Gene details: Additional test information

COMT

The COMT gene, residing on chromosome 22, encodes the enzyme catechol-O-methyltransferase, which degrades catecholamines such as the neurotransmitters dopamine, epinephrine, and norepinephrine.1 COMT enzyme activity is modulated by genetic variants, one of the best characterized being rs4680 (also known as Val158Met variant or c.322G>A).2

  1. COMT Gene (National Center for Biotechnology Information) [https://www.ncbi.nlm.nih.gov/gene/1312]
  2. Yates, A. et al. Ensembl 2016. 44, D710–6 (2015). http://grch37.ensembl.org/Homo_sapiens/Variation/Population?db=core;r=22:19950771- 19951771;v=rs4680;vdb=variation;vf=4460. Accessed 03/07/2017
HGVS rsID Nucleotide Change Alleles Reported
NM_000754.3:c.472G>A rs4680 472G>A rs4680 GG
rs4680 AG
rs4680 AA

CYP1A2

Located on the plus strand of chromosome 15, CYP1A2 encodes the cytochrome P450 family 1 subfamily A type 2 enzyme, which mediates liver metabolism of 9% of clinically important drugs, procarcinogens, and endogenous substrates.1,2,3 For many drugs CYP1A2 is not the sole metabolizing enzyme, nor is it active at the rate-limiting step.2,4 The genetic component of variation in CYP1A2 activity is estimated at up to 75%, with environmental factors (e.g., smoking) making up the remaining difference.2,5

  1. CYP1A2 Gene (National Center for Biotechnology Information) [https://www.ncbi.nlm.nih.gov/gene/1544]
  2. Thorn, C. F., Aklillu, E., Klein, T. E., & Altman, R. B. (2012). PharmGKB summary: very important pharmacogene information for CYP1A2. Pharmacogenetics and genomics, 22(1), 73.
  3. Zhou, S. F., Yang, L. P., Zhou, Z. W., Liu, Y. H., & Chan, E. (2009). Insights into the substrate specificity, inhibitors, regulation, and polymorphisms and the clinical impact of human cytochrome P450 1A2. The AAPS journal, 11(3), 481-494.
  4. Zanger, U. M., Turpeinen, M., Klein, K., & Schwab, M. (2008). Functional pharmacogenetics/genomics of human cytochromes P450 involved in drug biotransformation. Analytical and bioanalytical chemistry, 392(6), 1093-1108.
  5. Rasmussen, B. B., Brix, T. H., Kyvik, K. O., & Brøsen, K. (2002). The interindividual differences in the 3-demethylation of caffeine alias CYP1A2 is determined by both genetic and environmental factors. Pharmacogenetics and Genomics, 12(6), 473-478.
HGVS rsID Nucleotide Change Alleles Reported
NM_000761.4:c.-9-154C>A rs762551 -163C>A *1F, *1J, *1K, *1L, *1V, *1W
NM_000761.4:c.-10+103T>G rs2069526 -739T>G *1E, *1J, *1K, *1W
NM_000761.4:c.-10+113C>T rs12720461 -729C>T *1K
NM_000761.4:c.-1635delT rs35694136 -2467delT *1V, *1W
NG_008431.2:g.28338G>A rs2069514 -3860G>A *1C, *1L

CYP2B6

Located on the plus strand of chromosome 19, CYP2B6 encodes the cytochrome P450 family 2, subfamily B type 6 enzyme, which mediates liver and brain metabolism of 4% of the top 200 prescribed medications.1,2,3 CYP2B6 is highly inducible by several drugs and other xenobiotics.2,4 CYP2B6 expression varies over a 20-250-fold range, due to differences in transcriptional regulation and genetic variations.2,5,6 Pharmacogenomic guidelines published by professional associations exist for this gene and a certain medication.7

  1. CYP2B6 Gene (National Center for Biotechnology Information) [https://www.ncbi.nlm.nih.gov/gene/1555]
  2. Thorn, C. F., Lamba, J. K., Lamba, V., Klein, T. E., & Altman, R. B. (2010). PharmGKB summary: very important pharmacogene information for CYP2B6. Pharmacogenetics and genomics, 20(8), 520.
  3. Zanger, U. M., Turpeinen, M., Klein, K., & Schwab, M. (2008). Functional pharmacogenetics/genomics of human cytochromes P450 involved in drug biotransformation. Analytical and bioanalytical chemistry, 392(6), 1093-1108.
  4. Code, E. L., Crespi, C. L., Penman, B. W., Gonzalez, F. J., Chang, T. K., & Waxman, D. J. (1997). Human cytochrome P4502B6: interindividual hepatic expression, substrate specificity, and role in procarcinogen activation. Drug Metabolism and Disposition, 25(8), 985-993.
  5. Wang, H., & Tompkins, L. M. (2008). CYP2B6: new insights into a historically overlooked cytochrome P450 isozyme. Current drug metabolism, 9(7), 598-610.
  6. Zhang, H., Sridar, C., Kenaan, C., Amunugama, H., Ballou, D. P., & Hollenberg, P. F. (2011). Polymorphic variants of cytochrome P450 2B6 (CYP2B6. 4–CYP2B6. 9) exhibit altered rates of metabolism for bupropion and efavirenz: a charge-reversal mutation in the K139E variant (CYP2B6. 8) impairs formation of a functional cytochrome P450-reductase complex. Journal of Pharmacology and Experimental Therapeutics, 338(3), 803-809.
  7. Clinical Guideline Annotations (PharmGKB) [https://www.pharmgkb.org/guidelineAnnotations]
HGVS rsID Nucleotide Change Alleles Reported
NM_000767.4:c.516G>T rs3745274 516G>T *6, *7, *9
NM_000767.4:c.983T>C rs28399499 983T>C *16, *18
NM_000767.4:c.785A>G rs2279343 785A>G *4, *6, *7, *16
NM_000767.4:c.1459C>T rs3211371 1459C>T *5, *7

CYP2C9

Located on the plus strand of chromosome 10, CYP2C9 encodes the cytochrome P450 family 2 subfamily C type 9 enzyme, which is primarily expressed in the liver and mediates metabolic clearance of 15-20% of all drugs undergoing phase I metabolism.1,2,3,4 The gene coding for the CYP2C9 enzyme is highly polymorphic, including functional variants of major pharmacogenetic importance.2 Pharmacogenomic guidelines published by professional associations exist for this gene and certain medications.5

