Gene details: Additional test information

COMT

The catechol-O-methyltransferase (COMT) gene on chromosome 22 encodes two versions of the COMT enzyme: membrane-bound (MB-COMT), the longer transcript which is chiefly produced by nerve cells in the brain, and soluble (S-COMT), which is mainly produced by other tissues such as those in the liver and kidney.1,2 The production of these protein isoforms can be attributed to two different promoter regions within COMT that influence transcript production.3 With its function of degrading neurotransmitters called catecholamines, the production of MB-COMT within the prefrontal cortex is essential to cognitive processes.4 In other tissues, S-COMT helps to manage levels of various hormones. The enzymatic activity of COMT is modulated by genetic variants, with one of the best characterized being rs4680 (also known as Val158Met variant or c.322G>A).5

  1. COMT Gene (National Center for Biotechnology Information) [https://www.ncbi.nlm.nih.gov/gene/1312]
  2. COMT Gene -- Genetics Home Reference (National Center for Biotechnology Information) [www. ghr.nlm.nih.gov/gene] https://ghr.nlm.nih.gov/gene/COMT
  3. Tenhunen, J., Salminen, M., Lundström, K., Kiviluoto, T., Savolainen, R., & Ulmanen, I. (1994). Genomic organization of the human catechol O‐methyltransferase gene and its expression from two distinct promoters. European journal of biochemistry, 223(3), 1049-1059.
  4. Meloto, C. B., Segall, S. K., Smith, S., Parisien, M., Shabalina, S. A., Rizzatti-Barbosa, C. M., ... & Slade, G. D. (2015). COMT gene locus: new functional variants. Pain, 156(10), 2072.
  5. 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 Alleles Reported
NM_000754.3:c.472G>A rs4680 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.1 As an important metabolic enzyme in the liver, CYP1A2 metabolizes 9% of clinically important drugs, procarcinogens, and endogenous substrates.2,3 For many drugs CYP1A2 is not the sole metabolizing enzyme, nor is it active at the rate-limiting step.2,4 It is currently believed that up to 75% of the variance seen in CYP1A2 activity has a genetic basis with the remaining consisting of environmental influences like cigarette smoke.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 Alleles Reported
NM_000761.4:c.-9-154C>A rs762551 *1F, *1J, *1K, *1L, *1V, *1W
NM_000761.4:c.-10+103T>G rs2069526 *1E, *1J, *1K, *1W
NM_000761.4:c.-10+113C>T rs12720461 *1K
NM_000761.4:c.-1635delT rs35694136 *1D, *1L, *1V, *1W
NG_008431.2:g.28338G>A rs2069514 *1C, *1L

CYP2B6

CYP2B6, found on the plus strand of chromosome 19, encodes the cytochrome P450 family 2 subfamily B type 6 enzyme.1 CYP2B6 is responsible for the metabolism of 4% of the top 200 medications.2,3 Variation in CYP2B6 expression has been demonstrated in the 20-250-fold range as a result of its highly polymorphic nature and differences in transcriptional regulation.2,4,5 CYP2B6 is highly inducible by several medications and experiences significant alternative splicing following transcription.2,6,7 Professional organizations have published pharmacogenomic guidelines associating variations in this gene with medication considerations.8

  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. Wang, H., & Tompkins, L. M. (2008). CYP2B6: new insights into a historically overlooked cytochrome P450 isozyme. Current drug metabolism, 9(7), 598-610.
  5. 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.
  6. 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.
  7. Lamba, V., Lamba, J., Yasuda, K., Strom, S., Davila, J., Hancock, M. L., ... & Schuetz, E. G. (2003). Hepatic CYP2B6 expression: gender and ethnic differences and relationship to CYP2B6 genotype and CAR (constitutive androstane receptor) expression. Journal of Pharmacology and Experimental Therapeutics, 307(3), 906-922.
  8. Clinical Guideline Annotations (PharmGKB) [https://www.pharmgkb.org/guidelineAnnotations]
HGVS rsID Alleles Reported
NM_000767.4:c.516G>T rs3745274 *6, *7, *9
NM_000767.4:c.983T>C rs28399499 *16, *18
NM_000767.4:c.785A>G rs2279343 *4, *6, *7, *16
NM_000767.4:c.1459C>T rs3211371 *5, *7

CYP2C9

Located on the plus strand of chromosome 10, CYP2C9 encodes the cytochrome P450 family 2 subfamily C type 9 enzyme.1 Primarily expressed in the liver, CYP2C9 has the second highest expression level among CYP isoforms.2,3 Involved in the oxidation of both xenobiotic and endogenous compounds, CYP2C9 metabolizes approximately 15% of medications; this metabolic activity may be influenced by the presence of genetic variants.2,4 Professional organizations have published pharmacogenomic guidelines associating variations in this gene with medication considerations.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. Soars, M. G., Gelboin, H. V., Krausz, K. W., & Riley, R. J. (2003). A comparison of relative abundance, activity factor and inhibitory monoclonal antibody approaches in the characterization of human CYP enzymology. British journal of clinical pharmacology, 55(2), 175-181.
  4. Wang, B., Wang, J., Huang, S. Q., Su, H. H., & Zhou, S. F. (2009). Genetic polymorphism of the human cytochrome P450 2C9 gene and its clinical significance. Current drug metabolism, 10(7), 781-834.
  5. Clinical Guideline Annotations (PharmGKB) [https://www.pharmgkb.org/guidelineAnnotations]
HGVS rsID Alleles Reported
NM_000771.3:c.430C>T rs1799853 *2
NM_000771.3:c.1075A>C rs1057910 *3
NM_000771.3:C.1425A>T rs1057911 *3
NM_000771.3:c.1076T>C rs56165452 *4
NM_000771.3:c.1080C>G rs28371686 *5
NM_000771.3:c.817delA rs9332131 *6
NM_000771.3:c.449G>A rs7900194 *8
NM_000771.3:c.1003C>T rs28371685 *11

