scholarly journals Study on Genotyping Polymorphism and Sequencing of N-Acetyltransferase 2 (NAT2) among Al-Ahsa Population

2020 ◽  
Vol 2020 ◽  
pp. 1-9
Author(s):  
Mohammad Abu Zahra ◽  
Mahmoud Kandeel ◽  
Sara A. Aldossary ◽  
Abdulla Al-Taher
Keyword(s):  
Confidence Interval ◽  
High Frequency ◽  
Significant Snps ◽  
Slow Acetylators ◽  
Genetic Profile ◽  
Environmental Toxicants ◽  
Nucleotide Polymorphisms ◽  
Exon 2 ◽  
Therapeutic Drugs ◽  
The People

One of the well-studied phase II drug metabolizing enzymes is N-acetyltransferase 2 (NAT2) which has an essential role in the detoxification and metabolism of several environmental toxicants and many therapeutic drugs like isoniazid (antituberculosis, TB) and antimicrobial sulfonamides. According to the variability in the acetylation rate among different ethnic groups, individuals could be classified into slow, intermediate, and fast acetylators; these variabilities in the acetylation rate are a result of single nucleotide polymorphisms (SNPs) in the coding sequence of NAT2. The variety of NAT2 acetylation status is associated with some diseases such as bladder cancer, colorectal cancer, rheumatoid arthritis, and diabetes mellitus. The main objectives of this research are to describe the genetic profile of NAT2 gene among the people of the Al-Ahsa region, to detect the significant SNPs of this gene, to determine the frequency of major NAT2 alleles and genotypes, and then categorize them into fast, intermediate, and slow acetylators. Blood samples were randomly collected from 96 unrelated people from Al-Ahsa population, followed by DNA extraction then amplifying the NAT2 gene by polymerase chain reaction (PCR); finally, functional NAT2 gene (exon 2) was sequenced using the Sanger sequencing method. The well-known seven genetic variants of NAT2 gene are 191G>A, 282C>T, 341T>C, 481C>T, 590G>A, 803A>G, and 857G>A were detected with allele frequencies 1%, 35.4%, 42.7%, 41.1%, 29.2%, 51%, and 5.7%, respectively. The most common NAT2 genetic variant among Al-Ahsa population was 803A>G with a high frequency 0.510 (95% confidence interval 0.44-0.581) followed by 341T>C 0.427 (95% confidence interval 0.357-0.497). The most frequent two haplotypes of NAT2 were NAT2∗6C (25.00%) and NAT2∗5A (22.92%) which were classified as a slow acetylators. According to trimodal distribution of acetylation activity, the predicted phenotype of Al-Ahsa population was found to be 5.21% rapid acetylators, 34.38% intermediate acetylators, and 60.42% were slow acetylators. In addition, this study found four novel haplotypes NAT2∗5TB, NAT2∗5AB, NAT2∗5ZA, and NAT2∗6W which were slow acetylators. This study revealed a high frequency of the NAT2 gene with slow acetylators (60.42%) in Al-Ahsa population, which might alter the drug’s efficacy and vulnerability to some diseases.

Influence of the Acetylation Type on the Incidence of Isoniazid-Induced Hepatotoxicity in Patients with Newly Diagnosed Pulmonary Tuberculosis

2020 ◽  
Vol 65 (7-8) ◽  
pp. 31-36
Author(s):  
N. M. Krasnova ◽  
N. E. Evdokimova ◽  
A. A. Egorova ◽  
O. I. Filippova ◽  
E. A. Alekseeva ◽  
...  
Keyword(s):  
Pulmonary Tuberculosis ◽  
Clinical Laboratory ◽  
Clinical Manifestations ◽  
Normal Activity ◽  
Slow Acetylators ◽  
Nucleotide Polymorphisms ◽  
Newly Diagnosed ◽  
Single Nucleotide ◽  
Tuberculosis Chemotherapy ◽  
Genetically Determined

Introduction. Liver damage can be a dangerous side effect of using isoniazid. Individual susceptibility to isoniazid in humans is dependent on the presence of N-acetyltransferase 2 allelic variants in genome. It was imperative to assess the effect of genetically determined isoniazid acetylation rate in terms of risk of developing isoniazid-induced hepatotoxicity, as well as prevention of potential hepatopathy, and improvement of tuberculosis chemotherapy safety. Aim. To study the effect of acetylation type on the incidence of isoniazid hepatotoxicity in residents of the Sakha Republic (Yakutia) with newly diagnosed pulmonary tuberculosis. Methods. The study included 112 patients with newly diagnosed pulmonary tuberculosis. Genotyping was performed using real-time polymerase chain reaction. The following single nucleotide polymorphisms were studied: rs1801280, rs1799930, rs1799931, rs1799929, rs1208, rs1041983. Hepatotoxicity was determined based on the results of clinical laboratory monitoring and using the criteria developed by the European Association for the Study of the Liver (2019). Results. Hepatotoxic reactions developed more often in slow acetylators (43.2%), compared to fast acetylators (20.7%) and intermediate acetylators (10.9%); p=0.002. Serum alanine aminotransferase activity was 5 or more times above the upper limit of normal activity in 37.8% of slow acetylators, and in 8.7% of intermediate acetylators; p=0.001. Clinical manifestations of isoniazid hepatotoxicity were observed more often in slow acetylators (29.7%), than in fast acetylators (3.4%); p=0.000. Conclusion. Slow acetylation type ought to be considered an important risk factor for developing isoniazid hepatotoxicity in patients with pulmonary tuberculosis.