  1. CYP2C9 Gene (National Center for Biotechnology Information) [https://www.ncbi.nlm.nih.gov/gene/1559]
  2. Van Booven, D., Marsh, S., McLeod, H., Carrillo, M. W., Sangkuhl, K., Klein, T. E., & Altman, R. B. (2010). Cytochrome P450 2C9-CYP2C9. Pharmacogenetics and genomics, 20(4), 277.
  3. Ali, Z. K., Kim, R. J., & Ysla, F. M. (2009). CYP2C9 polymorphisms: considerations in NSAID therapy. Current opinion in drug discovery & development, 12(1), 108-114.
  4. Lee, C. R., Goldstein, J. A., & Pieper, J. A. (2002). Cytochrome P450 2C9 polymorphisms: a comprehensive review of the in-vitro and human data. Pharmacogenetics and Genomics, 12(3), 251-263.
  5. Clinical Guideline Annotations (PharmGKB) [https://www.pharmgkb.org/guidelineAnnotations]
HGVS rsID Nucleotide Change Alleles Reported
NM_000771.3:c.430C>T rs1799853 430C>T *2
NM_000771.3:c.1075A>C rs1057910 1075A>C *3
NM_000771.3:c.1076T>C rs56165452 1076T>C *4
NM_000771.3:c.1080C>G rs28371686 1080C>G *5
NM_000771.3:c.817delA rs9332131 818delA *6
NM_000771.3:c.449G>A rs7900194 449G>A *8
NM_000771.3:c.1003C>T rs28371685 1003C>T *11

CYP2C19

CYP2C19, located on the plus strand of chromosome 10, encodes the cytochrome P450 family 2 subfamily C type 19 enzyme, which mediates liver (and small intestinal) metabolic oxidation of 10-15% of clinically relevant drugs and drug classes.1,2,3 Variants in the gene include loss-of-function alleles (e.g., *2, *3) and a promoter variant that causes increased gene expression (e.g., *17).2,4 Pharmacogenomic guidelines published by professional associations exist for this gene and certain medications.5

  1. CYP2C19 Gene (National Center for Biotechnology Information) [https://www.ncbi.nlm.nih.gov/gene/1557]
  2. Scott, S. A., Sangkuhl, K., Shuldiner, A. R., Hulot, J. S., Thorn, C. F., Altman, R. B., & Klein, T. E. (2012). PharmGKB summary: very important pharmacogene information for cytochrome P450, family 2, subfamily C, polypeptide 19. Pharmacogenetics and genomics, 22(2), 159.
  3. Ebeshi, B. U., Edebi, V. N., & Onajemo, J. O. (2018). Oxidative Hydroxylation Of Omeprazole In Healthy Subjects Of Niger Delta Region By Thin Layer Chromatography.
  4. CYP2C19 -- PharmVar [https://www.pharmvar.org/gene/CYP2C19]
  5. Clinical Guideline Annotations (PharmGKB) [https://www.pharmgkb.org/guidelineAnnotations]
HGVS rsID Nucleotide Change Alleles Reported
NM_000769.2:c.681G>A rs4244285 681G>A *2
NM_000769.2:c.636G>A rs4986893 636G>A *3
NM_000769.2:c.-806C>T rs12248560 -806C>T *4B, *17
NM_000769.2:c.1A>G rs28399504 1A>G *4, *4B
NM_000769.2:c.680C>T rs6413438 680C>T *10

CYP2C Cluster

The single nucleotide polymorphism (SNP) rs12777823 is located in the CYP2C Cluster near the CYP2C18 gene on chromosome 10.1,2,3 This SNP is of therapeutic interest in combination with genotypes from CYP2C9, VKORC1, and CYP4F2.3 Pharmacogenomic guidelines published by a professional association exist for this gene and a certain medication.4

  1. Rs12777823 -- dbSNP (The Single Nucleotide Polymorphism Database) [https://www.ncbi.nlm.nih.gov/snp/rs12777823]
  2. CYP2C18 Gene (National Center for Biotechnology Information) [https://www.ncbi.nlm.nih.gov/gene/1562]
  3. Johnson, J. A., Caudle, K. E., Gong, L., Whirl‐Carrillo, M., Stein, C. M., Scott, S. A., ... & Anderson, J. L. (2017). Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for pharmacogenetics‐guided warfarin dosing: 2017 update. Clinical Pharmacology & Therapeutics, 102(3), 397-404.
  4. Clinical Guideline Annotations (PharmGKB) [https://www.pharmgkb.org/guidelineAnnotations]
HGVS rsID Nucleotide Change Genotypes Reported
NC_000010.11:g.94645745G>A rs12777823 94645745G>A rs12777823 GG
rs12777823 GA
rs12777823 AA

CYP2D6

CYP2D6, located on the minus strand of chromosome 22, encodes the cytochrome P450 family 2 subfamily D type 6 enzyme, which mediates hepatic first-pass metabolic oxidation of numerous drugs.1,2 Phenotypes for this gene range from poor to ultrarapid, as variants may result in reduced or abolished enzyme function, and variations in copy number and pseudogene rearrangements are also possible.3,4 Pharmacogenomic guidelines published by professional associations exist for this gene and certain medications.5

