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Pharmacogenomic Terminology and Nomenclature

The complex nomenclature systems that are essential to interpreting pharmacogenomic (PGx) results have been a major obstacle for the widespread acceptance and implementation of PGx testing in clinical practice. In this article we will review many of the definitions, terminology, and nomenclature systems that are essential to understanding PGx results.

As discussed in An Introduction to Genetics, it has been estimated that there are between 20,000 and 25,000 genes in the human genome. Each gene resides at a specific location on a chromosome and comprises about 27,000 base pairs, on average. Different versions of the same gene are known as alleles or variants and individuals inherit one from each parent for every gene.

The specific combination of alleles present in an individual is referred to as that individual’s genotype. Having two copies of the same allele for a particular gene is referred to as being homozygous while having two different alleles for the same gene is referred to as being heterozygous. An individual’s observable characteristics, which result from a combination of the effects of their genes and their environment, are referred to as their phenotype. 

What is a single nucleotide polymorphism?

Strands of DNA form a double helix structure and are composed of four different nucleotide building blocks: adenine (A), guanine (G), thymine (T), and cytosine (C). The pairing of these nucleotides forms the “rungs” of the ladder; adenine always pairs with thymine, and guanine always pairs with cytosine. While the common understanding that each individual has a unique genetic code is accurate, all humans’ functional DNA sequences are about 99.9% identical.

A single nucleotide polymorphism (SNP) refers to an individual nucleotide variation at one specific position in the genome. These minor differences can have dramatic effects on the proteins encoded by a particular gene and thus may result in significantly different outcomes.

Consider the Catechol-O-Methyltransferase (COMT) gene. COMT is an enzyme involved in the breakdown of dopamine in the frontal lobes of the brain. The gene encoding the COMT enzyme contains a functional polymorphism that is commonly known as Val158Met (rs4680). A SNP that results in a G to A substitution causes an amino acid change at location 158 of the polypeptide sequence of the COMT enzyme. Specifically, this results in a methionine (Met) rather than a valine (Val) at residue 158 of the polypeptide sequence. This change has a significant impact on COMT enzyme activity and its ability to degrade dopamine. For this particular SNP it is common to refer to the three possible genotypes as Val/Met (G/A), Val/Val (G/G), or Met/Met (A/A):1,2

  • Individuals with the heterozygous genotype (Val/Met) are considered to have normal levels of dopamine degradation as they possess one increased and one decreased function allele. Since this is the most common form of the SNP in the general population, it is referred to as the wild-type.
  • Individuals with the homozygous Val/Val genotype have elevated enzyme activity and consequently lower frontal cortex dopamine levels due to increased dopamine degradation.
  • Individuals with the homozygous Met/Met genotype have reduced enzyme activity and consequently higher frontal cortex dopamine levels due to decreased dopamine degradation.

What is an rs number?

Let’s now consider the Methylenetetrahydrofolate Reductase (MTHFR) gene. MTHFR is an enzyme essential for catalyzing the conversion of folic acid to the biologically active form, methylfolate. One SNP in the MTHFR gene involves the replacement of the common allele (C) by the minor allele (T) which reduces the activity of the enzyme by approximately 35% per T allele.3 Meanwhile, another SNP in the MTHFR gene involves the replacement of the common allele (A) by the minor allele (C) which reduces the activity of the MTHFR enzyme by approximately 20% per C allele.3 Without the implementation of the rs numbering system, differentiating these SNPs and interpreting these results would be very difficult.

Every SNP that has been submitted to the Single Nucleotide Polymorphism Database (dbSNP) is assigned a unique reference (rs) number. This number links the variant to a DNA base change at a specific genomic position. The implementation of the rs numbering system improves the consistency in reporting variants.4 In the MTHFR example above, the first SNP (rs1801133) is commonly referred to as C677T and the second SNP (rs1801131) is commonly referred to as A1298C. The majority of the genes analyzed by Genomind’s pharmacogenetic test are in fact SNPs and the rs number for each variant tested can be found in section V. Test Methodology/Literate References.

What is a haplotype?

While a SNP refers to one particular position in the genome, a haplotype refers to a combination of variants that are found on the same chromosome. PGx results are often reported as diplotypes (haplotype pairs). For many genes, such as the cytochrome P450 genes which we will discuss next, phenotypes are assigned to haplotypes rather than to specific SNPs.4

What is a star allele?

