Discovery of a novel nonfunctional cytochrome P450 2D6 allele, CYP2D6*42, in African American subjects

Gaedigk, Andrea; Ndjountché, Liliane; Gaedigk, Roger; Leeder, J. Steven; Bradford, L. DiAnne

doi:10.1016/s0009-9236(03)00067-5

Cited by 25 publications

(17 citation statements)

References 2 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The African American population utilized in this study included a total of 252 individuals (n ¼ 191 with parents and grandparents identified as African American and n ¼ 61 subjects who reported admixture in their parents or grandparents or descent was unknown). Genotyping data were presented previously 7,24,27,29,32 and have been updated to include results for new allelic variants described herein.…”

Section: Study Subjectsmentioning

confidence: 99%

“…Allele designation and nucleotide numbering is assigned according to http://www.imm.ki.se/CYPalleles/. 4 CYP2D6 genotyping was performed as described previously 7,24,27,32 and comprised the following alleles: CYP2D6*2, *3, *4, *5, *6, *7, *8, *9, *10, *11, *12, *14, *15, *17, *18, *29, *35, *40, *41 and *42, as well as *1 Â 2, *2 Â 2 and *4 Â 2 gene duplications. For regenotyping purposes, a 6.6 kb fragment that encompasses the entire CYP2D6 gene and upstream sequence was amplified by long-range PCR using JumpStart AccuTaq DNA polymerase (Sigma, St Louis, MO, USA) and primers 5 0 -ATG GCA GCT GCC ATA CAA TCC ACC TG (forward, AY545216: 2367-2392) and 5 0 -ACT GAG CCC TGG GAG GTA GGT AG (reverse, AY545216: 8931-8953).…”

Section: Cyp2d6 Genotypingmentioning

confidence: 99%

See 1 more Smart Citation

Identification and characterization of novel sequence variations in the cytochrome P4502D6 (CYP2D6) gene in African Americans

et al. 2005

Self Cite

View full text Add to dashboard Cite

Cytochrome P4502D6 (CYP2D6) genotyping reliably predicts poor metabolizer phenotype in Caucasians, but is less accurate in African Americans. To evaluate discordance we have observed in phenotype to genotype correlation studies, select African American subjects were chosen for complete resequencing of the CYP2D6 gene including 4.2 kb of the CYP2D7-2D6 intergenic region. Comparisons were made to a CYP2D6*1 reference sequence revealing novel SNPs in the upstream, coding and intervening sequences. These sequence variations, defining four functional alleles (CYP2D6*41B, *45A and B and *46), were characterized for their ability to influence splice site strength, transcription level or catalytic protein activity. Furthermore, their frequency was determined in a population of 251 African Americans. A À692 TGTG deletion (CYP2D6*45B) did not significantly decrease gene expression, nor could any other upstream SNP explain a genotype-discordant case. CYP2D6*45 and *46 have a combined frequency of 4% and can be identified by a common SNP. Carriers are predicted to exhibit an extensive or intermediate CYP2D6 phenotype.

show abstract

Section: Study Subjectsmentioning

confidence: 99%

Section: Cyp2d6 Genotypingmentioning

confidence: 99%

Identification and characterization of novel sequence variations in the cytochrome P4502D6 (CYP2D6) gene in African Americans

et al. 2005

Self Cite

View full text Add to dashboard Cite

show abstract

“…and account for the over-estimation of the true *2 allele frequency (see Table 2). [10][11][12][13][14][15][16]22 Frequency of deficient and intermediate metabolism Comparing observed and predicted frequencies for CYP2D6 allele combinations according to Hardy-Weinberg equilibrium suggests that healthy controls, psychiatric patients and the combined groups conform to the expected ratios (Table 3). An estimated 2.2% of African-Americans are expected to express the 'null' CYP2D6 phenotype based on currently tested/evaluated null CYP2D6 alleles.…”

Section: Resultsmentioning

confidence: 99%

“…8,9 Unfortunately, there remains a limited body of information on the frequency of the growing numbers of alleles associated with the CYP2D6 gene in the black population. One issue is whether or not CYP2D6 alleles reported in Caucasians are appropriate alleles to assess in African-Americans for drug disposition [10][11][12][13][14][15][16] and if not, what specific CYP2D6 alleles should be evaluated clinically among African-Americans. Racial divergence between black subjects and Caucasians is estimated to have occurred over 50 000 years ago, and it now appears that these different races may express a somewhat different constellation of CYP2D6 alleles.…”