  1. CYP2D6 Gene (National Center for Biotechnology Information) [https://www.ncbi.nlm.nih.gov/gene/1565]
  2. Thummel, K. E., Kunze, K. L., & Shen, D. D. (1997). Enzyme-catalyzed processes of first-pass hepatic and intestinal drug extraction [Abstract]. Advanced drug delivery reviews, 27(2-3), 99-127.
  3. Owen, R. P., Sangkuhl, K., Klein, T. E., & Altman, R. B. (2009). Cytochrome P450 2D6. Pharmacogenetics and genomics, 19(7), 559.
  4. Del Tredici, A. L., Malhotra, A., Dedek, M., Espin, F., Roach, D., Zhu, G. D., ... & Moreno, T. A. (2018). Frequency of CYP2D6 alleles including structural variants in the United States. Frontiers in pharmacology, 9, 305.
  5. Clinical Guideline Annotations (PharmGKB) [https://www.pharmgkb.org/guidelineAnnotations]
HGVS rsID Nucleotide Change Alleles Reported
NM_000106.5:c.-1584C>G rs1080985 -1584C>G *2A, *11, *14, *31, *35, *63
NM_000106.5:c.31G>A rs769258 31G>A *35
NM_000106.5:c.100C>T rs1065852 100C>T *4, *4J, *4N, *10, *36, *64, *68, *69, *114
NM_000106.5:c.124G>A rs5030862 124G>A *12
NM_000106.5:c.181-1G>C rs201377835 883G>C *11
NM_000106.5:c.505G>T rs5030865G>T 1758G>T *8
NM_000106.5:c.505G>A rs5030865G>A 1758G>A *14, *114
NM_000106.5:c.841_843delAAG rs5030656 2615_2617delAAG *9, *109
NM_000106.5:c.320C>T rs28371706 1023C>T *17, *64
NM_000106.5:c.454delT rs5030655 1707delT *6, *6C
NM_000106.5:c.506-1G>A rs3892097 1846G>A *4, *4J, *4M, *4N
NM_000106.5:c.775delA rs35742686 2549delA *3
NM_000106.5:c.971A>C rs5030867 2935A>C *7
NM_000106.5:c.1012G>A rs59421388 3183G>A *29, *70, *109
NM_000106.5:c.985+39G>A rs28371725 2988G>A *41, *69, *91
NM_000106.5:c.886C>T rs16947 2850C>T *2, *2A, *8, *11, *12, *14, *17, *19, *29, *31, *35, *41, *42, *63, *69, *91, *114
NM_000106.5:c.1457G>C rs1135840 4180G>C *2, *2A, *4, *4N, *6C, *8, *10, *11, *12, *14, *17, *19, *29, *31, *35 *36, *41, *42, *64, *69, *70, *114
NM_000106.5:c.1319G>A rs267608319 4042G>A *31
NM_000106.5:c.137_138insT rs774671100 137_138insT *13, *15
NM_000106.5:c.765_768delAACT rs72549353 2539_2542delAACT *19
NM_000106.5:c.1088_1089insGT rs72549346 3259_3260insGT *42
NM_000106.5:c.1411_1412insTGCCCACTG hCV32407220 (rs765776661) 4125_4133dupGTGCCCAC *18
NM_000106.5:c.975G>A rs79292917 975G>A *59

CYP3A4

Cytochrome P450 family 3 subfamily A type 4 enzyme (CYP3A4) is encoded by the CYP3A4 gene located on the minus strand of chromosome 7.1 Along with CYP3A5, CYP3A4 is the predominant cytochrome P450 enzyme expressed in the adult human liver.2,3,4 CYP3A4 activity predominates in Caucasians and CYP3A5 predominates in individuals of African descent.5,6 CYP3A is involved in the metabolism of about 50% of all drugs.7

  1. CYP3A4 Gene (National Center for Biotechnology Information) [https://www.ncbi.nlm.nih.gov/gene/1576]
  2. Lamba, J., Hebert, J. M., Schuetz, E. G., Klein, T. E., & Altman, R. B. (2012). PharmGKB summary: very important pharmacogene information for CYP3A5. Pharmacogenetics and genomics, 22(7), 555.
  3. Krekels, E. H. J., Rower, J. E., Constance, J. E., Knibbe, C. A., & Sherwin, C. M. (2017). Hepatic Drug Metabolism in Pediatric Patients. In Drug Metabolism in Diseases (pp. 181-206). Academic Press.
  4. Shimada, T., Yamazaki, H., Mimura, M., Inui, Y., & Guengerich, F. P. (1994). Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: studies with liver microsomes of 30 Japanese and 30 Caucasians. Journal of Pharmacology and Experimental Therapeutics, 270(1), 414-423.
  5. Xie, H. G., Kim, R. B., Wood, A. J., & Stein, C. M. (2001). Molecular basis of ethnic differences in drug disposition and response. Annual review of pharmacology and toxicology, 41(1), 815-850.
  6. Kuehl, P., Zhang, J., Lin, Y., Lamba, J., Assem, M., Schuetz, J., ... & Maurel, P. (2001). Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression. Nature genetics, 27(4), 383-391.
  7. Eichelbaum, M., & Burk, O. (2001). CYP3A genetics in drug metabolism. Nature medicine, 7(3), 285-287.
HGVS rsID Nucleotide Change Alleles Reported
NM_017460.5:c.-392G>A rs2740574 -392A>G *1B
NM_017460.5:c.522-191C>T rs35599367 15389C>T *22

CYP3A5

Cytochrome P450 family 3 subfamily A type 5 (CYP3A5) is encoded by the CYP3A5 gene, located on the minus strand of chromosome 7.1 Along with CYP3A4, CYP3A5 is the predominant cytochrome P450 enzyme expressed in the adult human liver.2,3,4 CYP3A4 activity predominates in Caucasians and CYP3A5 predominates in individuals of African descent.5,6 Most medications metabolized by CYP3A4 are also metabolized by CYP3A5, with a few exceptions.7 CYP3A5 poor metabolizer phenotype was the most prevalent phenotype in studies used to define standard dosing of medications.8 CYP3A5 normal metabolizers have increased enzyme activity relative to the poor metabolizer phenotype.9 Pharmacogenomic guidelines published by professional associations exist for this gene and a certain medication.10

