Pharmacogenetic comparison of CYP2D6 predictive and measured phenotypes in a South African cohort.

This corrects the article DOI: 10.1038/tpj.2015.76.

Pharmacogenetic comparison of CYP2D6 predictive and measured phenotypes in a South African cohort.

The relationship between genetic variation in CYP2D6 and variable drug response represents a potentially powerful pharmacogenetic tool. However, little is known regarding this relationship in the genetically diverse South African population. The aim was therefore to evaluate the relationship between predicted and measured CYP2D6 phenotype. An XL-PCR+Sequencing approach was used to determine CYP2D6 genotype in 100 healthy volunteers and phenotype was predicted using activity scores. With dextromethorphan as the probe drug, metabolic ratios served as a surrogate measure of in vivo CYP2D6 activity. Three-hour plasma metabolic ratios of dextrorphan/dextromethorphan were measured simultaneously using semi-automated online solid phase extraction coupled with tandem mass spectrometry. Partial adaptation of the activity score system demonstrated a strong association between genotype and phenotype, as illustrated by a kappa value of 0.792, inter-rater discrepancy of 0.051 and sensitivity of 72.7%. Predicted phenotype frequencies using the modified activity score were 1.3% for poor metabolisers (PM), 7.6% for intermediate metabolisers (IM) and 87.3% for extensive metabolisers (EM). Measured phenotype frequencies were 1.3% for PM, 13.9% for IM and 84.8% for EM. Comprehensive CYP2D6 genotyping reliably predicts CYP2D6 activity in this South African cohort and can be utilised as a valuable pharmacogenetic tool.

Comparative 1H NMR-based metabonomic analysis of HIV-1 sera.

(1)H NMR spectroscopy of sera from HIV-1 infected and uninfected individuals was performed on 300 and 600 MHz instruments. The resultant spectra were automatically data reduced to 90 and 180 integral segments of equal length. Analysis of variance identified significant differences between the sample groups, especially for the samples analyzed on 600 MHz and reduced to fewer segments. Linear discriminant analysis correctly classified 100% of the samples analyzed on the 300 MHz NMR (reduced to 180 segments); an increase in instrument sensitivity resulted in lower percentages of correctly classified samples. Multinomial logistic regression (MLR) resulted in 100% correct classification of all samples from both instruments. Thus (1)H-NMR metabonomics on either instrument distinguishes HIV-positive individuals using or not using anti retroviral therapy, but the sensitivity of the instrument impacts on data reduction. Furthermore, MLR is a novel multivariate statistical technique for improved classification of biological data analyzed in NMR.

Applying biofluid 1H NMR-based metabonomic techniques to distinguish between HIV-1 positive/AIDS patients on antiretroviral treatment and HIV-1 negative individuals.

Metabonomics, the study of metabolites and their role in various physiological states, is a novel methodology arising from the post-genomics era and has extensive biomedical application. This technology has exhibited vast success in the identification and study of human diseases and may find further application in the study of HIV/AIDS. Specifically, the wide range of clinical and metabolic abnormalities associated with the use of antiretroviral (ARV) treatment may be investigated. To this end, this preliminary study evaluated whether metabonomic techniques could distinguish between HIV-1 positive/AIDS patients utilizing antiretroviral therapy and HIV-1 negative individuals. Serum metabolic profiles determined by 1H nuclear magnetic resonance (NMR) spectroscopy combined with pattern recognition analysis of the data showed that this distinction was attainable; suggesting that ARV-associated side-effects could be monitored utilizing NMR metabonomic techniques.

Effect of blood vitamin A levels on the dark adaptation of mineworkers.

The average dark adaptation time for newly recruited Black mineworkers is longer than that reported for Whites. While this longer dark adaptation time may result from a number of pathological conditions, its most likely cause is a deficiency of vitamin A in the diet. A study was conducted in which the vitamin A level of the blood and the dark adaptation times were correlated in a group of Black mineworkers upon arrival and again after 4 - 6 months continuous work underground in a gold mine. The study indicated that a very marked decrease occurred in the miners' serum vitamin A level between the time of arrival at the mine and the second examination. This difference was found to be highly significant. This decrease was accompanied by an increase in mean dark adaptation time, which was significant at the 5% level. These observations accord with the findings of a previous study and are indicative of an inadequate dietary intake of vitamin A during the period when the miners were on the mine diet.