Section: Introductionmentioning

confidence: 99%

CYP2D6 genetic variation in healthy adults and psychiatric African-American subjects: implications for clinical practice and genetic testing

et al. 2006

View full text Add to dashboard Cite

AmpliChip CYP450 prototype microarray assay, along with allele-specific-PCR and PCR restriction fragment length polymorphism methods. No significant difference was noted between controls and psychiatric patients in any CYP2D6 allele frequencies. Three subjects were genotyped as poor metabolizers (1.4%; 0.0-2.9%, 95% confidence intervals (CI)), and 10 were classified as ultrarapid metabolizers (4.5%; 1.8-7.2%, 95% CI). A new CYP2D6 allele (*58) and two new duplicated CYP2D6 alleles (*17xn and *2Lxn) not previously reported were also identified. The frequency of the CYP2D6 overexpression in African-Americans may represent a greater therapeutic challenge than its deficiency based on these results. The most common alleles found in African-Americans including CYP2D6*1, *17 and *41 need to be investigated more closely for race-specific allelic variations and the mechanism responsible for differences in allele function more closely examined. The diversity of CYP2D6 alleles suggests that nucleotide arrays or similar methods are needed to efficiently test for the most prominent/ relevant CYP2D6 alleles in humans.

show abstract

“…Genomic DNA was isolated using the QIAamp DNA Blood Mini Kit (Qiagen, Valencia, CA), and CYP2D6 genotyping was conducted for CYP2D6*2, *3, *4, *5, *6, *7, *8, *9, *10, *11, *12, *15, *17, *29, *35, *36, *40, *41[2988G], *41[2988A], *42, and *45/46 alleles and the presence of *1 Â 2, *2 Â 2, and *10 Â 2 gene duplications, as originally described (Gaedigk et al, 1999) and subsequently modified (Gaedigk et al, 2002(Gaedigk et al, , 2003a(Gaedigk et al, , b, 2005a. Of note, personnel involved in the collection and evaluation of safety data were blinded to the results of CYP2D6 genotyping until all safety data were collected and all safety data queries were resolved.…”

Section: Cyp2d6 Genotypingmentioning

confidence: 99%

Multiple Dose Pharmacokinetics of Paroxetine in Children and Adolescents with Major Depressive Disorder or Obsessive–Compulsive Disorder

Findling

Nucci

Piergies³

et al. 2005

Neuropsychopharmacol

View full text Add to dashboard Cite

The current study examined the pharmacokinetics (PK), safety, and tolerability of paroxetine after repeated multiple oral dosing in children and adolescents with major depressive or obsessive-compulsive disorder. In this 6-week, open-label, repeat dose, dose-rising study, 62 patients (27 children and 35 adolescents) were treated with paroxetine 10 mg/day for the first 2 weeks of the study, 20 mg/day for the next 2 weeks, and 30 mg/day for the final 2 weeks. Pharmacokinetic sampling and safety assessments occurred at baseline and subsequently on the final treatment day of each dosing level. Between-patient variability in PK was pronounced at the 10 mg dose level, but markedly reduced at higher doses. A supra-proportional increase in plasma concentrations with increasing dose was evident in both age groups. Data for C max and AUC (0À24) indicated that, at each dose level, paroxetine steady-state systemic exposure was higher in children than in adolescents. The differences between age groups, however, diminished with each increasing dose, and were virtually abolished when differences in weight among different age groups were considered. Stepwise regression analysis indicated that both oral clearance and volume of distribution were highly dependent on paroxetine dose, cytochrome P4502D6 genotype, and weight (po0.0001), but not age or sex. Paroxetine was generally safe and well tolerated in both age groups, with the most frequently observed adverse events being largely consistent with those observed in prior paroxetine studies of adult psychiatric patients. Certain gastrointestinal and behavioral activation events (aggressive reaction and nervousness) were reported more frequently in the youngest age group.

show abstract

Discovery of a novel nonfunctional cytochrome P450 2D6 allele, CYP2D6*42, in African American subjects

Cited by 25 publications

References 2 publications

Identification and characterization of novel sequence variations in the cytochrome P4502D6 (CYP2D6) gene in African Americans

Identification and characterization of novel sequence variations in the cytochrome P4502D6 (CYP2D6) gene in African Americans

CYP2D6 genetic variation in healthy adults and psychiatric African-American subjects: implications for clinical practice and genetic testing

Multiple Dose Pharmacokinetics of Paroxetine in Children and Adolescents with Major Depressive Disorder or Obsessive–Compulsive Disorder

Contact Info

Product

Resources

About