  1. CYP3A5 Gene (National Center for Biotechnology Information) [https://www.ncbi.nlm.nih.gov/gene/1577]
  2. Lamba, J., Hebert, J. M., Schuetz, E. G., Klein, T. E., & Altman, R. B. (2012). PharmGKB summary: very important pharmacogene information for CYP3A5. Pharmacogenetics and genomics, 22(7), 555.
  3. Krekels, E. H. J., Rower, J. E., Constance, J. E., Knibbe, C. A., & Sherwin, C. M. (2017). Hepatic Drug Metabolism in Pediatric Patients. In Drug Metabolism in Diseases (pp. 181-206). Academic Press.
  4. Shimada, T., Yamazaki, H., Mimura, M., Inui, Y., & Guengerich, F. P. (1994). Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: studies with liver microsomes of 30 Japanese and 30 Caucasians. Journal of Pharmacology and Experimental Therapeutics, 270(1), 414-423.
  5. Xie, H. G., Kim, R. B., Wood, A. J., & Stein, C. M. (2001). Molecular basis of ethnic differences in drug disposition and response. Annual review of pharmacology and toxicology, 41(1), 815-850.
  6. Kuehl, P., Zhang, J., Lin, Y., Lamba, J., Assem, M., Schuetz, J., ... & Maurel, P. (2001). Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression. Nature genetics, 27(4), 383-391.
  7. Patwardhan, B., & Chaguturu, R. (2016). Innovative Approaches in Drug Discovery: Ethnopharmacology, Systems Biology and Holistic Targeting (pp 195-234). Academic Press.
  8. CYP3A5 -- Ensembl [https://uswest.ensembl.org/Homo_sapiens/Gene/Variation_Gene/Table?g=ENSG00000106258;r=7:99648194-99679998]
  9. Padmanabhan, S. (Ed.). (2014). Handbook of pharmacogenomics and stratified medicine (pp 971-998). Academic Press.
  10. Clinical Guideline Annotations (PharmGKB) [https://www.pharmgkb.org/guidelineAnnotations]
HGVS rsID Nucleotide Change Alleles Reported
NM_000777.4:c.219-237G>A rs776746 6986A>G *3
NM_000777.4:c.624G>A rs10264272 14690G>A *6
NM_000777.4:c.1035_1036insT rs41303343 27131_27132insT *7

CYP4F2

Cytochrome P450 family 4 subfamily F member 2 (CYP4F2) is encoded by the CYP4F2 gene, located on chromosome 19.1 CYP4F2 catalyzes the NADPH-dependent oxidation of the terminal carbon of long and very long-chain fatty acids, the side chains of vitamin K (K1, K2) and vitamin E (tocopherols and tocotrienols), arachidonic acid (AA), and leukotriene B4 (LTB4).2 Through its role as a vitamin K1 oxidase, the CYP4F2 variant rs2108622 is of therapeutic interest in combination with genotypes from CYP2C9, VKORC1, and rs12777823.3 Pharmacogenomic guidelines published by a professional association exist for this gene and a certain medication.4

  1. CYP4F2 Gene (National Center for Biotechnology Information) [https://www.ncbi.nlm.nih.gov/gene/8529]
  2. CYP4F2 gene -- Genetics Home Reference (National Center for Biotechnology Information) [https://ghr.nlm.nih.gov/gene/CYP4F2]
  3. Shendre, A., Brown, T. M., Liu, N., Hill, C. E., Beasley, T. M., Nickerson, D. A., & Limdi, N. A. (2016). Race‐Specific Influence of CYP 4F2 on Dose and Risk of Hemorrhage Among Warfarin Users. Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy, 36(3), 263-272.
  4. Clinical Guideline Annotations (PharmGKB) [https://www.pharmgkb.org/guidelineAnnotations]
HGVS rsID Nucleotide Change Alleles Reported
NM_001082.4:c.1297G>A rs2108622 c.1297G>A *3

DPYD

The DPYD gene, located on the minus strand of chromosome 1, encodes dihydropyrimidine dehydrogenase (DPD) enzyme, which is involved in the degradation pathway of certain medications.1,2 Decreased activity of DPD can lead to severe or fatal toxicity induced by these medications.2,3 Pharmacogenomic guidelines published by professional associations exist for this gene and certain medications.4

  1. DPYD Gene (National Center for Biotechnology Information) [https://www.ncbi.nlm.nih.gov/gene/1806]
  2. Kubota, T. (2003). 5-Fluorouracil and dihydropyrimidine dehydrogenase. International journal of clinical oncology, 8(3), 127-131.
  3. Fidai, S. S., Sharma, A. E., Johnson, D. N., Segal, J. P., & Lastra, R. R. (2018). Dihydropyrimidine dehydrogenase deficiency as a cause of fatal 5-Fluorouracil toxicity. Autopsy & case reports, 8(4).
  4. Clinical Guideline Annotations (PharmGKB) [https://www.pharmgkb.org/guidelineAnnotations]
HGVS rsID Nucleotide Change Genotypes Reported
NM_000110.3:c.1679T>G rs55886062 1679T>G rs55886062 AA
rs55886062 AC
rs55886062 CC
NM_000110.3:c.2846A>T rs67376798 2846A>T rs67376798 TT
rs67376798 TA
rs67376798 AA
NM_000110.3:c.1905+1G>A rs3918290 1905+1G>A rs3918290 CC
rs3918290 CT
rs3918290 TT

DRD2

The DRD2 gene, residing on the minus strand of chromosome 11, encodes dopamine receptor D2.1 Dopamine receptor D2 is a G protein-coupled receptor highly expressed in the pituitary gland and central nervous system.2,3 This receptor is targeted by certain medications.2 In particular, rs1799978 A>G is a promoter variant that influences receptor expression.4

  1. DRD2 Gene (National Center for Biotechnology Information) [https://www.ncbi.nlm.nih.gov/gene/1813]
  2. Mi, H., Thomas, P. D., Ring, H. Z., Jiang, R., Sangkuhl, K., Klein, T. E., & Altman, R. B. (2011). PharmGKB summary: dopamine receptor D2. Pharmacogenetics and genomics, 21(6), 350.
  3. Kidd, K. K., Morar, B., Castiglione, C. M., Zhao, H., Pakstis, A. J., Speed, W. C., ... & Nam, Y. S. (1998). A global survey of haplotype frequencies and linkage disequilibrium at the DRD2 locus. Human genetics, 103(2), 211-227.
  4. Zhang, X. C., Ding, M., Adnan, A., Liu, Y., Liu, Y. P., Xing, J. X., ... & Wang, B. J. (2019). No association between polymorphisms in the promoter region of dopamine receptor D2 gene and schizophrenia in the northern Chinese Han population: A case–control study. Brain and behavior, 9(2), e01193.
HGVS rsID Nucleotide Change Genotypes Reported
NM_000795.3:c.-585A>G rs1799978 -241A>G rs1799978 AA
rs1799978 GA
rs1799978 GG

