scholarly journals N-acetyltransferase 2 genotypes amongst Zulu Speaking South Africans and isoniazid / N-acetyl-isoniazid pharmacokinetics during anti-tuberculosis treatment

2019 ◽  
Author(s):  
Thuli Mthiyane ◽  
James Millard ◽  
John Adamson ◽  
Yusentha Balakrishna ◽  
Cathy Connolly ◽  
...  
Keyword(s):  
South African ◽  
Nucleotide Polymorphisms ◽  
Time Curve ◽  
Single Nucleotide ◽  
South Africans ◽  
High Prevalence ◽  
Median Area ◽  
Frequent Allele ◽  
Rapid Acetylator

AbstractBackgroundDistribution of N-acetyltransferase2 (NAT2) polymorphisms varies considerably among different ethnic groups. Information on NAT2 single-nucleotide polymorphisms in South African population is limited. We investigated NAT2 polymorphisms and their effect on isoniazid pharmacokinetics in Zulu black HIV-infected South Africans in Durban, South Africa. Methods: HIV-infected participants with culture-confirmed pulmonary tuberculosis (TB) were enrolled from two unrelated studies. Culture-confirmed participants were genotyped for NAT2 polymorphisms 282C>T, 341T>C, 481C>T, 857G>A, 590G>A and 803A>G using Life Technologies pre-validated Taqman assays (Life Technologies, Paisley, UK). Participants underwent sampling for determination of plasma isoniazid and N-acetylisoniazid concentrations.ResultsAmongst the 120 patients, 63/120 (52.5%) were slow metabolisers (NAT2*5/*5), 43/120 (35.8%) had intermediate (NAT2*5/12), and 12/120 (11.7%) had rapid genotype (NAT2*4/*11, NAT2*11/12 and NAT2*12/12). NAT2 alleles in this study were *4, *5C, *5D, *5E, *5J, *5K, *5KA, *5T, *11A, *12A/12C and *12M. NAT2*5 was the most frequent allele (70.4%) followed by NAT2*12 (27.9%). 34/40 had both PK results and NAT2 genotyping results. The median area under the concentration-time-curve to infinity (AUC0-∞) interquartile range (IQR) was 7.81 (5.87 – 16.83) μg/ml/hr and maximum concentration (Cmax) 3.14 μg/ml (2.42 – 4.36) μg/mL. Individual polymorphisms were not equally distributed, with some represented in small numbers. Genotype did not correlate with phenotype, rapid genotype showing higher AUC0-∞ than slow but not significant, p=0.43.ConclusionThere was high prevalence of slow followed by intermediate then rapid acetylator genotypes. The poor concordance between genotype and phenotype suggests that other factors or genetic loci influence INH metabolism, and warrants further investigation in this population.

scholarly journals N-Acetyltransferase 2 Genotypes among Zulu-Speaking South Africans and Isoniazid and N-Acetyl-Isoniazid Pharmacokinetics during Antituberculosis Treatment

2020 ◽  
Vol 64 (4) ◽  
Author(s):  
Thuli Mthiyane ◽  
James Millard ◽  
John Adamson ◽  
Yusentha Balakrishna ◽  
Cathy Connolly ◽  
...  
Keyword(s):  
Nucleotide Polymorphisms ◽  
Time Curve ◽  
Slow Acetylator ◽  
South Africans ◽  
Antituberculosis Treatment ◽  
High Prevalence ◽  
Acetylator Genotype ◽  
The Difference ◽  
Median Area ◽  
Rapid Acetylator