CYP2C19

Located on the plus strand of chromosome 10, CYP2C19 encodes the cytochrome P450 family 2 subfamily C type 19 enzyme.1 This gene is predominantly expressed in the liver and, to a lesser extent, in the small intestine.1,2 CYP2C19 is responsible for the metabolism of at least 10% of clinically relevant medications and plays a critical role in several drug-drug interactions.2,3 This enzyme possesses epoxygenase activity, meaning it oxidizes fatty acids in order to produce epoxides that are involved in a variety of important biological processes.4 Professional organizations have published pharmacogenomic guidelines associating variations in this gene with medication considerations.5

  1. CYP2C19 Gene (National Center for Biotechnology Information) [https://www.ncbi.nlm.nih.gov/gene/1557]
  2. CYP2C19 Gene -- Genetics Home Reference (National Center for Biotechnology Information) [https://ghr.nlm.nih.gov/gene/CYP2C19]
  3. 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.
  4. Spector, A. A., & Kim, H. Y. (2015). Cytochrome P450 epoxygenase pathway of polyunsaturated fatty acid metabolism. Biochimica et Biophysica Acta (BBA)-Molecular and Cell Biology of Lipids, 1851(4), 356-365.
  5. Clinical Guideline Annotations (PharmGKB) [https://www.pharmgkb.org/guidelineAnnotations]
HGVS rsID Alleles Reported
NM_000769.2:c.681G>A rs4244285 *2
NM_000769.2:c.636G>A rs4986893 *3
NM_000769.2:c.-806C>T rs12248560 *4B, *17
NM_000769.2:c.1A>G rs28399504 *4, *4B
NM_000769.2:c.680C>T rs6413438 *10

CYP2C Cluster

The CYP2C cluster on chromosome 10 encodes the P450-IIC enzymes, which are required for the metabolism of a number of endogenous steroid hormones and an estimated 20-30% of prescribed medications.1,2 Genetic variants found within this cluster, namely CYP2C18, CYP2C19, CYP2C9 and CYP2C8, have been functionally annotated with clinically relevant outcomes.2 Located in the CYP2C cluster, the rs12777823 variant is of therapeutic interest in combination with genotypes from CYP2C9, VKORC1, and CYP4F2.3,4 Although this variant is common in other ethnic populations, pharmacogenomic associations have only been observed in African Americans.4,5,6 Professional organizations have published pharmacogenomic guidelines associating a variant in this cluster with medication considerations.7

  1. Gray, I. C., Nobile, C., Muresu, R., Ford, S., & Spurr, N. K. (1995). A 2.4-megabase physical map spanning the CYP2C gene cluster on chromosome 10q24. Genomics, 28(2), 328-332.
  2. Suarez-Kurtz, G., Genro, J. P., De Moraes, M. O., Ojopi, E. B., Pena, S. D. J., Perini, J. A., ... & Struchiner, C. J. (2012). Global pharmacogenomics: Impact of population diversity on the distribution of polymorphisms in the CYP2C cluster among Brazilians. The pharmacogenomics journal, 12(3), 267-276.
  3. Rs12777823 -- dbSNP (The Single Nucleotide Polymorphism Database) [https://www.ncbi.nlm.nih.gov/snp/rs12777823]
  4. 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.
  5. Perera, M.A. et al. Genetic variants associated with warfarin dose in African-American individuals: a genome-wide association study. Lancet 382, 790–596 (2013).
  6. Alzubiedi, S. & Saleh, M.I. Pharmacogenetic-guided Warfarin Dosing Algorithm in African-Americans. J. Cardiovasc. Pharmacol. 67, 86–92 (2016).
  7. Clinical Guideline Annotations (PharmGKB) [https://www.pharmgkb.org/guidelineAnnotations]
HGVS rsID Genotypes Reported
NC_000010.11:g.94645745G>A rs12777823 rs12777823 GG
rs12777823 GA
rs12777823 AA

CYP2D6

Located on the minus strand of chromosome 22, CYP2D6 encodes the cytochrome P450 family 2 subfamily D type 6 enzyme, which plays an important role in the metabolism and bioactivation of 25% of clinically relevant medications.1,2 This gene is predominantly expressed in the liver and, to a lesser extent, in the small intestine.1 A large portion of variation seen in CYP2D6 activity can be attributed to its highly polymorphic nature.2 CYP2D6 is recognized as having a large variety of structural variants that impact enzymatic activity including deletions, duplications, and rearrangements.3 Professional organizations have published pharmacogenomic guidelines associating variations in this gene with medication considerations.4

