scholarly journals Pharmacogenetics of tenofovir and emtricitabine penetration into cerebrospinal fluid

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Eric H. Decloedt ◽  
Phumla Z. Sinxadi ◽  
Lubbe Wiesner ◽  
John A. Joska ◽  
David W. Haas ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
South African ◽  
Genetic Polymorphisms ◽  
Geometric Mean ◽  
Hiv Positive ◽  
P Value ◽  
Nucleotide Polymorphisms ◽  
Linear Regression Models ◽  
Single Nucleotide ◽  
Black South African

Background: Blood-cerebrospinal fluid (CSF) barrier transporters affect the influx and efflux of drugs. The antiretrovirals tenofovir and emtricitabine may be substrates of blood-brain barrier (BBB) and blood-CSF barrier transporters, but data are limited regarding the pharmacogenetics and pharmacokinetics of their central nervous system (CNS) penetration.Objectives: We investigated genetic polymorphisms associated with CSF disposition of tenofovir and emtricitabine.Method: We collected paired plasma and CSF samples from 47 HIV-positive black South African adults who were virologically suppressed on efavirenz, tenofovir and emtricitabine. We considered 1846 single-nucleotide polymorphisms from seven relevant transporter genes (ABCC5, ABCG2, ABCB1, SLCO2B1, SCLO1A2, SLCO1B1 and ABCC4) and 782 met a linkage disequilibrium (LD)-pruning threshold.Results: The geometric mean (95% confidence interval [CI]) values for tenofovir and emtricitabine CSF-to-plasma concentration ratios were 0.023 (0.021–0.026) and 0.528 (0.460–0.605), respectively. In linear regression models, the lowest p-value for association with the tenofovir CSF-to-plasma ratio was ABCB1 rs1989830 (p = 1.2 × 10−3) and for emtricitabine, it was ABCC5 rs11921035 (p = 1.4 × 10−3). None withstood correction for multiple testing.Conclusion: No genetic polymorphisms were associated with plasma, CSF concentrations or CSF-to-plasma ratios for either tenofovir or emtricitabine.

scholarly journals Lesion size is associated with genetic polymorphisms in TLR1, TLR6, and TIRAP genes in patients with major abscesses and diabetic foot infections

2019 ◽  
Vol 39 (2) ◽  
pp. 353-360 ◽  
Author(s):  
Valentino D’Onofrio ◽  
Annelie A. Monnier ◽  
Cécile Kremer ◽  
Mark H. T. Stappers ◽  
Mihai G. Netea ◽  
...  
Keyword(s):  
Genetic Polymorphisms ◽  
Diabetic Foot ◽  
Lesion Size ◽  
Allelic Variant ◽  
Nucleotide Polymorphisms ◽  
Toll Like Receptor ◽  
Linear Regression Models ◽  
Single Nucleotide ◽  
Diabetic Foot Infections ◽  
Complicated Skin

AbstractGenetic variation in Toll-like receptors (TLRs) has previously been associated with susceptibility to complicated skin and skin structure infections (cSSSIs). The aim of this study was to investigate associations between the severity of cSSSIs, i.e., major abscesses and diabetic foot infections (DFIs), and a set of genetic polymorphisms in the Toll-like receptor pathway. A total of 121 patients with major abscesses and 132 with DFIs participating in a randomized clinical trial were genotyped for 13 nonsynonymous single-nucleotide polymorphisms (SNPs) in genes coding for TLRs and the signaling adaptor molecule TIRAP. Infection severity was defined by lesion size at clinical presentation for both types of infections. The PEDIS infection score was also used to define severity of DFIs. Linear regression models were used to study factors independently associated with severity. In patients with large abscesses, hetero- or homozygosity for the allelic variant TLR6 (P249S) was associated with significantly smaller lesions while homozygosity for the allelic variant TLR1 (R80T) was associated with significantly larger lesions. PRRs genes were not significantly associated with PEDIS. However, patients with DFI hetero- or homozygous for the allelic variant TLR1 (S248N) had significantly larger lesions. Polymorphisms in TLR1 and TLR6 influence the severity of cSSSIs as assessed by the lesion size of major abscesses and DFIs. ClinicalTrial.gov Identifier: NCT 00402727

