Recommendations for Clinical CYP2D6 Genotyping Allele Selection

Pratt, Victoria M.; Cavallari, Larisa H.; Tredici, Andria L. Del; Gaedigk, Andrea; Hachad, Houda; Ji, Yuan; Kalman, Lisa V.; Ly, Reynold C.; Moyer, Ann M.; Scott, Stuart A.; Schaik, Ron H.N. van; Whirl‐Carrillo, Michelle; Weck, Karen E.

doi:10.1016/j.jmoldx.2021.05.013

Cited by 93 publications

(9 citation statements)

References 81 publications

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“…Haplotype blocks based on sample-specific linkage disequilibrium (LD) pattern from Haploview v4.1 28 29 were defined for all analysed SNPs according to gene-specific haplotype tables from the PharmVar homepage (https://www.pharmvar.org/gene; supplement 2). Haplotype coverage for CYP2D6 and CYP2C19 aligns with the recommended tier 1 alleles for CYP2D6 and CYP2C19 for 5 of 10 and 2 of 3, respectively 30 31 . From a total of 101 genotyped single markers located within 26 genes, we restricted our analyses to genes affecting pk (n=14), thus including 86 variants.…”

Section: Methodsmentioning

confidence: 59%

Effects of Pharmacokinetic Gene Variation on Therapeutic Drug Levels and Antidepressant Treatment Response

et al. 2022

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Introduction Pharmacogenetic testing is proposed to minimize adverse effects when considered in combination with pharmacological knowledge of the drug. As yet, limited studies in clinical settings have investigated the predictive value of pharmacokinetic (pk) gene variation on therapeutic drug levels as a probable mechanism of adverse effects, nor considered the combined effect of pk gene variation and drug level on antidepressant treatment response. Methods Two depression cohorts were investigated for the relationship between pk gene variation and antidepressant serum concentrations of amitriptyline, venlafaxine, mirtazapine and quetiapine, as well as treatment response. For the analysis, 519 patients (49% females; 46.6±14.1 years) were included. Results Serum concentration of amitriptyline was associated with CYP2D6 (higher concentrations in poor metabolizers compared to normal metabolizers), of venlafaxine with CYP2C19 (higher concentrations in intermediate metabolizers compared to rapid/ultrarapid metabolizers) and CYP2D6 (lower metabolite-to-parent ratio in poor compared to intermediate and normal metabolizers, and intermediate compared to normal and ultrarapid metabolizers). Pk gene variation did not affect treatment response. Discussion The present data support previous recommendations to reduce starting doses of amitriptyline and to guide dose-adjustments via therapeutic drug monitoring in CYP2D6 poor metabolizers. In addition, we propose including CYP2C19 in routine testing in venlafaxine-treated patients to improve therapy by raising awareness of the risk of low serum concentrations in CYP2C19 rapid/ultrarapid metabolizers. In summary, pk gene variation can predict serum concentrations, and thus the combination of pharmacogenetic testing and therapeutic drug monitoring is a useful tool in a personalized therapy approach for depression.

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Section: Methodsmentioning

confidence: 59%

Effects of Pharmacokinetic Gene Variation on Therapeutic Drug Levels and Antidepressant Treatment Response

et al. 2022

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“…This is not surprising since Naveen (2006) showed that the distribution of CYP2D6*2 is similar between the European and South Asian populations [ 63 ]. The prevalence of CYP2D6*2 is about 28% among Europeans, 12–29% in the Asian populations, and 16–20% in people of African ancestry [ 33 ]. Sistonen (2007) proposed that long-term selective pressure maintains a high frequency of haplotypes encoding a fully functional enzyme, causing a homogeneous geographic distribution of *1 and *2 alleles [ 62 ].…”

Section: Discussionmentioning

confidence: 99%

“…CYP2D6*10 is a decreased-function allele predominantly found in East and South Asian populations, where its prevalence ranges from 9% to 44%. Its frequency in African populations is between 4–6%, among Europeans < 2% [ 4 , 33 ], and it is also present in the Croatian Roma (6%). According to its prevalence, the Roma from Medjimurje (10%) are closest to the South Asians, especially South Indians [ 63 ], while the Balkan Roma (3%) are closer to European populations.…”

Section: Discussionmentioning

confidence: 99%

“…Finally, a decreased-function allele CYP2D6*41 is found in Croatian Roma at 14% frequency. Its prevalence among African populations is 4–11.5%, in Asian populations 2–12%, and about 9% in European populations [ 33 ]. Roma from Medjimurje (6%) are closer to European and South Asian populations, while the Balkan (17%) and Baranja Roma (18%) are closer to Middle East populations, which show the highest frequencies of *41 allele in the world ( Figure 4 ).…”

