CPIC Guideline for CYP2D6, CYP2C19, CYP2B6, SLC6A4 and HTR2A Genotypes and Serotonin Reuptake Inhibitor Antidepressants

The CPIC guideline for CYP2D6, CYP2C19, CYP2B6, SLC6A4 and HTR2A genotypes and Serotonin Reuptake Inhibitor Antidepressants has been published in the journal Clinical Pharmacology and Therapeutics. This new guideline updates the CPIC guideline for Selective Serotonin Reuptake Inhibitors and CYP2D6 and CYP2C19, and includes additional Serotonin Reuptake Inhibitor Antidepressants and three additional genes, CYP2B6, HTR2A, and SLC6A4.  

The guideline gives specific prescribing recommendations for:

• paroxetine, fluvoxamine, venlafaxine, and vortioxetine based on CYP2D6 phenotypes
• escitalopram and citalopram based on CYP2C19 phenotypes
• sertraline based on CYP2C19 and CYP2B6 phenotypes

Clinical recommendations are not provided for serotonin reuptake inhibitor antidepressants based on HTR2A and SLC6A4 genotypes because the current evidence is mixed and/or insufficient to support clinical validity and utility.
 
For specific recommendations and further details, please refer to the guideline and supplemental materials on the CPIC website. Annotations of the guideline, including an interactive genotype picker tool for the drugs mentioned above, are available on the PharmGKB website.

It’s national poetry month again!

I am not a mouse.
It’s the reference allele
(hg38).

I am not a mouse.
It's the common variant
In these folks tested.


Saw on minus strand
G is the major allele
In this group tested.


C is the minor
It’s the reference allele
(hg38).


Last year I wrote a haiku to highlight my gripe about authors declaring a patient a *1 but not stating which alleles were tested so not conclusively ruling out the presence of variants. This year I have a series of haiku on another gripe of mine - authors using the term “wild-type” when talking about humans. I’ve been guilty of it in the past but when we know better we do better. The one upside of it is it's a way one can avoid using terms major/minor allele when those might be different in different populations and thus ambiguous, but I think most study participants would not want to be categorized as wild-type, certainly most would not want to be called mutant (unless it comes with some X-men type powers). The terms I would recommend are “reference allele/genotype” (on genome build …) and “comparison allele/genotype”. If using major/minor allele then state explicitly what base that was in the given population, and describe the population, and which strand the allele was measured on (especially for C/G and A/T variants and genes on minus chromosomal strand). We have been seeing problems lately when authors assume the reference allele on the genome build hg38 is the major allele in most populations and that is not always the case. If in doubt give as much information as possible.

CYP2D6 allele function update

The CYP2D6 allele functionality file has been re-evaluated and updated by experts involved in CYP2D6-related CPIC guidelines. CYP2D6 functions are now assigned up to star allele 163. 

Part of the re-evaluation focused on alleles that include 100C>T (P34S) (*10 key SNP). Furthermore, the activity value of several decreased function alleles, e.g. *9 and *41, was downgraded to 0.25. 

The updated file can be accessed through CYP2D6-related guidelines on the CPIC website and through the CYP2D6 resource page on PharmGKB. The updated functions are also displayed on the PharmVar CYP2D6 page .

ClinGen Pharmacogenomics Working Group (PGxWG) Follow-Up Survey

The ClinGen Pharmacogenomics Working Group (PGxWG) has just launched a second survey to solicit feedback about the criteria and terminology that should be used to define clinical validity and actionability for pharmacogenes and variants from both the PGx community and the wider genetics and medical communities. Please note that this second survey is not independent of the first, and if you’ve taken the previous survey and have significant PGx familiarity or expertise, there is no need to take this iteration, as it would be redundant due to the overlap in questions.

The ClinGen PGxWG is a multi-disciplinary team of researchers and professionals with expertise in pharmacogenomics (PGx), clinical pharmacology, medical genetics, regulatory affairs, and molecular diagnostics. It was launched in February 2022 with the goal of developing a framework of tiered standard terminology and definitions that reflect clinical significance for genes and genomic variants implicated in drug response, in order to facilitate the incorporation of PGx knowledge into ClinGen and more consistent interpretation of PGx variants identified by panel testing and/or sequencing.

The survey is open now and can be accessed at: https://stanforduniversity.qualtrics.com/jfe/form/SV_1IdrrPWBXsV2Xt4. All responses are greatly appreciated, no matter who you are or where you are in the world. Unlike the previous survey, this survey does not assume PGx familiarity, though if you have not taken the previous survey and have PGx familiarity, your feedback is still greatly appreciated. The survey takes approximately 15 minutes to complete. We sincerely appreciate your time and attention, and your willingness to help.