scholarly journals Significant Associations of lncRNA H19 Genotypes with Susceptibility to Childhood Leukemia in Taiwan

2021 ◽  
Vol 14 (3) ◽  
pp. 235
Author(s):  
Jen-Sheng Pei ◽  
Chao-Chun Chen ◽  
Wen-Shin Chang ◽  
Yun-Chi Wang ◽  
Jaw-Chyun Chen ◽  
...  
Keyword(s):  
Confidence Interval ◽  
Childhood Leukemia ◽  
Healthy Controls ◽  
Nucleotide Polymorphisms ◽  
Wild Type ◽  
Single Nucleotide ◽  
Genotypic Distribution ◽  
Heterozygous Variant ◽  
Significant Difference ◽  
The Difference

The purpose of our study was to investigate whether genetic variations in lncRNA H19 were associated with susceptibility to childhood leukemia. Two hundred and sixty-six childhood leukemia patients and 266 healthy controls were enrolled in Taiwan, and two single nucleotide polymorphisms (SNPs), rs2839698 and rs217727, in H19 were genotyped and analyzed. There was a significant difference in the genotypic distribution of rs2839698 between patients and healthy controls (p = 0.0277). Compared to the wild-type CC genotype, the heterozygous variant CT and homozygous variant TT genotypes were associated with significantly increased risks of childhood leukemia with an adjusted odd ratio (OR) of 1.46 (95% confidence interval (CI), 1.08–2.14, p = 0.0429) and 1.94 (95%CI, 1.15–3.31, p = 0.0169), respectively (pfor tread = 0.0277). The difference in allelic frequencies between childhood leukemia patients and controls was also significant (T versus C, adjusted OR = 1.53, 95%CI, 1.13–1.79, p = 0.0077). There were no significant differences in the genotypic and allelic distributions of rs217727 between cases and controls. Interestingly, the average level of H19 rs2839698 was statistically significantly higher for patients with CT and TT genotypes than from those with the CC genotype (p < 0.0001). Our results indicate that H19 SNP rs2839698, but not rs217727, may serve as a novel susceptibility marker for childhood leukemia.

Arterial blood pressure responses to graded transient arousal from sleep in normal humans

1993 ◽  
Vol 74 (3) ◽  
pp. 1123-1130 ◽  
Author(s):  
R. J. Davies ◽  
P. J. Belt ◽  
S. J. Roberts ◽  
N. J. Ali ◽  
J. R. Stradling
Keyword(s):  
Blood Pressure ◽  
Obstructive Sleep Apnea ◽  
Sleep Apnea ◽  
Confidence Interval ◽  
Rem Sleep ◽  
High Frequency ◽  
Pressure Rise ◽  
Nrem Sleep ◽  
Blood Pressure Rise ◽  
Obstructive Sleep

During obstructive sleep apnea, transient arousal at the resumption of breathing is coincident with a substantial rise in blood pressure. To assess the hemodynamic effect of arousal alone, 149 transient stimuli were administered to five normal subjects. Two electroencephalograms (EEG), an electrooculogram, a submental electromyogram (EMG), and beat-to-beat blood pressure (Finapres, Ohmeda) were recorded in all subjects. Stimulus length was varied to produce a range of cortical EEG arousals that were graded as follows: 0, no increase in high-frequency EEG or EMG; 1, increased high-frequency EEG and/or EMG for < 10 s; 2, increased high-frequency EEG and/or EMG for > 10 s. Overall, compared with control values, average systolic pressure rose [nonrapid-eye-movement (NREM) sleep 10.0 +/- 7.69 (SD) mmHg; rapid-eye-movement (REM) sleep 6.0 +/- 6.73 mmHg] and average diastolic pressure rose (NREM sleep 6.1 +/- 4.43 mmHg; REM sleep 3.7 +/- 3.02 mmHg) over the 10 s following the stimulus (NREM sleep, P < 0.0001; REM sleep, P < 0.002). During NREM sleep, there was a trend toward larger blood pressure rises at larger grades of arousal (systolic: r = 0.22, 95% confidence interval 0.02–0.40; diastolic: r = 0.48, 95% confidence interval 0.31–0.62). The average blood pressure rise in response to the grade 2 arousals was approximately 75% of that during obstructive sleep apnea. Arousal stimuli that did not cause EEG arousal still produced a blood pressure rise (mean systolic rise 8.6 +/- 7.0 mmHg, P < 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Distribution of QPY and RAH haplotypes of granzyme B gene in distinct Brazilian populations