  1. CYP2D6 Gene (National Center for Biotechnology Information) [https://www.ncbi.nlm.nih.gov/gene/1565]
  2. Gaedigk, A. (2013). Complexities of CYP2D6 gene analysis and interpretation. International review of psychiatry, 25(5), 534-553.
  3. 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.
  4. Clinical Guideline Annotations (PharmGKB) [https://www.pharmgkb.org/guidelineAnnotations]
HGVS rsID Alleles Reported
NM_000106.5:c.-1584C>G rs1080985 *2A, *11, *14, *31, *35, *63
NM_000106.5:c.31G>A rs769258 *35
NM_000106.5:c.100C>T rs1065852 *4, *4J, *4N, *10, *36, *64, *68, *69, *114
NM_000106.5:c.124G>A rs5030862 *12
NM_000106.5:c.181-1G>C rs201377835 *11
NM_000106.5:c.505G>T rs5030865G>T *8
NM_000106.5:c.505G>A rs5030865G>A *14, *114
NM_000106.5:c.841_843delAAG rs5030656 *9, *109
NM_000106.5:c.320C>T rs28371706 *17, *64
NM_000106.5:c.454delT rs5030655 *6, *6C
NM_000106.5:c.506-1G>A rs3892097 *4, *4J, *4M, *4N
NM_000106.5:c.775delA rs35742686 *3
NM_000106.5:c.971A>C rs5030867 *7
NM_000106.5:c.1012G>A rs59421388 *29, *70, *109
NM_000106.5:c.985+39G>A rs28371725 *41, *69, *91
NM_000106.5:c.886C>T rs16947 *2, *2A, *8, *11, *12, *14, *17, *19, *29, *31, *35, *41, *42, *63, *69, *91, *114
NM_000106.5:c.1457G>C rs1135840 *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 *31
NM_000106.5:c.137_138insT rs774671100 *13, *15
NM_000106.5:c.765_768delAACT rs72549353 *19
NM_000106.5:c.1088_1089insGT rs72549346 *42
NM_000106.5:c.1411_1412insTGCCCACTG hCV32407220 (rs765776661) *18
NM_000106.5:c.975G>A rs79292917 *59

CYP3A4

Located on the minus strand of chromosome 7, cytochrome P450 family 3 subfamily A type 4 enzyme (CYP3A4) is encoded by the CYP3A4 gene.1 As members of the CYP3A gene family, both CYP3A4 and CYP3A5 are believed to be predominant cytochrome P450 enzymes expressed in the adult human liver.2,3 Shown to metabolize more than 1900 substrates, the activity of CYP3A4 is influenced by genetic variants, transcriptional regulation, and drug interactions.2,4,5

  1. CYP3A4 Gene (National Center for Biotechnology Information) [https://www.ncbi.nlm.nih.gov/gene/1576]
  2. Cacabelos, R., Cacabelos, P., & Torrellas, C. (2014). Personalized medicine of Alzheimer’s disease. Handbook of pharmacogenomics and stratified medicine, 563.
  3. Patwardhan, B., & Chaguturu, R. (2016). Innovative Approaches in Drug Discovery: Ethnopharmacology, Systems Biology and Holistic Targeting (pp 195-234). Academic Press.
  4. Lolodi, O., Wang, Y. M., Wright, W. C., & Chen, T. (2017). Differential regulation of CYP3A4 and CYP3A5 and its implication in drug discovery. Current drug metabolism, 18(12), 1095-1105.
  5. Wilkinson, G. R. (2005). Drug metabolism and variability among patients in drug response. New England Journal of Medicine, 352(21), 2211-2221.
HGVS rsID Alleles Reported
NM_017460.5:c.-392G>A rs2740574 *1B
NM_017460.5:c.522-191C>T rs35599367 *22

CYP3A5

Located on the minus strand of chromosome 7, cytochrome P450 family 3 subfamily A type 5 (CYP3A5) is encoded by the CYP3A5 gene.1 As members of the CYP3A gene family, both CYP3A4 and CYP3A5 are believed to be predominant cytochrome P450 enzymes expressed in the adult human liver.2,4 CYP3A5 is the predominant form expressed in extrahepatic tissues.3 Most medications metabolized by CYP3A4 are also metabolized by CYP3A5, with a few exceptions.4 CYP3A5 activity predominates in individuals of African descent due to differences in population allele frequencies; loss-of-function alleles, such as *3, are found in most Caucasians.5,6,7,8 Professional organizations have published pharmacogenomic guidelines associating variations in this gene with medication considerations.9

  1. CYP3A5 Gene (National Center for Biotechnology Information) [https://www.ncbi.nlm.nih.gov/gene/1577]
  2. Cacabelos, R., Cacabelos, P., & Torrellas, C. (2014). Personalized medicine of Alzheimer’s disease. Handbook of pharmacogenomics and stratified medicine, 563.
  3. 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.
  4. Patwardhan, B., & Chaguturu, R. (2016). Innovative Approaches in Drug Discovery: Ethnopharmacology, Systems Biology and Holistic Targeting (pp 195-234). Academic Press.
  5. Langman, L., van Gelder, T., & van Schaik, R. H. (2016). Pharmacogenomics aspect of immunosuppressant therapy. In Personalized Immunosuppression in Transplantation (pp. 109-124). Elsevier.
  6. Hustert, E., Haberl, M., Burk, O., Wolbold, R., He, Y. Q., Klein, K., ... & Koch, I. (2001). The genetic determinants of the CYP3A5 polymorphism. Pharmacogenetics and Genomics, 11(9), 773-779.
  7. 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.
  8. Van Schaik, R. H., Van Der Heiden, I. P., Van Den Anker, J. N., & Lindemans, J. (2002). CYP3A5 variant allele frequencies in Dutch Caucasians. Clinical chemistry, 48(10), 1668-1671.
  9. Clinical Guideline Annotations (PharmGKB) [https://www.pharmgkb.org/guidelineAnnotations]
HGVS rsID Alleles Reported
NM_000777.4:c.219-237G>A rs776746 *3
NM_000777.4:c.624G>A rs10264272 *6
NM_000777.4:c.1035_1036insT rs41303343 *7