F2

The F2 gene, residing on chromosome 11, encodes prothrombin (coagulation factor II), which is cleaved to form the serine protease thrombin during blood clotting.1 Genotyping F2 may be useful in identifying an increased risk of thrombosis due to prothrombin thrombophilia.2

  1. F2 Gene (National Center for Biotechnology Information) [https://www.ncbi.nlm.nih.gov/gene/2147]
  2. Kujovich, J. L. (2014). Prothrombin-related thrombophilia. In GeneReviews®[Internet]. University of Washington, Seattle.
HGVS rsID Nucleotide Change Genotypes Reported
NM_000506.4:c.*97G>A rs1799963 20210G>A rs1799963 GG
rs1799963 GA
rs1799963 AA

F5

The F5 gene, residing on the minus strand of chromosome 1, encodes the coagulation cofactor Factor 5.1 Genetic variations of F5 can lead to the formation of the Factor V Leiden protein, which cannot be inactivated normally by activated protein C (APC).2 The prolonged time for APC to inactivate Factor V Leiden leads to a prolonged clotting process, increasing the chance of developing abnormal blood clots.3 Genotyping F5 may be useful in identifying an increased risk of thrombosis due to Factor V Leiden thrombophilia.2

  1. F5 Gene (National Center for Biotechnology Information) [https://www.ncbi.nlm.nih.gov/gene/2153]
  2. Kujovich, J. L. (2011). Factor v Leiden thrombophilia. Genetics in Medicine, 13(1), 1-16.
  3. Factor V Leiden thrombophilia -- Genetics Home Reference (National Center for Biotechnology Information) [https://ghr.nlm.nih.gov/condition/factor-v-leiden-thrombophilia]
HGVS rsID Nucleotide Change Genotypes Reported
NM_000130.4:c.1601G>A rs6025 1691G>A rs6025 GG
rs6025 GA
rs6025 AA

GRIK4

The GRIK4 gene, residing on chromosome 11, encodes the glutamate receptor, ionotropic, kainate 4.1 It is involved in glutamate neurotransmission, with glutamate being the main neurotransmitter in the human brain.2,3

  1. GRIK4 Gene (National Center for Biotechnology Information) [https://www.ncbi.nlm.nih.gov/gene/2900]
  2. GRIK4 -- UniProt [https://www.uniprot.org/uniprot/Q16099]
  3. GRIK4 -- OMIM (Online Mendelian Inheritance in Man) [https://www.omim.org/entry/600282?search=grik4&highlight=grik4]
HGVS rsID Nucleotide Change Genotypes Reported
NM_001282470.2:c.83-10039T>C rs1954787 Chr11:120663363T>C rs1954787 TT
rs1954787 TC
rs1954787 CC

HLA-A

The HLA-A gene, located at chromosome 6p22.1, codes for the major histocompatibility complex (MHC), class I, A molecules.1 This group of proteins, also called human leukocyte antigens (HLAs), are major players in normal immune response, specifically in adaptive immunity as their role is to present antigen peptides to T lymphocytes.2 Certain alleles are associated with severe allergic drug reactions.2 The HLA-A*31:01 allele has been associated with hypersensitivity reactions including Stevens-Johnson syndrome (SJS), maculopapular exanthema (MEP), and toxic epidermal necrolysis (TEN) following administration of certain drugs, particularly in Japanese, Korean and Caucasian populations.3 Pharmacogenomic guidelines published by professional associations exist for this gene and certain medications.4

  1. HLA-A Gene (National Center for Biotechnology Information) [https://www.ncbi.nlm.nih.gov/gene/3105]
  2. Fan, W. L., Shiao, M. S., Hui, R. C. Y., Su, S. C., Wang, C. W., Chang, Y. C., & Chung, W. H. (2017). HLA association with drug-induced adverse reactions. Journal of immunology research, 2017.
  3. Yip, V. L. M., & Pirmohamed, M. (2017). The HLA-A* 31: 01 allele: influence on carbamazepine treatment. Pharmacogenomics and personalized medicine, 10, 29.
  4. Clinical Guideline Annotations (PharmGKB) [https://www.pharmgkb.org/guidelineAnnotations]
HGVS rsID Nucleotide Change Reported Results
NM_002116 (interrogated at exon 2) HLA00097 N/A 3101 Negative
3101 Positive

HLA-B

The HLA-B gene, located at chromosome 6p21.33, codes for the major histocompatibility complex (MHC) class I, B molecules.1 This group of proteins, also called human leukocyte antigens (HLAs) are major players in normal immune response, specifically in adaptive immunity as their role is to present antigen peptides to T lymphocytes.2 Certain alleles are associated with allergic drug reactions.2 In particular, HLA-B*15:02, HLA-B*57:01, and HLA-B*58:01 have been reported to be strongly associated with adverse reactions induced by certain medications.2 The HLA-B*15:02 allele has been strongly associated with drug-induced Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN).2 Pharmacogenomic guidelines published by professional associations exist for this gene and certain medications.3

  1. HLA-B Gene (National Center for Biotechnology Information) [https://www.ncbi.nlm.nih.gov/gene/3106]
  2. Fan, W. L., Shiao, M. S., Hui, R. C. Y., Su, S. C., Wang, C. W., Chang, Y. C., & Chung, W. H. (2017). HLA association with drug-induced adverse reactions. Journal of immunology research, 2017.
  3. Clinical Guideline Annotations (PharmGKB) [https://www.pharmgkb.org/guidelineAnnotations]
HGVS rsID Nucleotide Change Reported Results
NM_005514.7:c.1012+104A>T rs144012689 31355003G>C 1502 Positive
1502 Negative
NM_005514 (interrogated at exon 3) HLA00381 N/A 57:01 Positive
57:01 Negative
NM_005514 (interrogated at exon 2 and intron 2) HLA00386 N/A 58:01 Positive
58:01 Negative

HTR2A

The HTR2A gene, residing on chromosome 13, encodes the 5-hydroxytryptamine (serotonin) receptor 2A.1 This metabotropic receptor is found to be downregulated as a pharmacodynamic effect of certain medications.2 Variants in this gene are of therapeutic interest, in particular rs7997012 A>G.2

