Abstract:
INTRODUCTION:Efavirenz is primarily metabolized by CYP2B6, with a minor contribution from CYP1A2, CYP2A6, CYP3A4 and CYP3A5. Genetic variability in these genes contributes towards differences in plasma efavirenz concentration, which ultimately leads to either development of adverse drug events or emergence of virus resistance. However, the clinical utility or validity of introducing genotype-assisted dosing is not known. The aim of this study was therefore to evaluate the effects of 14 single-nucleotide polymorphisms (SNPs) in five drug-metabolizing enzyme genes on steady-state plasma efavirenz levels in South African HIV/AIDS patients as well as their clinical validity. METHODS:HIV/AIDS patients were recruited from Themba Lethu Clinic, at Helen Joseph Hospital, Johannesburg. Blood samples for plasma drug levels and DNA extraction were obtained from each participant. PCR/RFLP and SNaPshot genotyping were used for SNPs in CYP1A2, CYP2A6, CYP2B6, CYP3A4 and CYP3A5 among 464 Bantu-speaking South Africans. Plasma efavirenz concentrations were measured using LC/MS/MS. Genotypes and plasma efavirenz levels were used to calculate predictive values. Multivariate analysis was used to select the minimal set of SNPs with significant clinical validity. RESULTS:Qualitative and quantitative differences in allele frequencies were observed when comparing South Africans with African, Caucasian and Asian populations. CYP2B6 516T and 785G (*6) and CYP2B6 983C (*18) alleles were significantly associated with high plasma efavirenz levels. CYP2B6 A-G-A-C-C and A-T-G-T-C haplotypes (with respect to CYP2B6 136A>G; CYP2B6 516G>T; CYP2B6 785A>G; CYP2B6 983T>C; and CYP2B6 1459C>T) were associated with higher levels of efavirenz, whereas G-G-A-T-C and A-G-A-T-C haplotypes showed significantly lower levels of efavirenz. The CYP2B6*1/*6 genotype was significantly associated with an increased risk of loss to follow-up. The sensitivity, specificity and positive predictive values for the CYP2B6*6/*6 genotype in predicting efavirenz levels above 4 µg/ml were 46, 97 and 88%, respectively. However, these values improved to 49, 100 and 100%, respectively, when either the CYP1A2 -163A (*1F) allele or the NR1I3 8784C/C genotype was present. CONCLUSION:Screening for CYP2B6 516G>T SNP has a high specificity and positive predictive value for efavirenz levels above 4 µg/ml and could be used in deciding on efavirenz dosage among individuals homozygous for this variant, which could lead to better precision medication.
journal_name
Pharmacogenet Genomicsjournal_title
Pharmacogenetics and genomicsauthors
Swart M,Skelton M,Ren Y,Smith P,Takuva S,Dandara Cdoi
10.1097/FPC.0b013e328363176fsubject
Has Abstractpub_date
2013-08-01 00:00:00pages
415-27issue
8eissn
1744-6872issn
1744-6880journal_volume
23pub_type
杂志文章abstract:OBJECTIVES:The emergency department (ED) is a challenging setting to conduct pharmacogenomic studies and integrate that data into fast-paced and potentially life-saving treatment decisions. Therefore, our objective is to present the methods and feasibility of a pilot pharmacogenomic study set in the ED that measured pe...
journal_title:Pharmacogenetics and genomics
pub_type: 杂志文章
doi:10.1097/FPC.0000000000000414
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abstract::Small heterodimer partner 1 (SHP1, NR0B2) is a member of the superfamily of nuclear receptors (NRs). Even if this orphan receptor, unlike other NRs, lacks the DNA-binding domain, it is capable of regulating transcription by repressing the activity of other NRs by direct protein-protein interaction. Accordingly, SHP1 i...
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abstract:OBJECTIVE:Studies found a strong association between allopurinol-induced Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) and the HLA-B*58:01 allele. HLA-B*58:01 screening-guided therapy may mitigate the risk of allopurinol-induced SJS/TEN. This study aimed to evaluate the cost-effectiveness of HLA-B*58:...
journal_title:Pharmacogenetics and genomics
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journal_title:Pharmacogenetics and genomics
pub_type: 杂志文章
doi:10.1097/01.fpc.0000199497.01101.93
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abstract::The aryl hydrocarbon receptor (AhR) is a key regulator of the transcriptional expression for the cytochrome P450 1 (CYP1) genes. CYP1A2 is one of the major CYP1 enzymes that catalyse 2-hydroxylation of estrogen, a hormone that plays a critical role in the etiology of breast cancer. In this study, we investigated wheth...
journal_title:Pharmacogenetics and genomics
pub_type: 杂志文章
doi:10.1097/01.fpc.0000189803.34339.ed
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abstract::Two recent screens for copy-number variations in the entire human genome found 12.4 gene copy number variations per person, including 2.5% of individuals with gains between 7q21.1 and 7q22.1, the chromosomal location of CYP3A4. CYP3A4 is involved in the metabolism of approximately 50% of all drugs, including many canc...
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doi:10.1097/FPC.0000000000000153
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pub_type: 杂志文章,meta分析
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doi:10.1097/01213011-200503000-00004
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pub_type: 临床试验,杂志文章,多中心研究
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pub_type: 杂志文章,多中心研究,随机对照试验
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更新日期:2012-06-01 00:00:00
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更新日期:2010-06-01 00:00:00
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pub_type: 杂志文章,随机对照试验
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更新日期:2017-08-01 00:00:00