CYP4F2

Cytochrome P450 family 4 subfamily F member 2 (CYP4F2) is encoded by the CYP4F2 gene, located on chromosome 19.1 Expressed in the liver, and, to a lesser extent, the kidney and gastrointestinal tract, CYP4F2 is involved in the metabolism of various endogenous substrates, including fatty acids, eicosanoids and vitamins.1,2 Products of CYP4F2 metabolism are associated with regulating inflammation, as well as renal tubular and vascular function.3,4 In conjunction with genotypes from CYP2C9, VKORC1, and the CYP2C cluster, CYP4F2 variants are of therapeutic interest for hemostatic processes in those of European and Asian ancestry.5,6,7,8 A professional organization has published a pharmacogenomic guideline associating a variant in this gene with medication considerations.9

  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. CYP4F2 -- OMIM (Online Mendelian Inheritance in Man) [https://www.omim.org/entry/604426]
  4. Stec, D. E., Roman, R. J., Flasch, A., & Rieder, M. J. (2007). Functional polymorphism in human CYP4F2 decreases 20-HETE production. Physiological genomics.
  5. 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.
  6. 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.
  7. Danese, E. et al. Impact of the CYP4F2 p.V433M polymorphism on coumarin dose requirement: systematic review and meta-analysis. Clin. Pharmacol. Ther. 92, 746–756 (2012).
  8. Zhang, J.E. et al. Effects of CYP4F2 genetic polymorphisms and haplotypes on clinical outcomes in patients initiated on warfarin therapy. Pharmacogenet. Genomics 19, 781–789 (2009).
  9. Clinical Guideline Annotations (PharmGKB) [https://www.pharmgkb.org/guidelineAnnotations]
HGVS rsID Alleles Reported
NM_001082.4:c.1297G>A rs2108622 *3

DPYD

The DPYD gene, located on the minus strand of chromosome 1, encodes the dihydropyrimidine dehydrogenase (DPD) enzyme.1 DPD is a pyrimidine catabolic enzyme involved in the degradation pathway of chemotherapeutic agents.2,3 Administration of these agents in individuals with decreased DPD activity can lead to severe or fatal toxicity.3,4 Professional organizations have published pharmacogenomic guidelines associating variations in this gene with medication considerations.5

  1. DPYD Gene (National Center for Biotechnology Information) [https://www.ncbi.nlm.nih.gov/gene/1806]
  2. Ameyaw, M. M., & Mcleod, H. L. (2006). Improving The Efficacy And Safety Of Anticancer Agents—the Role Of Pharmacogenetics. In Novel Anticancer Agents (Summary). Academic Press. [https://www.sciencedirect.com/science/article/pii/B9780120885619500132?via%3Dihub]
  3. Kubota, T. (2003). 5-Fluorouracil and dihydropyrimidine dehydrogenase. International journal of clinical oncology, 8(3), 127-131.
  4. 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).
  5. Clinical Guideline Annotations (PharmGKB) [https://www.pharmgkb.org/guidelineAnnotations]
HGVS rsID Genotypes Reported
NM_000110.3:c.1679T>G rs55886062 rs55886062 AA
rs55886062 AC
rs55886062 CC
NM_000110.3:c.2846A>T rs67376798 rs67376798 TT
rs67376798 TA
rs67376798 AA
NM_000110.3:c.1905+1G>A rs3918290 rs3918290 CC
rs3918290 CT
rs3918290 TT

DRD2

Located on the minus strand of chromosome 11, the DRD2 gene encodes the D2 subtype of the dopamine receptor, a class of G protein-coupled receptors.1 Highly expressed in the pituitary gland and central nervous system, alternative splicing of DRD2 results in short (D2S) and long (D2L) isoforms; D2L is predominantly a postsynaptic receptor while D2S functions as a presynaptic autoreceptor.2,3 These receptors are targeted by certain medications and are involved in several cerebral physiological processes.2,4 A promoter variant, rs1799978, may influence expression of DRD2.5

  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. Beaulieu, J. M., & Gainetdinov, R. R. (2011). The physiology, signaling, and pharmacology of dopamine receptors. Pharmacological reviews, 63(1), 182-217.
  4. Della Torre, O. H., Paes, L. A., Henriques, T. B., de Mello, M. P., Celeri, E. H. R. V., Dalgalarrondo, P., ... & dos Santos-Júnior, A. (2018). Dopamine D2 receptor gene polymorphisms and externalizing behaviors in children and adolescents. BMC medical genetics, 19(1), 65.
  5. 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 Genotypes Reported
NM_000795.3:c.-585A>G rs1799978 rs1799978 AA
rs1799978 GA
rs1799978 GG

F2

Residing on chromosome 11, the F2 gene encodes prothrombin (coagulation factor II), an essential protein for blood clotting. Inactive prothrombin is produced primarily in liver cells and circulated through the bloodstream; activation to thrombin occurs at the time of vascular injury.2 Thrombin catalyzes the conversion of fibrinogen into soluble fibrin, which in turn is the primary protein involved in formation of blood clots.2 Genotyping F2 may be useful in identifying an increased risk of thrombosis due to prothrombin thrombophilia.3