  1. HTR2A Gene (National Center for Biotechnology Information) [https://www.ncbi.nlm.nih.gov/gene/3356]
  2. McMahon, F. J., Buervenich, S., Charney, D., Lipsky, R., Rush, A. J., Wilson, A. F., ... & Trivedi, M. H. (2006). Variation in the gene encoding the serotonin 2A receptor is associated with outcome of antidepressant treatment. The American Journal of Human Genetics, 78(5), 804-814.
HGVS rsID Nucleotide Change Genotypes Reported
NM_000621.4:c.614-2211T>C rs7997012 Chr13:47411985T>C rs7997012 TT
rs7997012 TC
rs7997012 CC

HTR2C

The HTR2C gene, residing on the X chromosome, encodes the 5-hydroxytryptamine (serotonin) receptor 2C.1 Many agonists or antagonists of this metabotropic receptor cause downregulation.2

  1. HTR2C Gene (National Center for Biotechnology Information) [https://www.ncbi.nlm.nih.gov/gene/3358]
  2. Van Oekelen, D., Luyten, W. H., & Leysen, J. E. (2003). 5-HT2A and 5-HT2C receptors and their atypical regulation properties. Life sciences, 72(22), 2429-2449.
HGVS rsID Nucleotide Change Genotypes Reported
NM_000868.3:c.-759C>T rs3813929 -759C>T rs3813929 CC
rs3813929 CT
rs3813929 TT

IFNL4

The IFNL4 gene, residing on the minus strand of chromosome 19, encodes interferon, lambda 4, and was recently identified as important to the immune response to hepatitis C.1 A variant in this gene, rs12979860 C>T, is associated with variability in hepatitis C sustained virologic response (SVR) rate.2 Until recently, rs12979860 C>T was thought to be located in a regulatory region upstream of IFNL3 (also referred to as IL28B).3,4 Therefore, this gene may also be referred to as IL28B or IFNL3. Pharmacogenomic guidelines published by professional associations exist for this gene and certain medications.5

  1. IFNL4 Gene (National Center for Biotechnology Information) [https://www.ncbi.nlm.nih.gov/gene/101180976]
  2. Khubaib, B., Saleem, S., Idrees, M., Afzal, S., & Wasim, M. (2015). The genotype CC of IL‐28B SNP rs12979860 is significantly associated with a sustained virological response in chronic HCV‐infected Pakistani patients. Journal of Digestive Diseases, 16(5), 293-298.
  3. O’Brien, T. R., Pfeiffer, R. M., Paquin, A., Kuhs, K. A. L., Chen, S., Bonkovsky, H. L., ... & Morgan, T. R. (2015). Comparison of functional variants in IFNL4 and IFNL3 for association with HCV clearance. Journal of hepatology, 63(5), 1103-1110.
  4. Prokunina-Olsson, L., Muchmore, B., Tang, W., Pfeiffer, R. M., Park, H., Dickensheets, H., ... & Chen, S. (2013). A variant upstream of IFNL3 (IL28B) creating a new interferon gene IFNL4 is associated with impaired clearance of hepatitis C virus. Nature genetics, 45(2), 164-171.
  5. Clinical Guideline Annotations (PharmGKB) [https://www.pharmgkb.org/guidelineAnnotations]
HGVS rsID Nucleotide Change Genotypes Reported
NM_001276254.2:c.151-152G>A rs12979860 Chr10:39248147C>T rs12979860 CC
rs12979860 CT
rs12979860 TT

MTHFR

Note: MTHFR is available to providers as an optional, complimentary add-on to the RightMed Test. MTHFR is not available to patients who purchase the test online (ordered through the independent physician network).

The MTHFR gene, residing on the minus strand of chromosome 1, encodes the enzyme methylenetetrahydrofolate reductase.1 This enzyme is integrally involved in the DNA synthesis pathway, specifically the conversion of homocysteine to methionine through the methylation cycle of folic acid.1,2 Common variants in this gene, namely 677C>T (rs1801133) and 1298A>C (rs1801131), can disrupt this pathway, altering folic acid metabolism and/or leading to hyperhomocysteinemia.3 However, the American College of Medical Genetics and Genomics (ACMG) determined that MTHFR genotyping has minimal clinical utility as part of the routine evaluation for thrombophilia.4

  1. MTHFR Gene (National Center for Biotechnology Information) [https://www.ncbi.nlm.nih.gov/gene/4524]
  2. Abbasi, I. H. R., Abbasi, F., Wang, L., El Hack, M. E. A., Swelum, A. A., Hao, R., ... & Cao, Y. (2018). Folate promotes S-adenosyl methionine reactions and the microbial methylation cycle and boosts ruminants production and reproduction. Amb Express, 8(1), 65.
  3. Brustolin, S., Giugliani, R., & Félix, T. M. (2010). Genetics of homocysteine metabolism and associated disorders. Brazilian Journal of Medical and Biological Research, 43(1), 1-7.
  4. Hickey, S. E., Curry, C. J., & Toriello, H. V. (2013). ACMG Practice Guideline: lack of evidence for MTHFR polymorphism testing. Genetics in Medicine, 15(2), 153-156.
HGVS rsID Nucleotide Change Genotypes Reported
NM_005957.4:c.665C>T rs1801133 677C>T rs1801133 CC
rs1801133 CT
rs1801133 TT
NM_005957.4:c.1286A>C rs1801131 1298A>C rs1801131 AA
rs1801131 AC
rs1801131 CC

NUDT15

The NUDT15 gene, residing on the plus strand of chromosome 13, encodes nucleotide diphosphate linked moiety X (nudix)-type hydrolase motif 15.1,2 This type of protein catalyzes the hydrolysis of nucleoside diphosphates that are oxidized bases that can result in base mispairing during nucleic acid synthesis, and thereby cause translational errors.3 NUDT15 also inactivates thiopurine metabolites.4 Variants causing impaired NUDT15 activity, specifically rs116855232 C>T, are associated with a higher risk of thiopurine-related toxicities.4,5 Pharmacogenomic guidelines published by professional associations exist for this gene and certain medications.6