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 Sex Differences in Circadian Clock Genes and Myocardial Infarction Susceptibility

2021 ◽  
Vol 8 (5) ◽  
pp. 53
Author(s):  
Ivana Škrlec ◽  
Jasminka Talapko ◽  
Martina Juzbašić ◽  
Robert Steiner
Keyword(s):  
Myocardial Infarction ◽  
Cardiovascular Disease ◽  
Circadian Rhythm ◽  
Single Nucleotide Polymorphisms ◽  
Clock Genes ◽  
P Value ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Biological Sex ◽  
Significant Difference

The growing body of evidence shows a significant difference in the circadian rhythm of cardiovascular disease based on biological sex. The incidence of cardiovascular disease varies between women and men. Additionally, biological sex is vital for the timely application of therapy—chronotherapy, which benefits both sexes. This study aimed to examine the potential difference of single nucleotide polymorphisms (SNPs) of the circadian rhythm genes ARNTL, CLOCK, CRY2 and PER2 in women and men with myocardial infarction. A cross-sectional study was conducted, including 200 patients with myocardial infarction. Altogether, ten single nucleotide polymorphisms in the ARNTL, CLOCK, CRY2 and PER2 genes were analyzed. The Chi-square test yielded statistically significant differences in CLOCK gene rs11932595 polymorphism in a recessive genotype model between women and men with a p-value of 0.03 and an odds ratio 2.66, and a corresponding 95% confidence interval of 1.07 to 6.66. Other analyzed polymorphisms of the circadian rhythm genes ARNTL, CRY2, and PER2 did not significantly differ between the sexes. According to the study’s current results, the CLOCK gene’s genetic variability might affect myocardial infarction concerning biological sex.

scholarly journals Association of single-nucleotide polymorphisms in the ESR2 and FSHR genes with poor ovarian response in infertile Jordanian women

2021 ◽  
Vol 48 (1) ◽  
pp. 69-79
Author(s):  
Amer Mahmoud Sindiani ◽  
Osamah Batiha ◽  
Esra’a Al-zoubi ◽  
Sara Khadrawi ◽  
Ghadeer Alsoukhni ◽  
...  
Keyword(s):  
Single Nucleotide Polymorphisms ◽  
Statistical Significance ◽  
Ovarian Response ◽  
Control Group ◽  
P Value ◽  
Case Group ◽  
Nucleotide Polymorphisms ◽  
Poor Ovarian Response ◽  
Single Nucleotide ◽  
Number Of Patients

Objective: Poor ovarian response (POR) refers to a subnormal follicular response that leads to a decrease in the quality and quantity of the eggs retrieved after ovarian stimulation during assisted reproductive treatment (ART). The present study investigated the associations of multiple variants of the estrogen receptor 2 (ESR2) and follicle-stimulating hormone receptor (FSHR) genes with POR in infertile Jordanian women undergoing ART.Methods: Four polymorphisms, namely ESR2 rs1256049, ESR2 rs4986938, FSHR rs6165, and FSHR rs6166, were investigated in 60 infertile Jordanian women undergoing ART (the case group) and 60 age-matched fertile women (the control group), with a mean age of 33.60±6.34 years. Single-nucleotide polymorphisms (SNPs) were detected by restriction fragment length polymorphism and then validated using Sanger sequencing.Results: The p-value of the difference between the case and control groups regarding FSHR rs6166 was very close to 0.05 (p=0.054). However, no significant differences were observed between the two groups in terms of the other three SNPs, namely ESR2 rs1256049, ESR2 rs4986938, and FSHR rs6165 (p=0.561, p=0.433, and p=0.696, respectively).Conclusion: The association between FSHR rs6166 and POR was not statistically meaningful in the present study, but the near-significant result of this experiment suggests that statistical significance might be found in a future study with a larger number of patients.