ClinGen Pharmacogenomics Working Group (PGxWG) Survey

The ClinGen Pharmacogenomics Working Group (PGxWG) has launched a survey to solicit feedback about the criteria and terminology that should be used to define clinical validity and actionability for pharmacogenes and variants. 

The ClinGen PGxWG is a multi-disciplinary team of researchers and professionals with expertise in pharmacogenomics (PGx), clinical pharmacology, medical genetics, regulatory affairs, and molecular diagnostics. It was launched in February 2022 with the goal of developing a framework of tiered standard terminology and definitions that reflect clinical significance for genes and genomic variants implicated in drug response, in order to facilitate the incorporation of PGx knowledge into ClinGen and more consistent interpretation of PGx variants identified by panel testing and/or sequencing.

The survey is open now and can be accessed at: https://stanforduniversity.qualtrics.com/jfe/form/SV_bKqeKf2YmCVS1LM.  All responses are greatly appreciated, no matter who you are or where you are in the world. This survey does assume some PGx familiarity, though we plan to launch another survey targeting those with less PGx experience in the near future. The survey takes approximately 10 minutes to complete. We sincerely appreciate your time and attention, and your willingness to help.

PharmVar updates for CYP3A4 star allele definitions

 PharmVar announces several updates for CYP3A4 star allele definitions.

Retirement of the CYP3A4*1G allele: this allele was defined by a common variant in intron 10 (c.1026+12G>A) which was also found on many other haplotypes (or star alleles). PharmVar transiently designated the CYP3A4*1G allele as *36 due to a possible role of c.1025+12G>A being involved in the regulation of CYP3A4 expression. However, owing to the growing body of inconsistent findings regarding associations of c.1026+12G>A and higher or lower expression levels and/or CYP3A4 activity, PharmVar withdrew this redesignation in January 2023 (v5.2.17) which led to the retirement of the CYP3A4*36 (former *1G) allele. Per PharmVar rules, intronic variants are only utilized for star allele definitions if there is convincing evidence that the variant impacts protein function. Therefore, c.1026+12G>A was also removed from all other star allele definitions.

CYP3A4 gene regulation is complex and appears to be governed by a layer of processes, among them long noncoding RNAs, microRNAs and transcription factors which may also influence CYP3A5 activity. Furthermore, there is substrate overlap between CYP3A4 and CYP3A5 and thus, variation in the CYP3A5 gene, further complicates the characterization of CYP3A4 allele function. Investigators are encouraged to include c.1026+12G>A in their carefully designed investigations to produce conclusive evidence regarding the functional impact of c.1026+12G>A.      

We would also like to highlight the addition of a novel star allele, CYP3A4*38 which is characterized by two variants which on their own define CYP3A4*3 and *11. Noteworthy, the CYP3A4*3-defining variant c.1334T>C (p.M445T) has also been found together with the intronic SNP defining CYP3A4*22; this allele was designated CYP3A4*37. Consequently, samples heterozygous for these SNPs could have CYP3A4*1/*37 or *3/*22 or *1/*38 or *3/*11 genotypes, respectively. Since the functional impact of c.1334T>C (p.M445T) remains elusive it is unknown whether alternate genotypes differ in function.

Lastly, the evidence level of several alleles has been updated from ‘Limited’ or ‘Moderate’ to ‘Definitive’ indicating that these alleles are now fully characterized. 

These efforts were only possible by the dedicated work of the PharmVar Team and the CYP3A4 gene experts for volunteering their time and expertise.

CYP4F2 is now fully curated by PharmVar

CYP4F2 contributes to the synthesis of cholesterol, steroids and other lipids. It has been shown to regulate the bioavailability of vitamin E and vitamin K, a co-factor that is critical to blood clotting. Variations in this important pharmacogene can affect vitamin K levels and thus, the dosing of vitamin K antagonists such as the widely used anticoagulant drug warfarin (CPIC level A and PharmGKB 1A evidence level) among others.

We are excited to announce that CYP4F2 is now fully curated by PharmVar and its gene page content reviewed by an international expert panel. Furthermore, the PharmVar Team has generated new data to provide a more comprehensive catalog of genetic variation of this gene. Not only have the two previously defined CYP4F2*2 and *3 now been fully characterized, several other novel haplotypes (or star alleles) have been identified and designated by PharmVar. Notably, the new and relatively commonly observed CYP4F2*4 allele has both sequence variants that otherwise define *2 (c.34T>G, W12G) and *3(c.1297G>A, V433M), respectively while the other three novel star alleles (CYP4F2*5, *6 and *7) are each characterized by a single amino acid change. Interestingly, CYP4F2*5 and *6 appear to be absent or rare in Asian populations; in contrast, *7 seems to be mostly present in African populations and their descendants. These new star alleles may contribute to unexplained variability in daily warfarin dosage requirements in non-White populations. We encourage the research and clinical communities to include this new knowledge in their investigations.