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

F5

The F5 gene, residing on the minus strand of chromosome 1, encodes coagulation factor V.1,2 Primarily produced by liver cells, this protein circulates the bloodstream in its inactive form until vascular injury occurs.2,3 Following injury, factor V forms an active complex with other coagulation cofactors to facilitate conversion of prothrombin (factor II) to active thrombin, thereby advancing the coagulation process.2 Inactivation of factor V by activated protein C (APC) hinders coagulation.2 However, genetic variants within F5 can lead to the formation of the Factor V Leiden protein, which cannot be inactivated normally by APC.3 As a result, the clotting process is prolonged, thereby increasing the chance of developing abnormal blood clots.4 Genotyping F5 may be useful in identifying an increased risk of thrombosis due to Factor V Leiden thrombophilia.3

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

GRIK4

The GRIK4 gene, residing on chromosome 11, encodes the glutamate ionotropic receptor kainate-type subunit 4.1 As a member of the glutamate-gated ion channel family, this protein is involved in glutamate neurotransmission.1,2 Glutamate is the principal excitatory neurotransmitter within the vertebrate nervous system and may be involved in cognitive functions like learning and memory.3,4 An intronic variant in GRIK4, rs1954787 T>C, may influence the efficacy of certain medications.5

  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. Meldrum, B. S. (2000). Glutamate as a neurotransmitter in the brain: review of physiology and pathology. The Journal of nutrition, 130(4), 1007S-1015S.
  4. McEntee, W. J., & Crook, T. H. (1993). Glutamate: its role in learning, memory, and the aging brain [Abstract]. Psychopharmacology, 111(4), 391-401.
  5. Kawaguchi, D. M., & Glatt, S. J. (2014). GRIK4 polymorphism and its association with antidepressant response in depressed patients: a meta-analysis. Pharmacogenomics, 15(11), 1451-1459.
HGVS rsID Genotypes Reported
NM_001282470.2:c.83-10039T>C rs1954787 rs1954787 TT
rs1954787 TC
rs1954787 CC

HLA-A

Residing on chromosome 6, the HLA-A gene codes for the human leukocyte antigen (HLA) class I histocompatibility antigen, A alpha chain.1 As the human version of the major histocompatibility complex (MHC), HLA proteins are cell surface receptors expressed in nearly all cells.2,3 Functioning as major players in the adaptive immune response, they are responsible for presenting antigen peptides on cell surfaces for recognition by T lymphocytes, thereby triggering downstream immune responses.3 Histocompatibility complex genes are subject to variation, allowing variability in the individual immune response to a wide range of foreign invaders; some HLA-A alleles are associated with adverse drug reactions.2,3 In particular, HLA-A*31:01 is associated with hypersensitivity reactions in Japanese, Korean and Caucasian populations.4 Professional organizations have published pharmacogenomic guidelines associating variations in this gene with medication considerations.5

  1. HLA-A -- UniProt [https://www.uniprot.org/uniprot/P04439]
  2. Histocompatibility Complex -- Genetics Home Reference (National Center for Biotechnology Information) [https://ghr.nlm.nih.gov/primer/genefamily/hla]
  3. 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.
  4. Yip, V. L. M., & Pirmohamed, M. (2017). The HLA-A* 31: 01 allele: influence on carbamazepine treatment. Pharmacogenomics and personalized medicine, 10, 29.
  5. Clinical Guideline Annotations (PharmGKB) [https://www.pharmgkb.org/guidelineAnnotations]
HGVS rsID Reported Results
NM_002116 (interrogated at exon 2) HLA00097 3101 Negative
3101 Positive

HLA-B

The HLA-B gene, residing on chromosome 6, codes for the human leukocyte antigen (HLA) class I histocompatibility antigen, B alpha chain.1,2 As the human version of the major histocompatibility complex (MHC), HLA proteins are cell surface receptors expressed in nearly all cells.3,4 Functioning as major players in the adaptive immune response, they are responsible for presenting antigen peptides on cell surfaces for recognition by T lymphocytes, thereby triggering downstream immune responses.4 Histocompatibility complex genes are subject to variation, allowing variability in the individual immune response to a wide range of foreign invaders.3,4 Certain HLA-B alleles, such as HLA-B*15:02, HLA-B*57:01, and HLA-B*58:01, are associated with adverse drug reactions.3,4 Professional organizations have published pharmacogenomic guidelines associating variations in this gene with medication considerations.5

  1. HLA-B Gene (National Center for Biotechnology Information) [https://www.ncbi.nlm.nih.gov/gene/3106]
  2. HLA-B -- UniProt [https://www.uniprot.org/uniprot/P01889]
  3. Histocompatibility Complex -- Genetics Home Reference (National Center for Biotechnology Information) [https://ghr.nlm.nih.gov/primer/genefamily/hla]
  4. 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.
  5. Clinical Guideline Annotations (PharmGKB) [https://www.pharmgkb.org/guidelineAnnotations]
HGVS rsID Reported Results
NM_005514.7:c.1012+104A>T rs144012689 1502 Positive
1502 Negative
NM_005514 (interrogated at exon 3) HLA00381 57:01 Positive
57:01 Negative
NM_005514 (interrogated at exon 2 and intron 2) HLA00386 58:01 Positive
58:01 Negative

