathways Score Top Affiliating Genes
1
Show member pathways
11.72 CYP2C9 CYP4F2
2
Show member pathways
11.56 CYP2C9 CYP4F2
3
Show member pathways
11.26 CYP2A6 CYP2C9
4
Show member pathways
11.2 CYP2A6 CYP2C9
5 10.94 CYP2A6 CYP2C9
6
Show member pathways
10.84 CYP2C9 CYP4F2
7
Show member pathways
10.78 CYP2A6 CYP2C9
8 10.7 CYP2A6 CYP2C9
9 10.58 CYP2A6 CYP2C9
10 10.46 CYP2A6 CYP2C9
11 10.07 CYP2A6 CYP2C9
12 9.98 CYP4F2 F9 VKORC1

GO Terms for Coumarin Resistance

Cellular components related to Coumarin Resistance according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 endoplasmic reticulum GO:0005783 9.55 CYP2A6 CYP2C9 CYP4F2 MCFD2 VKORC1
2 intracellular membrane-bounded organelle GO:0043231 9.43 CYP2A6 CYP2C9 CYP4F2
3 organelle membrane GO:0031090 9.13 CYP2A6 CYP2C9 CYP4F2
4 endoplasmic reticulum membrane GO:0005789 9.02 CYP2A6 CYP2C9 CYP4F2 MCFD2 VKORC1

Biological processes related to Coumarin Resistance according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 oxidation-reduction process GO:0055114 9.71 CYP2A6 CYP2C9 CYP4F2 VKORC1
2 blood coagulation GO:0007596 9.54 CYP4F2 F9 VKORC1
3 ER to Golgi vesicle-mediated transport GO:0006888 9.46 F9 MCFD2
4 steroid metabolic process GO:0008202 9.43 CYP2A6 CYP2C9
5 exogenous drug catabolic process GO:0042738 9.32 CYP2A6 CYP2C9
6 peptidyl-glutamic acid carboxylation GO:0017187 9.26 F9 VKORC1
7 omega-hydroxylase P450 pathway GO:0097267 9.16 CYP2C9 CYP4F2
8 epoxygenase P450 pathway GO:0019373 9.13 CYP2A6 CYP2C9 CYP4F2
9 drug metabolic process GO:0017144 8.92 CYP2A6 CYP2C9 CYP4F2 VKORC1

Molecular functions related to Coumarin Resistance according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 metal ion binding GO:0046872 9.83 CYP2A6 CYP2C9 CYP4F2 F9 MCFD2
2 oxidoreductase activity GO:0016491 9.62 CYP2A6 CYP2C9 CYP4F2 VKORC1
3 iron ion binding GO:0005506 9.43 CYP2A6 CYP2C9 CYP4F2
4 monooxygenase activity GO:0004497 9.4 CYP2C9 CYP4F2
5 steroid hydroxylase activity GO:0008395 9.37 CYP2A6 CYP2C9
6 heme binding GO:0020037 9.33 CYP2A6 CYP2C9 CYP4F2
7 oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen GO:0016705 9.13 CYP2A6 CYP2C9 CYP4F2
8 arachidonic acid epoxygenase activity GO:0008392 8.8 CYP2A6 CYP2C9 CYP4F2

Sources for Coumarin Resistance

3 CDC
7 CNVD
9 Cosmic
10 dbSNP
11 DGIdb
16 ExPASy
18 FMA
27 GO
28 GTR
29 HGMD
30 HMDB
31 HPO
32 ICD10
33 ICD10 via Orphanet
34 ICD9CM
35 IUPHAR
36 KEGG
37 LifeMap
39 MedGen
41 MeSH
42 MESH via Orphanet
43 MGI
45 NCI
46 NCIt
47 NDF-RT
50 NINDS
51 Novoseek
53 OMIM
54 OMIM via Orphanet
58 PubMed
60 QIAGEN
65 SNOMED-CT via HPO
66 SNOMED-CT via Orphanet
67 TGDB
68 Tocris
69 UMLS
70 UMLS via Orphanet
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