2012 ◽  
Vol 45 (4) ◽  
pp. 496-499
Author(s):  
Fernanda Bernadelli Garcia ◽  
Simone Kashima ◽  
Evandra Strazza Rodrigues ◽  
Israel Tojal Silva ◽  
Tathiane Maistro Malta ◽  
...  
Keyword(s):  
Granzyme B ◽  
Treatment Strategies ◽  
Cytotoxic Lymphocytes ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Exon 2 ◽  
Significant Difference ◽  
Novel Treatment Strategies ◽  
Brazilian Populations ◽  
Afro Brazilian

INTRODUCTION: The cytolysis mediated by granules is one of the most important effector functions of cytotoxic T lymphocytes and natural killer cells. Recently, three single nucleotide polymorphisms (SNPs) were identified at exons 2, 3, and 5 of the granzyme B gene, resulting in a haplotype in which three amino acids of mature protein Q48P88Y245 are changed to R48A88H245, which leads to loss of cytotoxic activity of the protein. In this study, we evaluated the frequency of these polymorphisms in Brazilian populations. METHODS: We evaluated the frequency of these polymorphisms in Brazilian ethnic groups (white, Afro-Brazilian, and Asian) by sequencing these regions. RESULTS: The allelic and genotypic frequencies of SNP 2364A/G at exon 2 in Afro-Brazilian individuals (42.3% and 17.3%) were significantly higher when compared with those in whites and Asians (p < 0.0001 and p = 0.0007, respectively). The polymorphisms 2933C/G and 4243C/T also were more frequent in Afro-Brazilians but without any significant difference regarding the other groups. The Afro-Brazilian group presented greater diversity of haplotypes, and the RAH haplotype seemed to be more frequent in this group (25%), followed by the whites (20.7%) and by the Asians (11.9%), similar to the frequency presented in the literature. CONCLUSIONS: There is a higher frequency of polymorphisms in Afro-Brazilians, and the RAH haplotype was more frequent in these individuals. We believe that further studies should aim to investigate the correlation of this haplotype with diseases related to immunity mediated by cytotoxic lymphocytes, and if this correlation is confirmed, novel treatment strategies might be elaborated.

scholarly journals Genome-Wide Association study Identifies a Novel Association Between a Cardiovascular Gene Polymorphism and Superior Athletic Performance

2020 ◽  
Author(s):  
Mohamed Elrayess ◽  
Fatima Al-Khelaifi ◽  
Noha Yousri ◽  
Omar Al-Bagha
Keyword(s):  
Athletic Performance ◽  
Genome Wide Association Study ◽  
Endurance Athlete ◽  
Meta Analysis ◽  
Significant Snps ◽  
Nucleotide Polymorphisms ◽  
Replication Studies ◽  
Genome Wide ◽  
Small Effect Size ◽  
Metabolomics Analysis

Research into the genetic predisposition to superior athletic performance has been a hindered by the underpowered studies and the small effect size of identified genetic variants. The aims of this study were to investigate the association of common single-nucleotide polymorphisms (SNPs) with endurance athlete status in a large cohort of elite European athletes using GWAS approach, followed by replication studies in Russian and Japanese elite athletes and functional validation using metabolomics analysis. Results: The association of 476,728 SNPs of Illumina DrugCore Gene chip and endurance athlete status was investigated in 796 European international-level athletes (645 males, 151 females) by comparing allelic frequencies between athletes specialized in sports with high (n=662) and low/moderate (n=134) aerobic component. Validation of results was performed by comparing the frequencies of the most significant SNPs between 242 and 168 elite Russian high and low/moderate aerobic athletes, respectively, and between 60 elite Japanese endurance athletes and 406 controls. A meta-analysis has identified rs1052373 (GG homozygotes) in Myosin Binding Protein (MYBPC3; implicated in cardiac hypertrophic myopathy) gene to be associated with endurance athlete status (P=1.43E-08, odd ratio 2.2). Homozygotes carriers of rs1052373 G allele in Russian athletes had significantly greater VO2max than carriers of the AA+AG (P = 0.005). Subsequent metabolomics analysis revealed several amino acids and lipids associated with rs1052373 G allele (1.82x10-05) including the testosterone precursor androstenediol (3beta, 17beta) disulfate. Conclusion: This is the first report of genome-wide significant SNP and related metabolites associated with elite athlete status. Further investigations of the functional relevance of the identified SNPs and metabolites in relation to enhanced athletic performance are warranted.