  1. NUDT15 Gene (National Center for Biotechnology Information) [https://www.ncbi.nlm.nih.gov/gene/55270]
  2. NUDT15 gene -- Gene Cards [https://www.genecards.org/cgi-bin/carddisp.pl?gene=NUDT15]
  3. NUDT15 gene -- Genetics Home Reference (National Center for Biotechnology Information) [https://ghr.nlm.nih.gov/gene/NUDT15]
  4. Moriyama, T., Nishii, R., Perez-Andreu, V., Yang, W., Klussmann, F. A., Zhao, X., ... & Hofmann, U. (2016). NUDT15 polymorphisms alter thiopurine metabolism and hematopoietic toxicity. Nature genetics, 48(4), 367-373.
  5. Yang, S. K., Hong, M., Baek, J., Choi, H., Zhao, W., Jung, Y., ... & Park, S. K. (2014). A common missense variant in NUDT15 confers susceptibility to thiopurine-induced leukopenia. Nature genetics, 46(9), 1017.
  6. Clinical Guideline Annotations (PharmGKB) [https://www.pharmgkb.org/guidelineAnnotations]
HGVS rsID Nucleotide Change Genotypes Reported
NM_018283.3:c.415C>T rs116855232 415C>T rs116855232 CC
rs116855232 CT
rs116855232 TT

OPRM1

The OPRM1 gene, residing on chromosome 6, encodes the mu-1 opioid receptor, a G protein-coupled receptor highly expressed in the spinal cord and other areas of the central nervous system.1,2,3 The rs1799971 A>G variant has been linked to sensitivity to the effects of certain substrates that act on the mu-1 opioid receptor.3

  1. OPRM1 Gene (National Center for Biotechnology Information) [https://www.ncbi.nlm.nih.gov/gene/4988]
  2. Sun, J., Chen, S. R., & Pan, H. L. (2020). μ-Opioid receptors in primary sensory neurons are involved in supraspinal opioid analgesia. Brain Research, 1729, 146623.
  3. Deer, T., Leong, M., & Gordin, V. (2015). Treatment of chronic pain by medical approaches (pp. 21-31). Springer. In.
HGVS rsID Nucleotide Change Genotypes Reported
NM_000914.4:c.118A>G rs1799971 118A>G rs1799971 AA
rs1799971 AG
rs1799971 GG

SLC6A4

The SLC6A4 gene, residing on chromosome 17, encodes the serotonin transporter (SERT), or 5HTT, which is primarily involved in serotonin reuptake.1 A 44 base pair insertion in the promoter region of SLC6A4 gives rise to two variants: the "L" or long variant and the "S" or short variant.2 The L variant is associated with increased transcriptional activity of the serotonin transporter and is also linked to the rs25531 A>G variant, which further modulates transcription.2,3,4 The minor allele substitution A>G is almost always in phase with the L allele and has been postulated to decrease the transcriptional activity comparable to that of the S allele.5,6,7

  1. SLC6A4 Gene (National Center for Biotechnology Information) [https://www.ncbi.nlm.nih.gov/gene/6532]
  2. Porcelli, S., Fabbri, C., & Serretti, A. (2012). Meta-analysis of serotonin transporter gene promoter polymorphism (5-HTTLPR) association with antidepressant efficacy. European Neuropsychopharmacology, 22(4), 239-258.
  3. Heils, A., Teufel, A., Petri, S., Stöber, G., Riederer, P., Bengel, D., & Lesch, K. P. (1996). Allelic variation of human serotonin transporter gene expression. Journal of neurochemistry, 66(6), 2621-2624.
  4. Hu, X. Z., Lipsky, R. H., Zhu, G., Akhtar, L. A., Taubman, J., Greenberg, B. D., ... & Murphy, D. L. (2006). Serotonin transporter promoter gain-of-function genotypes are linked to obsessive-compulsive disorder. The American Journal of Human Genetics, 78(5), 815-826.
  5. Serretti, A., Kato, M., De Ronchi, D., & Kinoshita, T. (2007). Meta-analysis of serotonin transporter gene promoter polymorphism (5-HTTLPR) association with selective serotonin reuptake inhibitor efficacy in depressed patients. Molecular psychiatry, 12(3), 247-257.
  6. Kraft, J. B., Slager, S. L., McGrath, P. J., & Hamilton, S. P. (2005). Sequence analysis of the serotonin transporter and associations with antidepressant response. Biological psychiatry, 58(5), 374-381.
  7. Schürks, M., Frahnow, A., Diener, H. C., Kurth, T., Rosskopf, D., & Grabe, H. J. (2014). Bi-allelic and tri-allelic 5-HTTLPR polymorphisms and triptan non-response in cluster headache. The journal of headache and pain, 15(1), 46.
HGVS rsID Nucleotide Change Results Reported
NM_001045.5:c-1936A>G rs25531 c.-1810A>G AA
AG
GG
NM_001045.5:c.-1917_-1875del43 rs774676466 -1791_-1749del43 LL
LS
SS

SLCO1B1

Located on the plus strand of chromosome 19, SLCO1B1 encodes the OATP1B1 transporter, which mediates the transport of substrates from the blood into the liver.1 SLCO1B1 variants affect transporter function, which may impact substrates of OATP1B1.2 Pharmacogenomic guidelines published by professional associations exist for this gene and certain medications.3

  1. SLCO1B1 Gene (National Center for Biotechnology Information) [https://www.ncbi.nlm.nih.gov/gene/10599]
  2. Oshiro, C., Mangravite, L., Klein, T., & Altman, R. (2010). PharmGKB very important pharmacogene: SLCO1B1. Pharmacogenetics and genomics, 20(3), 211.
  3. Clinical Guideline Annotations (PharmGKB) [https://www.pharmgkb.org/guidelineAnnotations]
HGVS rsID Nucleotide Change Alleles Reported
NM_006446.4:c.521T>C rs4149056 37041T>C *5, *15, *17
NM_006446.4:c.-910G>A rs4149015 -11187G>A *15, *21
NM_006446.4:c.388A>G rs2306283 ‡388A>G *1B, *15, *17,*21