scholarly journals Polymorphisms in RAS/RAF/MEK/ERK Pathway Are Associated with Gastric Cancer

Genes ◽  
2018 ◽  
Vol 10 (1) ◽  
pp. 20 ◽  
Author(s):  
Patricio Gonzalez-Hormazabal ◽  
Maher Musleh ◽  
Marco Bustamante ◽  
Juan Stambuk ◽  
Raul Pisano ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Additive Model ◽  
P Value ◽  
Erk Pathway ◽  
Nucleotide Polymorphisms ◽  
Functional Effect ◽  
Cellular Functions ◽  
Single Nucleotide ◽  
Gastric Cancer Patients ◽  
Control Study

The RAS/RAF/MEK/ERK pathway regulates certain cellular functions, including cell proliferation, differentiation, survival, and apoptosis. Dysregulation of this pathway leads to the occurrence and progression of cancers mainly by somatic mutations. This study aimed to assess if polymorphisms of the RAS/RAF/MEK/ERK pathway are associated with gastric cancer. A case-control study of 242 gastric cancer patients and 242 controls was performed to assess the association of 27 single nucleotide polymorphisms (SNPs) in the RAS/RAF/MEK/ERK pathway genes with gastric cancer. Analyses performed under the additive model (allele) showed four significantly associated SNPs: RAF1 rs3729931 (Odds ratio (OR) = 1.54, 95%, confidence interval (CI): 1.20–1.98, p-value = 7.95 × 10−4), HRAS rs45604736 (OR = 1.60, 95% CI: 1.16–2.22, p-value = 4.68 × 10−3), MAPK1 rs2283792 (OR = 1.45, 95% CI: 1.12–1.87, p-value = 4.91 × 10−3), and MAPK1 rs9610417 (OR = 0.60, 95% CI: 0.42–0.87, p-value = 6.64 × 10−3). Functional annotation suggested that those variants or their proxy variants may have a functional effect. In conclusion, this study suggests that RAF1 rs3729931, HRAS rs45604736, MAPK1 rs2283792, and MAPK1 rs9610417 are associated with gastric cancer.

scholarly journals MassARRAY-based single nucleotide polymorphism analysis in breast cancer of north Indian population

BMC Cancer ◽  
2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Divya Bakshi ◽  
Ashna Nagpal ◽  
Varun Sharma ◽  
Indu Sharma ◽  
Ruchi Shah ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Mutations ◽  
Cost Effective ◽  
P Value ◽  
Polymorphism Analysis ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Cost Effective Method ◽  
Common Genetic Variants ◽  
Underlying Causes

Abstract Background Breast Cancer (BC) is associated with inherited gene mutations. High throughput genotyping of BC samples has led to the identification and characterization of biomarkers for the diagnosis of BC. The most common genetic variants studied are SNPs (Single Nucleotide Polymorphisms) that determine susceptibility to an array of diseases thus serving as a potential tool for identifying the underlying causes of breast carcinogenesis. Methods SNP genotyping employing the Agena MassARRAY offers a robust, sensitive, cost-effective method to assess multiple SNPs and samples simultaneously. In this present study, we analyzed 15 SNPs of 14 genes in 550 samples (150 cases and 400 controls). We identified four SNPs of genes TCF21, SLC19A1, DCC, and ERCC1 showing significant association with BC in the population under study. Results The SNPs were rs12190287 (TCF21) having OR 1.713 (1.08–2.716 at 95% CI) p-value 0.022 (dominant), rs1051266 (SLC19A1) having OR 3.461 (2.136–5.609 at 95% CI) p-value 0.000000466 (dominant), rs2229080 (DCC) having OR 0.6867 (0.5123–0.9205 at 95% CI) p-value 0.0116 (allelic) and rs2298881 (ERCC1) having OR 0.669 (0.46–0.973 at 95% CI), p-value 0.035 (additive) respectively. The in-silico analysis was further used to fortify the above findings. Conclusion It is further anticipated that the variants should be evaluated in other population groups that may aid in understanding the genetic complexity and bridge the missing heritability.

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.

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