scholarly journals Interictal high frequency background activity as a biomarker of epileptogenic tissue

2021 ◽  
Author(s):  
Truman Stovall ◽  
Brian Hunt ◽  
Simon Glynn ◽  
William C Stacey ◽  
Stephen V Gliske
Keyword(s):  
Logistic Regression ◽  
Confidence Interval ◽  
High Frequency ◽  
High Frequency Oscillation ◽  
Epileptogenic Zone ◽  
Odds Ratios ◽  
Seizure Onset ◽  
High Frequency Oscillations ◽  
Seizure Onset Zone ◽  
Background Data

Abstract High Frequency Oscillations are very brief events that are a well-established biomarker of the epileptogenic zone, but are rare and comprise only a tiny fraction of the total recorded EEG. We hypothesize that the interictal high frequency “background” data, which has received little attention but represents the majority of the EEG record, also may contain additional, novel information for identifying the epileptogenic zone. We analyzed intracranial EEG (30–500 Hz frequency range) acquired from 24 patients who underwent resective surgery. We computed 38 quantitative features based on all usable, interictal data (63–307 hours per subject), excluding all detected high frequency oscillations. We assessed association between each feature and the seizure onset zone and resected volume using logistic regression. A pathology score per channel was also created via principle component analysis and logistic regression, using hold-out-one-patient cross validation to avoid in-sample training. Association of the pathology score with the seizure onset zone and resected volume was quantified using an asymmetry measure. Many features were associated with the seizure onset zone: 23/38 features had odds ratios &gt;1.3 or &lt; 0.7 and 17/38 had odds ratios different than zero with high significance (p &lt; 0.001/39, logistic regression with Bonferroni Correction). The pathology score, the rate of high frequency oscillations, and their channel-wise product were each strongly associated with the seizure onset zone (median asymmetry &gt; =0.44, good surgery outcome patients; median asymmetry &gt; =0.40, patients with other outcomes; 95% confidence interval &gt; 0.27 in both cases). The pathology score and the channel-wise product also had higher asymmetry with respect to the seizure onset zone than the high frequency oscillation rate alone (median difference in asymmetry &gt; =0.18, 95% confidence interval &gt;0.05). These results support that the high frequency background data contains useful information for determining the epileptogenic zone, distinct and complementary to information from detected high frequency oscillations. The concordance between the high frequency activity pathology score and the rate of high frequency oscillations appears to be a better biomarker of epileptic tissue than either measure alone.

scholarly journals Exome resequencing and GWAS for growth, ecophysiology, and chemical and metabolomic composition of wood of Populus trichocarpa

BMC Genomics ◽  
2019 ◽  
Vol 20 (1) ◽  
Author(s):  
Fernando P. Guerra ◽  
Haktan Suren ◽  
Jason Holliday ◽  
James H. Richards ◽  
Oliver Fiehn ◽  
...  
Keyword(s):  
Biomass Production ◽  
Complex Traits ◽  
Association Studies ◽  
Populus Trichocarpa ◽  
Significant Snps ◽  
Snp Markers ◽  
Exome Capture ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Improvement Programs

Abstract Background Populus trichocarpa is an important forest tree species for the generation of lignocellulosic ethanol. Understanding the genomic basis of biomass production and chemical composition of wood is fundamental in supporting genetic improvement programs. Considerable variation has been observed in this species for complex traits related to growth, phenology, ecophysiology and wood chemistry. Those traits are influenced by both polygenic control and environmental effects, and their genome architecture and regulation are only partially understood. Genome wide association studies (GWAS) represent an approach to advance that aim using thousands of single nucleotide polymorphisms (SNPs). Genotyping using exome capture methodologies represent an efficient approach to identify specific functional regions of genomes underlying phenotypic variation. Results We identified 813 K SNPs, which were utilized for genotyping 461 P. trichocarpa clones, representing 101 provenances collected from Oregon and Washington, and established in California. A GWAS performed on 20 traits, considering single SNP-marker tests identified a variable number of significant SNPs (p-value < 6.1479E-8) in association with diameter, height, leaf carbon and nitrogen contents, and δ15N. The number of significant SNPs ranged from 2 to 220 per trait. Additionally, multiple-marker analyses by sliding-windows tests detected between 6 and 192 significant windows for the analyzed traits. The significant SNPs resided within genes that encode proteins belonging to different functional classes as such protein synthesis, energy/metabolism and DNA/RNA metabolism, among others. Conclusions SNP-markers within genes associated with traits of importance for biomass production were detected. They contribute to characterize the genomic architecture of P. trichocarpa biomass required to support the development and application of marker breeding technologies.

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