HTR2A

Residing on chromosome 13, the HTR2A gene encodes the 5-hydroxytryptamine (serotonin) receptor 2A (5-HT2A).1 5-HT2A is a G protein-coupled receptor highly expressed throughout the central nervous system, especially in brain regions essential for learning and cognition.2 Functioning as a postsynaptic target for serotonin and various medications, HTR2A is found to be downregulated as a result of pharmacodynamic effects of certain medications.2,3,4 Variants in this gene, such as rs7997012 A>G, are of therapeutic interest.4

  1. HTR2A Gene (National Center for Biotechnology Information) [https://www.ncbi.nlm.nih.gov/gene/3356]
  2. Zhang, G., & Stackman Jr, R. W. (2015). The role of serotonin 5-HT2A receptors in memory and cognition. Frontiers in pharmacology, 6, 225.
  3. Smith, R. M., Papp, A. C., Webb, A., Ruble, C. L., Munsie, L. M., Nisenbaum, L. K., ... & Sadee, W. (2013). Multiple regulatory variants modulate expression of 5-hydroxytryptamine 2A receptors in human cortex. Biological psychiatry, 73(6), 546-554.
  4. 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 Genotypes Reported
NM_000621.4:c.614-2211T>C rs7997012 rs7997012 TT
rs7997012 TC
rs7997012 CC

HTR2C

The HTR2C gene, residing on the X chromosome, encodes the 5-hydroxytryptamine (serotonin) receptor 2C (5-HT2C).1 5-HT2C is a G protein-coupled receptor highly expressed in the brain that is involved in the regulation of key physiological functions like food intake and sleep.1,2 HTR2C activity is found to be regulated by alternative splicing and downregulated as a result of pharmacodynamic effects of certain medications.2,3 Variants in this gene, such as rs3813929 T>C, are of therapeutic interest.4

  1. HTR2C Gene (National Center for Biotechnology Information) [https://www.ncbi.nlm.nih.gov/gene/3358]
  2. Stamm, S., Gruber, S. B., Rabchevsky, A. G., & Emeson, R. B. (2017). The activity of the serotonin receptor 2C is regulated by alternative splicing. Human genetics, 136(9), 1079-1091.
  3. 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.
  4. Rs3813929-- SNPedia [https://www.snpedia.com/index.php/Rs3813929]
HGVS rsID Genotypes Reported
NM_000868.3:c.-759C>T rs3813929 rs3813929 CC
rs3813929 CT
rs3813929 TT

IFNL4

Found on the minus strand of chromosome 19, the IFNL4 gene encodes interferon lambda 4.1 As a cytokine protein, IFNL4 is involved in the immune response to viral infection and has specifically been linked to infection by hepatitis C.2,3,4 A variant in this gene, rs12979860 C>T, is associated with variability in hepatitis C (HCV) sustained virologic response (SVR) rate.3 IFNL4 genotype is also demonstrated to be a predictor of hepatic inflammation and fibrosis.5 Until recently, rs12979860 was thought to be located in a regulatory region upstream of IFNL3 (also referred to as IL28B). Therefore, this gene may also be referred to as IL28B or IFNL3.4,6 A professional organization has published pharmacogenomic guidelines associating variations in this gene with medication considerations.7

  1. IFNL4 Gene (National Center for Biotechnology Information) [https://www.ncbi.nlm.nih.gov/gene/101180976]
  2. Egli, A., Santer, D. M., O’Shea, D., Tyrrell, D. L., & Houghton, M. (2014). The impact of the interferon-lambda family on the innate and adaptive immune response to viral infections. Emerging microbes & infections, 3(1), 1-12.
  3. 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.
  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. Eslam, M., Hashem, A. M., Leung, R., Romero-Gomez, M., Berg, T., Dore, G. J., ... & Adams, L. A. (2015). Interferon-λ rs12979860 genotype and liver fibrosis in viral and non-viral chronic liver disease. Nature communications, 6(1), 1-10.
  6. 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.
  7. Clinical Guideline Annotations (PharmGKB) [https://www.pharmgkb.org/guidelineAnnotations]
HGVS rsID Genotypes Reported
NM_001276254.2:c.151-152G>A rs12979860 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 request the test online (ordered through the independent physician network).

Residing on the minus strand of chromosome 1, the MTHFR gene encodes the rate-limiting enzyme methylenetetrahydrofolate reductase.1 This enzyme is integrally involved in the DNA synthesis pathway, specifically in the conversion of homocysteine to methionine through the methylation cycle of folic acid.1,2,3 Common variants in this gene, namely rs1801133 and rs1801131, can disrupt this pathway, thereby 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 Genotypes Reported
NM_005957.4:c.665C>T rs1801133 rs1801133 CC
rs1801133 CT
rs1801133 TT
NM_005957.4:c.1286A>C rs1801131 rs1801131 AA
rs1801131 AC
rs1801131 CC

NUDT15

Located on the plus strand of chromosome 13, the NUDT15 gene encodes nudix hydrolase 15.1,2 As a member of the nudix superfamily, this enzyme is responsible for the hydrolysis of nucleoside diphosphates.2 Produced through oxidative damage, nucleoside diphosphates can cause base mispairing during nucleic acid synthesis, thereby causing translational errors.2 Additionally, NUDT15 plays a role in the inactivation of thiopurine metabolites.3 Variants that impair NUDT15 activity are associated with a higher risk of thiopurine-related toxicities; these variants are common in individuals of Asian and Hispanic descent.3,4,5 Professional organizations have published pharmacogenomic guidelines associating variations in this gene with medication considerations.6