ABSTRACT The distribution of N-acetyltransferase 2 gene (NAT2) polymorphisms varies considerably among different ethnic groups. Information on NAT2 single-nucleotide polymorphisms in the South African population is limited. We investigated NAT2 polymorphisms and their effect on isoniazid pharmacokinetics (PK) in Zulu black HIV-infected South Africans in Durban, South Africa. HIV-infected participants with culture-confirmed pulmonary tuberculosis (TB) were enrolled from two unrelated studies. Participants with culture-confirmed pulmonary TB were genotyped for the NAT2 polymorphisms 282C>T, 341T>C, 481C>T, 857G>A, 590G>A, and 803A>G using Life Technologies prevalidated TaqMan assays (Life Technologies, Paisley, UK). Participants underwent sampling for determination of plasma isoniazid and N-acetyl-isoniazid concentrations. Among the 120 patients, 63/120 (52.5%) were slow metabolizers (NAT2*5/*5), 43/120 (35.8%) had an intermediate metabolism genotype (NAT2*5/12), and 12/120 (11.7%) had a rapid metabolism genotype (NAT2*4/*11, NAT2*11/12, and NAT2*12/12). The NAT2 alleles evaluated in this study were *4, *5C, *5D, *5E, *5J, *5K, *5KA, *5T, *11A, *12A/12C, and *12M. NAT2*5 was the most frequent allele (70.4%), followed by NAT2*12 (27.9%). Fifty-eight of 60 participants in study 1 had PK results. The median area under the concentration-time curve from 0 to infinity (AUC0–∞) was 5.53 (interquartile range [IQR], 3.63 to 9.12 μg h/ml), and the maximum concentration (Cmax) was 1.47 μg/ml (IQR, 1.14 to 1.89 μg/ml). Thirty-four of 40 participants in study 2 had both PK results and NAT2 genotyping results. The median AUC0–∞ was 10.76 μg·h/ml (IQR, 8.24 to 28.96 μg·h/ml), and the Cmax was 3.14 μg/ml (IQR, 2.39 to 4.34 μg/ml). Individual polymorphisms were not equally distributed, with some being represented in small numbers. The genotype did not correlate with the phenotype, with those with a rapid acetylator genotype showing higher AUC0–∞ values than those with a slow acetylator genotype, but the difference was not significant (P = 0.43). There was a high prevalence of slow acetylator genotypes, followed by intermediate and then rapid acetylator genotypes. The poor concordance between genotype and phenotype suggests that other factors or genetic loci influence isoniazid metabolism, and these warrant further investigation in this population.

Development of a simple method for the determination of single nucleotide polymorphisms

2010 ◽  
Vol 34 (8) ◽  
pp. S75-S75
Author(s):  
Weifeng Zhu ◽  
Zhuoqi Liu ◽  
Daya Luo ◽  
Xinyao Wu ◽  
Fusheng Wan
Keyword(s):  
Single Nucleotide Polymorphisms ◽  
Nucleotide Polymorphisms ◽  
Simple Method ◽  
Single Nucleotide

Assessing single nucleotide polymorphism selection methods for the development of a low-density panel optimized for imputation in South African Drakensberger beef cattle

2021 ◽  
Author(s):  
Simon F Lashmar ◽  
Donagh P Berry ◽  
Rian Pierneef ◽  
Farai C Muchadeyi ◽  
Carina Visser
Keyword(s):  
South African ◽  
Clustering Algorithm ◽  
Imputation Accuracy ◽  
Developed Countries ◽  
Genotype Imputation ◽  
Selection Strategy ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Single Nucleotide Polymorphism Selection ◽  
The Mean

Abstract A major obstacle in applying genomic selection (GS) to uniquely adapted local breeds in less-developed countries has been the cost of genotyping at high densities of single nucleotide polymorphisms (SNP). Cost reduction can be achieved by imputing genotypes from lower to higher densities. Locally adapted breeds tend to be admixed and exhibit a high degree of genomic heterogeneity thus necessitating the optimization of SNP selection for downstream imputation. The aim of this study was to quantify the achievable imputation accuracy for a sample of 1,135 South African (SA) Drakensberger using several custom-derived lower-density panels varying in both SNP density and how the SNP were selected. From a pool of 120,608 genotyped SNP, subsets of SNP were chosen 1) at random, 2) with even genomic dispersion, 3) by maximizing the mean minor allele frequency (MAF), 4) using a combined score of MAF and linkage disequilibrium (LD), 5) using a partitioning-around-medoids (PAM) algorithm, and finally 6) using a hierarchical LD-based clustering algorithm. Imputation accuracy to higher density improved as SNP density increased; animal-wise imputation accuracy defined as the within-animal correlation between the imputed and actual alleles ranged from 0.625 to 0.990 when 2,500 randomly selected SNP were chosen versus a range of 0.918 to 0.999 when 50,000 randomly selected SNP were used. At a panel density of 10,000 SNP, the mean (standard deviation) animal-wise allele concordance rate was 0.976 (0.018) versus 0.982 (0.014) when the worst (i.e., random) as opposed to the best (i.e., combination of MAF and LD) SNP selection strategy was employed. A difference of 0.071 units was observed between the mean correlation-based accuracy of imputed SNP categorized as low (0.01<MAF≤0.1) versus high MAF (0.4<MAF≤0.5). Greater mean imputation accuracy was achieved for SNP located on autosomal extremes when these regions were populated with more SNP. The presented results suggested that genotype imputation can be a practical cost-saving strategy for indigenous breeds such as the South African Drakensberger. Based on the results, a genotyping panel consisting of approximately 10,000 SNP selected based on a combination of MAF and LD would suffice in achieving a less than 3% imputation error rate for a breed characterized by genomic admixture on the condition that these SNP are selected based on breed-specific selection criteria.

