The convergence of therapeutic drug monitoring and pharmacogenetic testing to optimize efavirenz therapy.

The aim of this study was to show the benefits of combining therapeutic drug monitoring (TDM) and pharmacogenetic analyses to optimize efavirenz (EFV) therapy. Patients were selected to minimize nongenetic differences between patients: 32 HIV adherent patients without drug interactions treated with an EFV nonindividualized dose over at least 1 year and included in a TDM program were genotyped according to minimum steady-state concentrations (C ss min). The EFV plasma concentrations (n = 158) were quantified by high-performance liquid chromatography-ultraviolet, and genetic polymorphisms were analyzed using the PHARMAchip. Central nervous system side effects were assessed systematically. Genetic polymorphisms were detected in 79.2% of patients with EFV Css min outside the therapeutic range (1-4 mg/L), showing the high diagnostic efficacy of combining TDM with pharmacogenetic testing. CYP2B6 (516 G>T) polymorphisms were associated with a significant decrease in EFV plasma clearance in 80% of the poor metabolizer patients (G/T, T/T). All homozygous patients had C ss min greater than 4 mg/L, 75% of them showing central nervous system side effects. For such patients, pharmacogenetic testing with TDM could be advantageous because the polymorphism is a determinant of these circumstances and TDM would allow reductions in dose to be specified without assuming an equal dose for any given genotype. In fact, poor metabolizer patients required less than a 600 mg standard starting dose, implying that if CYP2B6 screening were available, EFV therapy could be started at 400 mg and later TDM-individualized. The results of this study clarify the genotype versus phenotype debate for optimizing drug therapy. Pharmacogenetic testing together with TDM links genotype to phenotypic differences in drug concentrations and adverse events, providing additional support for dosage adjustment and a more efficient use of both approaches. As genotype screens become cheaper, and in combination with TDM, adjusting dosages in the light of genetic polymorphisms will become a reality.

The paternal polymorphism rs5370 in the EDN1 gene decreases the risk of preeclampsia.

OBJECTIVE: To evaluate whether the maternal, paternal or the combined maternal/paternal contribution of SNP rs5370 of the EDN1 gene is associated with preeclampsia and drove its expression in placenta. STUDY DESIGN: This case-control study included 61 preeclamptic patients and their partners and 49 healthy pregnant women and their partners. The population was sub-divided into three groups: women-only, men-only and combined (women/men). The analysis included genotyping of rs5370 in mothers and fathers and evaluating the expression profile of the EDN1 gene in placenta. Comparisons of categorical variables were performed using chi-square and/or Fisher's exact tests. The intergroup comparisons were analysed with the Mann-Whitney U test. The association between the polymorphism and the disease was evaluated through multivariate regression analysis. Spearman's correlation was performed to test the relationship between pre-gestational history and clinical features of the affected patients with EDN1 gene expression. RESULTS: The analysis of paternal risk factors associated with preeclampsia revealed no differences between groups. A negative association between SNP rs5370 and preeclampsia was found in men group (OR 0.42; CI 95% 0.18-0.94, p=0.034) but not in women or combined groups. The adjustment for paternal protective factors increased the observed negative association, and the opposite was observed in the presence of paternal risk factors. The expression of the EDN1 gene in the placenta was significantly higher in the group of cases and was not associated with the rs5370 polymorphism. CONCLUSION: The paternal rs5370 polymorphism decreases the risk for preeclampsia and is not associated with placental expression of the EDN1 gene.

Genetic diversity of Histoplasma capsulatum isolated from infected bats randomly captured in Mexico, Brazil, and Argentina, using the polymorphism of (GA)(n) microsatellite and its flanking regions.

The genetic diversity of 47 Histoplasma capsulatum isolates from infected bats captured in Mexico, Brazil, and Argentina was studied, using sequence polymorphism of a 240-nucleotides (nt) fragment, which includes the (GA)(n) length microsatellite and its flanking regions within the HSP60 gene. Three human clinical strains were used as geographic references. Based on phylogenetic analyses of 240-nt fragments achieved, the relationships among H. capsulatum isolates were resolved using neighbour-joining and maximum parsimony methods. The tree topologies obtained by both methods were identical and highlighted two major clusters of isolates. Cluster I had three sub-clusters (Ia, Ib, and Ic), all of which contained Mexican H. capsulatum samples, while cluster II consisted of samples from Brazil and Argentina. Sub-cluster Ia included only fungal isolates from the migratory bat Tadarida brasiliensis. An average DNA mutation rate of 2.39 × 10(-9) substitutions per site per year was estimated for the 240-nt fragment for all H. capsulatum isolates. Nucleotide diversity analysis of the (GA)(n) and flanking regions from fungal isolates of each cluster and sub-cluster underscored the high similarity of cluster II (Brazil and Argentina), sub-clusters Ib, and Ic (Mexico). According to the genetic distances among isolates, a network of the 240-nt fragment was graphically represented by (GA)(n) length haplotype. This network showed an association between genetic variation and both the geographic distribution and the ecotype dispersion of H. capsulatum, which are related to the migratory behaviour of the infected bats studied.