  1. NUDT15 Gene (National Center for Biotechnology Information) [https://www.ncbi.nlm.nih.gov/gene/55270]
  2. NUDT15 Gene -- Genetics Home Reference (National Center for Biotechnology Information) [https://ghr.nlm.nih.gov/gene/NUDT15]
  3. 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.
  4. 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.
  5. Relling, M. V., Schwab, M., Whirl‐Carrillo, M., Suarez‐Kurtz, G., Pui, C. H., Stein, C. M., ... & Caudle, K. E. (2019). Clinical pharmacogenetics implementation consortium guideline for thiopurine dosing based on TPMT and NUDT 15 genotypes: 2018 update. Clinical Pharmacology & Therapeutics, 105(5), 1095-1105.
  6. Clinical Guideline Annotations (PharmGKB) [https://www.pharmgkb.org/guidelineAnnotations]
HGVS rsID Genotypes Reported
NM_018283.3:c.415C>T rs116855232 rs116855232 CC
rs116855232 CT
rs116855232 TT

OPRM1

The OPRM1 gene resides on chromosome 6 and encodes the mu-1 opioid receptor (MOR1).1 As the first opioid receptor to be discovered, MOR1 is the primary receptor for endogenous opioids called beta-endorphin and enkephalins.2 The MOR receptor family are G protein-coupled receptors highly expressed in the central nervous system that neuromodulate several physiological functions, in particular nociception.3,4,5,6 A genetic variant in OPRM1, rs1799971 A>G, is associated with individual response to the analgesic effects of some clinically relevant medications.7,8

  1. OPRM1 Gene (National Center for Biotechnology Information) [https://www.ncbi.nlm.nih.gov/gene/4988]
  2. OPRM1 Gene -- Genetics Home Reference (National Center for Biotechnology Information)[https://ghr.nlm.nih.gov/gene/OPRM1]
  3. 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.
  4. Deer, T., Leong, M., & Gordin, V. (2015). Treatment of chronic pain by medical approaches (pp. 21-31). Springer. In.
  5. Ugur, M., Derouiche, L., & Massotte, D. (2018). Heteromerization modulates mu opioid receptor functional properties in vivo. Frontiers in pharmacology, 9, 1240.
  6. Kieffer, B. L., & Evans, C. J. (2009). Opioid receptors: from binding sites to visible molecules in vivo. Neuropharmacology, 56, 205-212.
  7. Campa, D., Gioia, A., Tomei, A., Poli, P., & Barale, R. (2008). Association of ABCB1/MDR1 and OPRM1 gene polymorphisms with morphine pain relief. Clinical pharmacology & therapeutics, 83(4), 559-566.
  8. Boswell, M. V., Stauble, M. E., Loyd, G. E., Langman, L., Ramey-Hartung, B., Baumgartner, R. N., ... & Jortani, S. A. (2013). The role of hydromorphone and OPRM1 in postoperative pain relief with hydrocodone. Pain Physician, 16(3), E227-E235.
HGVS rsID Genotypes Reported
NM_000914.4:c.118A>G rs1799971 rs1799971 AA
rs1799971 AG
rs1799971 GG

SLC6A4

Residing on chromosome 17, the SLC6A4 gene encodes the serotonin transporter (5HTT).1 Primarily involved in serotonin reuptake, this protein functions as an integral membrane transporter that brings serotonin from synaptic spaces into presynaptic neurons.1 A 44 base pair insertion/deletion in the promoter region of SLC6A4 gives rise to two isoforms: the "L" or long allele and the "S" or short allele.2 The L allele is associated with increased transcriptional activity of 5HTT; however, a second variant almost always in phase with the L allele, rs25531 A>G, has been postulated to decrease transcriptional activity to a level comparable to that of the S allele.2,3,4,5,6 Genetic variants within SLC6A4 are associated with the efficacy of certain medications.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. 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.
  4. 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.
  5. 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.
  6. 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.
  7. Stevenson, J. M. (2018). Insights and barriers to clinical use of serotonin transporter pharmacogenetics in antidepressant therapy.
HGVS rsID Results Reported
NM_001045.5:c-1936A>G rs25531 AA
AG
GG
NM_001045.5:c.-1917_-1875del43 rs774676466 LL
LS
SS

SLCO1B1

Located on the plus strand of chromosome 19, the SLCO1B1 gene encodes the organic anion transporting polypeptide 1B1 (OATP1B1) transporter.1 As a major transporter on the sinusoidal membrane of human hepatocytes, OATP1B1 mediates the influx of various endogenous compounds and clinically relevant drugs.2 Some medications are found to inhibit OATP1B1, thereby causing pharmacokinetic drug–drug interactions.3 Genetic variants within SLCO1B1 can affect transporter function, which may impact the efficacy of drugs identified as OATP1B1 substrates.4 Professional organizations have published pharmacogenomic guidelines associating a variant in this gene with medication considerations.5