scholarly journals Genome Analysis of A Novel South African Cydia pomonella granulovirus (CpGV-SA) with Resistance-Breaking Potential

Viruses ◽  
2019 ◽  
Vol 11 (7) ◽  
pp. 658 ◽  
Author(s):  
Boitumelo Motsoeneng ◽  
Michael D. Jukes ◽  
Caroline M. Knox ◽  
Martin P. Hill ◽  
Sean D. Moore
Keyword(s):  
South African ◽  
Complete Genome ◽  
Cydia Pomonella ◽  
Codling Moth ◽  
Type I ◽  
Nucleotide Polymorphisms ◽  
Pome Fruit ◽  
Single Nucleotide ◽  
Resistance Breaking ◽  
Cydia Pomonella Granulovirus

The complete genome of an endemic South African Cydia pomonella granulovirus isolate was sequenced and analyzed. Several missing or truncated open reading frames (ORFs) were identified, including a 24 bp deletion in the pe38 gene which is reported to be associated with type I resistance-breaking potential. Comparison of single nucleotide polymorphisms (SNPs) with five other fully sequenced CpGV isolates identified 67 unique events, 47 of which occurred within ORFs, leading to several amino acid changes. Further analysis of single nucleotide variations (SNVs) within CpGV-SA revealed that this isolate consists of mixed genotypes. Phylogenetic analysis using complete genome sequences placed CpGV-SA basal to M, I12 and E2 and distal to S and I07 but with no distinct classification into any of the previously defined CpGV genogroups. These results suggest that CpGV-SA is a novel and genetically distinct isolate with significant potential as a biopesticide for management of codling moth (CM), not only in South Africa, but potentially in other pome fruit producing countries, particularly where CM resistance to CpGV has been reported.

scholarly journals POLYMORPHISMS IN THE GENES OF REPARATIONS AMONG EMPLOYEES OF THE ATOMIC INDUSTRY OF KAZAKHSTAN

2020 ◽  
Vol 1 (337) ◽  
pp. 5-10
Author(s):  
D. M. Botbаeyev ◽  
А. M. Belkozhаev ◽  
A. K. Khanseitova ◽  
A. Zh. Borbayeva ◽  
N. А. Аitkhozhinа
Keyword(s):  
Nuclear Industry ◽  
Repair System ◽  
Nucleotide Polymorphisms ◽  
Low Dose Radiation ◽  
Nucleotide Substitutions ◽  
Single Nucleotide ◽  
Variable Regions ◽  
And Control ◽  
Dose Radiation

Single nucleotide polymorphisms (SNPs) are the most convenient marker and the widespread subject of polymorphism testing. To identify the presence or absence of the effects of chronic low-dose radiation on nuclear industry personnel, the occurrence of single-nucleotide substitutions at the polymorphic sites of the genes of the repair system 3 and 6 of the introns of the APC gene P53.11 gene, in positions -2549 of the VEGF gene, XPD gene rs313181 ( Lys751Gln) and rs25487 of the XRCC gene (Аrg399Gln) were compared. Analysis of allele frequencies and distribution of genotypes in the variable regions of the tested genes was performed by the method of polymerase chain reaction (PCR), followed by determination of restriction fragment length polymorphism (RFLP). When com-paring the frequencies of alleles and the distribution of genotypes between the second group of miners (11–20 years’ experience) and control, differences in the distribution of genotypes in the rs25487 XRCC plot (χ2 = 7.11, p = 0.028) were revealed. These differences satisfy the criterion p <0.05 and, accordingly, are statistically significant. Key words: polymorphism, genes, a nuclear industry.

scholarly journals Biochemical markers predicting response to radiation- and radiochemo-therapy in cancer patients

2012 ◽  
Vol 58 (6) ◽  
pp. 635-650 ◽  
Author(s):  
S.D. Ivanov
Keyword(s):  
Response Prediction ◽  
Molecular Profiling ◽  
Nucleotide Polymorphisms ◽  
Dna Array ◽  
Single Nucleotide ◽  
Tumor Tissues ◽  
Specific Proteins ◽  
Profiling Analysis

In last years there is increasing interest in radiogenomics and the characterization of DNA array molecular profiles that can predict tumor and no tumor tissues radioresponse. Ongoing studies carried out worldwide in the banking of tumor and no tumor samples give evidence that perspective markers for response prediction in individual patient to intended radiation therapy can be some apoptotic indexes, spectrum a number of specific proteins, and DNA-based microarray molecular profiling analysis as well determination of single nucleotide polymorphisms in genome of the patients. So far there are only a few robust reports of molecular markers predicting tumor and no tumor tissues response to radiation. The results of new studies, which in future should be validated in larger definitive trials, are likely to see in nearest years. It is needed to determine technologies of methods and to define more precisely areas of its applications.