Section: Discussionmentioning

confidence: 99%

“…Some alleles are present at similar frequencies across the world, while others are ethnically or geographically specific. The nonfunctional allele CYP2D6*4 is the most frequently found in Europe, the decreased-function CYP2D6*10 allele is mostly present in Asia and East Asia, alleles CYP2D6*17 and *29 are characteristic for Africa and Afro-descendant populations, while CYP2D6*41 allele and gene amplifications are the most common in Middle Eastern populations [ 4 , 32 , 33 ]. Despite the proven functional role of CYP2D6 enzyme and its extensive research worldwide, knowledge of CYP2D6 allele frequencies within isolated populations like the Roma population, Basques, Ashkenazi Jews, and Saami is very limited [ 34 ].…”

Section: Introductionmentioning

confidence: 99%

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Untangling SNP Variations within CYP2D6 Gene in Croatian Roma

Marković

Petranović

Tomas

et al. 2022

JPM

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CYP2D6 is a highly polymorphic gene whose variations affect its enzyme activity. To assess whether the specific population history of Roma, characterized by constant migrations and endogamy, influenced the distribution of alleles and thus phenotypes, the CYP2D6 gene was sequenced using NGS (Next Generation Sequencing) method - targeted sequencing in three groups of Croatian Roma (N = 323) and results were compared to European and Asian populations. Identified single nucleotide polymorphisms (SNPs) were used to reconstruct haplotypes, which were translated into the star-allele nomenclature and later into phenotypes. A total of 43 polymorphic SNPs were identified. The three Roma groups differed significantly in the frequency of alleles of polymorphisms 6769 A > G, 6089 G > A, and 5264 A > G (p < 0.01), as well as in the prevalence of the five most represented star alleles: *1, *2, *4, *10, and *41 (p < 0.0001). Croatian Roma differ from the European and Asian populations in the accumulation of globally rare SNPs (6089 G > A, 4589 C > T, 4622 G > C, 7490 T > C). Our results also show that demographic history influences SNP variations in the Roma population. The three socio-culturally different Roma groups studied differ significantly in the distribution of star alleles, which confirms the importance of a separate study of different Roma groups.

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Multigenetic Pharmacogenomics–Guided Treatment vs Treatment As Usual Among Hospitalized Men With Schizophrenia

Kang,

Qin,

Sun

et al. 2023

JAMA Netw Open

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ImportanceLimited evidence supports multigenetic pharmacogenomics–guided treatment (MPGT) in schizophrenia.ObjectiveTo evaluate the clinical effectiveness of MPGT in schizophrenia in a randomized clinical trial (RCT).Design, Setting, and ParticipantsThis RCT was conducted from March 2020 to March 2022. Male Chinese Han inpatients aged 18 to 60 years diagnosed with schizophrenia with a Positive and Negative Symptom Scale (PANSS) score of 60 or more from 2 selected study hospitals were included. Patients and raters were masked to MPGT or treatment as usual (TAU) randomization.InterventionsParticipants were randomly assigned in a 1:1 ratio to receive either MPGT or TAU for 12 weeks.Main Outcomes and MeasuresThe primary efficacy outcome was the percentage change in PANSS total scores (range, 30 to 210) from baseline to week 6 analyzed by a modified intention-to-treat mixed model for repeated measures. The secondary outcome included response and symptomatic remission rates.ResultsA total of 210 participants (mean [SD] age, 29.2 [8.8] years) were enrolled and analyzed, with 113 assigned to MPGT and 97 to TAU. Compared with those randomized to TAU, participants randomized to MPGT demonstrated a significantly higher percentage change in PANSS score (74.2% vs 64.9%; adjusted mean difference, 9.2 percentage points; 95% CI, 4.4-14.1 percentage points; P &lt; .001) and a higher response rate (93 of 113 [82.3%] vs 63 of 97 [64.9%]; adjusted odds ratio, 2.48; 95% CI, 1.28-4.80; P = .01) at the end of week 6.Conclusions and RelevanceIn this RCT of MPGT, MPGT was more effective than TAU in treating patients with schizophrenia. These findings suggest that multigenetic pharmacogenomic testing could serve as an effective tool to guide the treatment of schizophrenia.Trial RegistrationChinese Clinical Trial Registry Identifier: ChiCTR2000029671

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Recommendations for Clinical CYP2D6 Genotyping Allele Selection

Cited by 93 publications

References 81 publications

Effects of Pharmacokinetic Gene Variation on Therapeutic Drug Levels and Antidepressant Treatment Response

Effects of Pharmacokinetic Gene Variation on Therapeutic Drug Levels and Antidepressant Treatment Response

Untangling SNP Variations within CYP2D6 Gene in Croatian Roma

Multigenetic Pharmacogenomics–Guided Treatment vs Treatment As Usual Among Hospitalized Men With Schizophrenia

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