TPMT

The TPMT gene, residing on the minus strand of chromosome 6, encodes the thiopurine S-methyltransferase enzyme that catalyzes S-methylation of heterocyclic sulfhydryl compounds in thiopurine metabolites.1,2 The methylation of these metabolites is the inactivation pathway, so decreased activity of this enzyme leads to toxicity due to overexposure to active medication.2 The 3A allele is comprised of the two SNPs rs1800460 and rs1142345, which are in high linkage disequilibrium, though may occur as individual variations, denoted as 3B and 3C respectively.2,3 Pharmacogenomic guidelines published by professional associations exist for this gene and certain medications.4

  1. TPMT Gene (National Center for Biotechnology Information) [https://www.ncbi.nlm.nih.gov/gene/7172]
  2. Murugesan, R., Vahab, S. A., Patra, S., Rao, R., Rao, J., Rai, P., ... & Satyamoorthy, K. (2010). Thiopurine S-methyltransferase alleles, TPMT* 2,* 3B and* 3C, and genotype frequencies in an Indian population. Experimental and therapeutic medicine, 1(1), 121-127.
  3. Wang, L., Pelleymounter, L., Weinshilboum, R., Johnson, J. A., Hebert, J. M., Altman, R. B., & Klein, T. E. (2010). Very important pharmacogene summary: thiopurine S-methyltransferase. Pharmacogenetics and genomics, 20(6), 401.
  4. Clinical Guideline Annotations (PharmGKB) [https://www.pharmgkb.org/guidelineAnnotations]
HGVS rsID Nucleotide Change Alleles Reported
NM_000367.3:c.238G>C rs1800462 238G>C *2
NM_000367.3:c.460G>A rs1800460 460G>A *3A, *3B
NM_000367.3:c.719A>G rs1142345 719A>G *3A, *3C
NM_000367.3:c.626-1G>A rs1800584 Chr6:18131012C>T *4

UGT1A1

The UGT1A1 gene, located on chromosome 2, belongs to the family of UDP-glucuronosyltransferases, which mediate glucuronidation of target substrates.1,2 Glucuronidation renders the substrates water soluble, thus making them available for renal elimination.2,3 UGT1A1 is expressed in the liver, colon, intestine, and stomach.2,4,5 In the liver, it is the sole enzyme responsible for the metabolism of bilirubin, the hydrophobic breakdown product of heme catabolism.2,3,6 UGT1A1 also is involved in the metabolism of some medications.2 Pharmacogenomic guidelines published by professional associations exist for this gene and certain medications.7

  1. UGT1A1 Gene (National Center for Biotechnology Information) [https://www.ncbi.nlm.nih.gov/gene/54658]
  2. Barbarino, J. M., Haidar, C. E., Klein, T. E., & Altman, R. B. (2014). PharmGKB summary: very important pharmacogene information for UGT1A1. Pharmacogenetics and genomics, 24(3), 177.
  3. Strassburg, C. P. (2008). Pharmacogenetics of Gilbert’s syndrome.
  4. Strassburg, C. P., Kneip, S., Topp, J., Obermayer-Straub, P., Barut, A., Tukey, R. H., & Manns, M. P. (2000). Polymorphic gene regulation and interindividual variation of UDP-glucuronosyltransferase activity in human small intestine. Journal of Biological Chemistry, 275(46), 36164-36171.
  5. Strassburg, C. P., Nguyen, N., Manns, M. P., & Tukey, R. H. (1998). Polymorphic Expression of the UDP-GlucuronosyltransferaseUGT1A Gene Locus in Human Gastric Epithelium. Molecular Pharmacology, 54(4), 647-654.
  6. Bosma, P. J., Seppen, J., Goldhoorn, B., Bakker, C., Elferink, R. O., Chowdhury, J. R., ... & Jansen, P. L. (1994). Bilirubin UDP-glucuronosyltransferase 1 is the only relevant bilirubin glucuronidating isoform in man. Journal of Biological Chemistry, 269(27), 17960-17964.
  7. Clinical Guideline Annotations (PharmGKB) [https://www.pharmgkb.org/guidelineAnnotations]
HGVS rsID Nucleotide Change Alleles Reported
NM_001072.3:c.862-6536G>A rs4148323 211G>A *6
NM_001072.3:c.862-9697A>G rs1976391 -2936A>G *28 (TA7)

VKORC1

The VKORC1 gene, residing on the minus strand of chromosome 16, encodes vitamin K epoxide reductase (VKOR), which is a key enzyme in the Vitamin K cycle.1 VKOR mediates conversion of vitamin K-epoxide to Vitamin K, which is the rate-limiting step in physiological Vitamin K recycling.2,3 The availability of reduced Vitamin K is of particular importance for several coagulation factor proteins that require it as a cofactor.2,4 A single variant in VKORC1 promoter, rs9923231 G>A is of therapeutic interest, presumably resulting in fewer functional copies of the mature VKORC1 protein.2 Pharmacogenomic guidelines published by professional associations exist for this gene and a certain medication.5

  1. VKORC1 Gene (National Center for Biotechnology Information) [https://www.ncbi.nlm.nih.gov/gene/79001]
  2. Owen, R. P., Gong, L., Sagreiya, H., Klein, T. E., & Altman, R. B. (2010). VKORC1 pharmacogenomics summary. Pharmacogenetics and genomics, 20(10), 642.
  3. Wajih, N., Sane, D. C., Hutson, S. M., & Wallin, R. (2005). Engineering of a recombinant vitamin K-dependent γ-carboxylation system with enhanced γ-carboxyglutamic acid forming capacity evidence for a functional cxxc redox center in the system. Journal of Biological Chemistry, 280(11), 10540-10547.
  4. Stafford, D. W. (2005). The vitamin K cycle. Journal of Thrombosis and Haemostasis, 3(8), 1873-1878.
  5. Clinical Guideline Annotations (PharmGKB) [https://www.pharmgkb.org/guidelineAnnotations]
HGVS rsID Nucleotide Change Genotypes Reported
NM_001311311.1:c.-1639G>A rs9923231 -1639G>A rs9923231 GG
rs9923231 GA
rs9923231 AA
NM_001311311.1:c.442C>T rs7200749 c.358C>T rs9923231 GG
rs9923231 GA
rs9923231 AA