scholarly journals Analysis of the genetic diversity of Phalaenopsis orchids with single nucleotide polymorphisms and snap markers derived from the Pto gene

2021 ◽  
Vol 53 (4) ◽  
pp. 620-631
Keyword(s):  
Genetic Diversity ◽  
Single Nucleotide Polymorphisms ◽  
Genomic Sequence ◽  
Nucleotide Polymorphisms ◽  
Multiple Sequence ◽  
Functional Link ◽  
Single Nucleotide ◽  
Functional Changes ◽  
Interspecies Variability

The Pto gene is a plant gene that has been reported to be involved in resistance to bacterial pathogens. A partial genomic sequence corresponding to Pto (~449 bp) was isolated from 16 species and four hybrids of Phalaenopsis during 2017 at the Department of Agronomy and Horticulture, IPB University, Bogor, Indonesia. Multiple sequence analysis was performed to find putative single nucleotide polymorphisms (SNPs) and design the corresponding single nucleotide-amplified polymorphism (SNAP) markers, which were in turn used to estimate the genetic diversity of 25 Phalaenopsis species. In total, 20 SNPs, of which 14 were nonsynonymous, were identified from the partial Pto sequences. Eighteen SNAP primers were then developed based on these 14 nonsynonymous and four synonymous SNPs. Validation results showed that 15 SNAP primers showed a polymorphism information content exceeding 0.3, suggesting the existence of more than two alleles for this locus. Upon their use, the SNAP markers described 86% of all interspecies variability. The Pto 52, Pto 349, Pto 229, and Pto 380 SNAP markers were very informative in the determination of genetic diversity. Notably, the existence of these nonsynonymous SNPs implied the possibility of functional changes within the amino acid sequence of the putative PTO protein. Thus, the resulting differences in the activity of the PTO protein may be used to breed tolerance to pathogen infection. Further work may be required to establish a functional link between tolerance to pathogens and the presence of Pto-SNAP markers in Phalaenopsis properly.

scholarly journals Molecular surveillance of anti-malarial resistance Pfdhfr and Pfdhps polymorphisms in African and Southeast Asia Plasmodium falciparum imported parasites to Wuhan, China

2020 ◽  
Vol 19 (1) ◽  
Author(s):  
Tingting Jiang ◽  
Weijia Cheng ◽  
Yi Yao ◽  
Huabing Tan ◽  
Kai Wu ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Migrant Workers ◽  
Nucleotide Polymorphisms ◽  
Triple Mutant ◽  
Single Nucleotide ◽  
Molecular Surveillance ◽  
High Prevalence ◽  
The Status ◽  
Quadruple Mutant ◽  
Antifolate Resistance

Abstract Background Anti-malarial drug resistance is a severe challenge for eventual control and global elimination of malaria. Resistance to sulfadoxine-pyrimethamine (SP) increases as mutations accumulate in the Pfdhfr and Pfdhps genes. This study aimed to assess the polymorphisms and prevalence of mutation in these genes in the Plasmodium falciparum infecting migrant workers returning to Wuhan, China. Methods Blood samples were collected for 9 years (2011–2019). Parasite genomic DNA was extracted from blood spots on filter paper. The mutations were evaluated by nested PCR and sequencing. The single-nucleotide polymorphisms (SNPs) and haplotypes of the Pfdhfr and Pfdhps genes were analysed. Results Pfdhfr codon 108 showed a 94.7% mutation rate, while for Pfdhps, the rate for codon 437 was 79.0%. In total, five unique haplotypes at the Pfdhfr locus and 11 haplotypes at the Pfdhps locus were found while the Pfdhfr-Pfdhps combined loci revealed 28 unique haplotypes. A triple mutant (IRNI) of Pfdhfr was the most prevalent haplotype (84.4%). For Pfdhps, a single mutant (SGKAA) and a double mutant (SGEAA) were detected at frequencies of 37.8 and 22.3%, respectively. Among the combined haplotypes, a quadruple mutant (IRNI-SGKAA) was the most common, with a 30.0% frequency, followed by a quintuplet mutant (IRNI-SGEAA) with a frequency of 20.4%. Conclusion The high prevalence and saturation of Pfdhfr haplotypes and the medium prevalence of Pfdhps haplotypes demonstrated in the present data will provide support for predicting the status and progression of antifolate resistance in malaria-endemic regions and imported malaria in nonendemic areas. Additional interventions to evaluate and prevent SP resistance should be continuously considered.

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