  1. SLCO1B1 Gene (National Center for Biotechnology Information) [https://www.ncbi.nlm.nih.gov/gene/10599]
  2. Nies, A. T., Niemi, M., Burk, O., Winter, S., Zanger, U. M., Stieger, B., ... & Schaeffeler, E. (2013). Genetics is a major determinant of expression of the human hepatic uptake transporter OATP1B1, but not of OATP1B3 and OATP2B1. Genome medicine, 5(1), 1-11.
  3. Kalliokoski, A., & Niemi, M. (2009). Impact of OATP transporters on pharmacokinetics. British journal of pharmacology, 158(3), 693-705.
  4. Oshiro, C., Mangravite, L., Klein, T., & Altman, R. (2010). PharmGKB very important pharmacogene: SLCO1B1. Pharmacogenetics and genomics, 20(3), 211.
  5. Clinical Guideline Annotations (PharmGKB) [https://www.pharmgkb.org/guidelineAnnotations]
HGVS rsID Alleles Reported
NM_006446.4:c.521T>C rs4149056 *5, *15, *17
NM_006446.4:c.-910G>A rs4149015 *15, *21
NM_006446.4:c.388A>G rs2306283 *1B, *15, *17,*21

TPMT

The TPMT gene is located on the minus strand of chromosome 6 and encodes the thiopurine S-methyltransferase enzyme.1 As a cytoplasmic enzyme, TPMT catalyzes the inactivation of heterocyclic sulfhydryl compounds found in thiopurine metabolites through S-methylation.2 Genetic variants within TPMT confer decreased activity and therefore decreased methylation of these compounds.2 As a result, these variants increase the risk of toxicity due to increased drug exposure.2 Variants resulting in TPMT deficiency are the primary genetic cause of thiopurine intolerance in individuals of European and African descent; TPMT*2, *3A, *3B, and *3C are the most common variants detected in over 80% of individuals with decreased activity.2,3 Professional organizations have published pharmacogenomic guidelines associating variations in this gene with medication considerations.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. Relling, M. V., Schwab, M., Whirl‐Carrillo, M., Suarez‐Kurtz, G., Pui, C. H., Stein, C. M., ... & Caudle, K. E. (2019). Clinical pharmacogenetics implementation consortium guideline for thiopurine dosing based on TPMT and NUDT 15 genotypes: 2018 update. Clinical Pharmacology & Therapeutics, 105(5), 1095-1105.
  4. Clinical Guideline Annotations (PharmGKB) [https://www.pharmgkb.org/guidelineAnnotations]
HGVS rsID Alleles Reported
NM_000367.3:c.238G>C rs1800462 *2
NM_000367.3:c.460G>A rs1800460 *3A, *3B
NM_000367.3:c.719A>G rs1142345 *3A, *3C
NM_000367.3:c.626-1G>A rs1800584 *4

UGT1A1

Located on chromosome 2, the UGT1A1 gene encodes the UDP-glucuronosyltransferase 1A1 enzyme.1,2 UGT1A1 is expressed in the liver, colon, intestine, and stomach.3,4,5 Involved in the glucuronidation pathway, this enzyme aids in the transformation of small lipophilic molecules, including the intermediate products of some medications, into water-soluble, excretable metabolites.1,3,6,7 In the liver, it is the sole enzyme responsible for the metabolism of bilirubin, the hydrophobic breakdown product of heme catabolism.3,6,8 Professional organizations have published pharmacogenomic guidelines associating variations in this gene with medication considerations.9

  1. UGT1A1 Gene (National Center for Biotechnology Information) [https://www.ncbi.nlm.nih.gov/gene/54658]
  2. UGT1A1 -- UniProt [https://www.uniprot.org/uniprot/P22309]
  3. 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.
  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. Strassburg, C. P. (2008). Pharmacogenetics of Gilbert’s syndrome.
  7. Dean, L. (2018). Irinotecan therapy and UGT1A1 genotype.
  8. 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.
  9. Clinical Guideline Annotations (PharmGKB) [https://www.pharmgkb.org/guidelineAnnotations]
HGVS rsID Alleles Reported
NM_001072.3:c.862-6536G>A rs4148323 *6
NM_001072.3:c.862-9697A>G rs1976391 *28 (TA7)

VKORC1

The VKORC1 gene resides on the minus strand of chromosome 16 and encodes vitamin K epoxide reductase (VKOR).1 As a key enzyme in the vitamin K cycle, VKOR mediates the conversion of vitamin K epoxide to vitamin K, which is the rate-limiting step in physiological vitamin K recycling.1,2,3 As an important cofactor for several coagulation proteins, the availability of reduced vitamin K is of particular importance.2,4

A single variant in the VKORC1 promoter, rs9923231 G>A, alters a transcription factor binding site and reduces gene expression as a result, presumably resulting in fewer functional copies of the mature VKOR protein.2,5 Professional organizations have published pharmacogenomic guidelines associating a variant in this gene with medication considerations.6

  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. Yuan, H. Y., Chen, J. J., Lee, M. M., Wung, J. C., Chen, Y. F., Charng, M. J., ... & Wu, J. Y. (2005). A novel functional VKORC1 promoter polymorphism is associated with inter-individual and inter-ethnic differences in warfarin sensitivity. Human molecular genetics, 14(13), 1745-1751.
  6. Clinical Guideline Annotations (PharmGKB) [https://www.pharmgkb.org/guidelineAnnotations]
HGVS rsID Genotypes Reported
NM_001311311.1:c.-1639G>A rs9923231 rs9923231 GG
rs9923231 GA
rs9923231 AA
NM_001311311.1:c.442C>T rs7200749 rs9923231 GG
rs9923231 GA
rs9923231 AA