PharmGKB summary

Barbarino, Julia M.; Kroetz, Deanna L.; Altman, Russ B.; Klein, Teri E.

doi:10.1097/fpc.0000000000000040

Cited by 9 publications

(9 citation statements)

References 44 publications

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“…ADH1A and UGT1A1 are the only genes known to be involved in the metabolism of NRTIs and the burden test p-values for these genes with triple NRTI regimens were 0.017 and 0.029, respectively. ADH1A and UGT1A1 are both involved in the metabolism of the NRTI abacavir [ 37 ]. SNPs in these regions could slow drug metabolism, possibly resulting in higher serum concentrations and more effective responses.…”

Section: Discussionmentioning

confidence: 99%

Pharmacogenetic Associations with ADME Variants and Virologic Response to an Initial HAART Regimen in HIV-Infected Women

Pearce

Stram

Wiensch

et al. 2017

IJHR

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Background Clinical response to highly active antiretroviral therapy (HAART) varies among different populations. A portion of this variability may be due to variation in genes involved in the absorption, distribution, metabolism, and excretion (ADME) of HAART. Design To identify genetic factors involved in virologic responses to HAART, 13 genes in ADME pathways were analyzed in a cohort of HIV-infected women on HAART. A total of 569 HIV-positive participants from the Women’s Interagency HIV Study who initiated HAART from 1994–2012 and had genotype data were included in these analyses. Methods Admixture maximum likelihood burden testing was used to evaluate gene-level associations between common genetic variation and virologic response (achieving <80 viral copies/mL) to HAART overall and with specific drug classes. Results: Six statistically significant (P<0.05) gene-level burden tests were observed with response to specific regimen types. CYP2B6, CYP2C19 and CYP2C9 were significantly associated with response to protease inhibitor (PI)-based regimens. CYP2C9, ADH1A and UGT1A1 were significantly associated with response to triple nucleoside reverse transcriptase inhibitor (NRTI) treatment. Conclusions Although no genome-wide associations with virologic response to HAART overall were detected in this cohort of HIV-infected women, more statistically significant gene-level burden tests were observed than would be expected by chance (two and a half expected, six observed). It is likely that variation in one of the significant genes is associated with virologic response to certain HAART regimens. Further characterization of the genes associated with response to PI-based treatment is warranted.

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Section: Discussionmentioning

confidence: 99%

Pharmacogenetic Associations with ADME Variants and Virologic Response to an Initial HAART Regimen in HIV-Infected Women

Pearce

Stram

Wiensch

et al. 2017

IJHR

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“…Abacavir is used for treatment of HIV, and is metabolized into an active form, carbovir 5′-triphosphate (CBV-TP), by various enzymes. CBV-TP blocks the action of HIV reverse transcriptase, which plays a vital role in the replication cycle of the HIV virus 20 . Abacavir is generally well-tolerated, however approximately 5–8% of patents experience a hypersensitivity reaction within the first 6 weeks of treatment, with symptoms such as fever, rash, and gastrointestinal symptoms.…”

Section: Pharmacodynamicsmentioning

confidence: 99%

“…These symptoms typically improve within 24 hours of discontinuation, but drug re-challenge after discontinuation can lead to a potentially life-threatening allergic reaction. This hypersensitivity reaction is strongly linked with the presence of the HLA-B*57:01 variant 20 . The HLA-B protein is responsible for presenting peptides to immune system cells, triggering an immune reaction if the peptide is recognized as coming from a pathogen.…”

Section: Pharmacodynamicsmentioning

confidence: 99%

PharmGKB: A worldwide resource for pharmacogenomic information

Barbarino

Whirl‐Carrillo

Altman

et al. 2018

WIREs Mechanisms of Disease

Self Cite

259

196

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As precision medicine becomes increasingly relevant in healthcare, the field of pharmacogenomics (PGx) also continues to gain prominence in the clinical setting. Leading institutions have begun to implement PGx testing, and the amount of published PGx literature increases yearly. The Pharmacogenomics Knowledgebase (PharmGKB; www.pharmgkb.org) is one of the foremost worldwide resources for PGx knowledge, and the organization has been adapting and refocusing its mission along with the current revolution in genomic medicine. The PharmGKB website provides a diverse array of PGx information, from annotations of the primary literature to guidelines for adjusting drug treatment based on genetic information. It is freely available, and accessible to everyone from researchers to clinicians to everyday citizens. PharmGKB was founded over 17 years ago, but continues to be a vital resource for the entire PGx community and the general public.

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“…This indicates that other genes and environmental factors are likely involved in the development of an abacavir-induced HSR. Research in this area has been scarce, but several studies have suggested a member of the 70 kilodalton heat shock protein (HSP70) family as a potential factor [60-62]. …”

Section: Important Variantsmentioning

confidence: 99%