Tuesday, September 26, 2023

Frequencies of Pharmacogenomic Alleles across UK Biobank Biogeographic Groups Published

We are happy to announce the publication of our latest research article in the American Journal of Human Genetics (AJHG), titled “Frequencies of Pharmacogenomic Alleles across Biogeographic Groups in a Large-Scale Biobank.” The paper is now available online on the AJHG website.

Genetic biobanks provide rich data sets to investigate population-specific pharmacogenomic (PGx) allele frequencies and the implications of equitable and inclusive implementation. Using an integrated UK Biobank 200K genetic dataset (N = 200,044), we estimated the pharmacogenomic (PGx) allele frequencies for seventeen (17) pharmacogenes in five (5) biogeographic groups. 
  • Pharmacogenes included ABCG2, CACNA1S, CYP2B6, CYP2C19, CYP2C9, CYP3A5, CYP4F2, DPYD, G6PD, IFNL3, NUDT15, RYR1, SLCO1B1, TPMT, UGT1A1, and VKORC1. CFTR and the CYP2C cluster variant (rs12777823) were also investigated. CYP2D6 alleles that could be determined from VCF, and therefore not including structural variants, were also predicted.
  • The five (5) biogeographic groups are Europeans (n = 187,660), Central/South Asians (n = 3,460), East Asians (n = 637), African Americans/Afro-Caribbeans (n = 1,926), and Sub-Saharan Africans (n = 1,235)
  • Frequencies of PGx alleles, diplotypes, phenotypes, and/or activity scores, if applicable, were reported for each gene in each biogeographic group.

We found that 100% of the UK Biobank participants harbored at least one genetic variant found in known PGx haplotypes. 

The main takeaways messages are:

1. UK Biobank PGx frequencies complemented the CPIC frequency tables.

2. This study reported frequencies for a nontrivial number of PGx alleles that are rare or seldom tested, especially in the non-European group.

3. There are uncataloged PGx alleles.

PGx frequencies estimated from this study will be disseminated via PharmGKB. Biobank-derived allele frequencies can provide guidance for future PGx studies and clinical genetic test panel design, and better serve individuals from wider biogeographic backgrounds.

Monday, September 25, 2023

Disulfiram Pathway published in Pharmacogenetics and Genomics

Substance abuse disorders are a significant public health cost [PMID: 34453125]. Prescribers have limited choices for pharmaceutical therapies with only three FDA-approved choices for alcohol use disorder and zero for cocaine use disorder. Disulfiram is an FDA-approved treatment for alcohol use disorder which is also used for cocaine use disorder. There are some preliminary studies on the PGx of disulfiram but little replication.

PharmGKB together with Dr Aneysis De Las Mercedes Gonzalez (Stanford University School of Medicine), have published PharmGKB summary: disulfiram pathway in Pharmacogenetics and Genomics, 2023 Sep 21. doi: 10.1097/FPC.0000000000000509. Online ahead of print. PMID: 37728645. It summarizes the candidate genes involved in disulfiram PGx in pharmacokinetics and action in dopaminergic, seratonergic and noradrenergic neurons and highlights the knowledge gaps.

As always interactive versions of the diagrams with underlying linked evidence, are available on PharmGKB:

Disulfiram Pathway, Pharmacokinetics,

Disulfiram Pathway, Pharmacodynamics (Cocaine and Ethanol PK)

Disulfiram Pathway, Pharmacodynamics (Dopaminergic neuron)

Disulfiram Pathway, Pharmacodynamics (Serotonergic neuron)

Sympathetic Nerve Pathway (Neuroeffector Junction)