Many pharmacogenes utilize the star allele nomenclature system. This system assigns each haplotype a unique label that comprises the name of the gene followed by the major star (*) allele assignment and subvariant assignments. The Pharmacogene Consortium (PharmVar) provides a unified allele designation system to facilitate the translation of genotypes into phenotypes and the clinical implementation of PGx. These efforts are synchronized between PharmVar, the Clinical Pharmacogenetics Implementation Consortium (CPIC), and the Pharmacogenomic Knowledgebase (PharmGKB)5

CPIC is leading an effort to establish standardized terminology for allele function and phenotype assignments. CPIC has created guidelines that simplify the information a clinician would need in order to translate patient-specific diplotypes into clinical phenotypes and provides therapeutic recommendations based on these predicted phenotypes.

In most cases, the *1 allele reflects the fully functional reference allele or haplotype (wild-type) based on the subpopulation that the gene was initially studied in. It is important to recognize that this does not necessarily indicate that it is the most common allele in all populations. Other designations (*2, *3, etc.) reflect haplotypes carrying one or more variants.

As an example, consider the CYP2C19 gene. Variations in the CYP2C19 liver enzyme can result in altered drug metabolism and unexpected drug serum levels. For CYP2C19:

  • The *1/*1 genotype confers normal activity of CYP2C19
  • The *1/*3 genotype confers intermediate activity of CYP2C19
  • The *2/*2 genotype confers low activity of CYP2C19
  • The *17/*17 genotype confers high activity of of CYP2C19

Several medications are CYP2C19 substrates and can be influenced by these genetic variations. CPIC has produced dosing guidelines based on genotype for selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), clopidogrel, proton pump inhibitors (PPIs), and more.

In conclusion

Genomind’s pharmacogenetic test report simplifies and summarizes all of this information so that clinicians can easily find an individual’s predicted phenotype and make appropriate treatment decisions, including the latest guidance from CPIC, FDA or other pertinent authorities. Furthermore, Genomind provides ordering clinicians access to Precision Medicine Software, Genomind’s gene-drug-drug interaction and clinical decision support tool that allows them to navigate and apply pharmacogenetic guidelines that are applicable to each patient.

Genomind’s Precision Medicine Software serves as a comprehensive tool to help evaluate both gene-drug and drug-drug interactions, pharmacogenetic guideline recommendations, and alternative medication options, as appropriate. This robust interaction database provides guidance on a great majority of prescribed medications (not limited to psychiatry) and can help clinicians assess personalized medication options and regimens for their patients.

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  1. Sheldrick, A.J., et al., Effect of COMT val158met genotype on cognition and personality. Eur Psychiatry, 2008. 23(6): p. 385-9.
  2. Solís-Ortiz S, Pérez-Luque E, Morado-Crespo L, Gutiérrez-Muñoz M. Executive functions and selective attention are favored in middle-aged healthy women carriers of the Val/Val genotype of the catechol-o-methyltransferase gene: a behavioral genetic study. Behav Brain Funct. 2010;6:67.
  3. Van der Put, N. M. et al. A second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural‐tube defects? American journal of human genetics 62, 1044‐1051, doi:10.1086/301825 (1998).
  4. M. Whirl-Carrillo, E.M. McDonagh, J. M. Hebert, L. Gong, K. Sangkuhl, C.F. Thorn, R.B. Altman and T.E. Klein. “Pharmacogenomics Knowledge for Personalized Medicine” Clinical Pharmacology & Therapeutics (2012) 92(4): 414-417.
  5. Gaedigk A, Ingelman-Sundberg M, Miller NA, et al. The Pharmacogene Variation (PharmVar) Consortium: Incorporation of the Human Cytochrome P450 (CYP) Allele Nomenclature Database. Clin Pharmacol Ther. 2018;103(3):399-401.
  6. Caudle KE, Gammal RS, Whirl-Carrillo M, Hoffman JM, Relling MV, Klein TE. Evidence and resources to implement pharmacogenetic knowledge for precision medicine. Am J Health Syst Pharm. 2016;73(23): 1977-1985. doi:10.2146/ajhp150977
  7. Kalman LV, Agúndez J, Appell ML, et al. Pharmacogenetic allele nomenclature: International workgroup recommendations for test result reporting. Clin Pharmacol Ther. 2016;99(2):172-185. doi:10.1002/cpt.280

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