Allele Genotype Research Articles

Ginkgo biloba for Tardive Dyskinesia and Plasma MnSOD Activity: Association with MnSOD Ala-9Val Variant: A Randomized, Double-blind Trial.

Excessive free radicals are implicated in the pathophysiology of tardive dyskinesia (TD), and Ginkgo biloba extract (EGb761) scavenges free radicals, thereby enhancing antioxidant enzymes such as mitochondrial manganese superoxide dismutase (MnSOD). This study examined whether EGb761 treatment would improve TD symptoms and increase MnSOD activity, particularly in TD patients with specific MnSOD Val-9Ala genotype. An EGb761 (240 mg/day) 12-week double-blind clinical trial with 157 TD patients was randomized. The severity of TD was measured by the Abnormal Involuntary Movement Scale (AIMS) and plasma MnSOD activity was assayed before and after 12 weeks of treatment. Further, in an expanded sample, we compared MnSOD activity in 159 TD, 227 non-TD and 280 healthy controls, as well as the allele frequencies and genotypes for the MnSOD Ala-9Val polymorphism in 352 TD, 486 non-TD and 1150 healthy controls. EGb761 significantly reduced TD symptoms and increased MnSOD activity in TD patients compared to placebo (both p < 0.01). Moreover, we found an interaction between genotype and treatment response (p < 0.001). Furthermore, in the EGb761 group, patients carrying the Ala allele displayed a significantly lower AIMS total score than patients with the Val/Val genotype. In addition, MnSOD activity was significantly lower at baseline in TD patients compared with healthy controls or non-TD patients. EGb761 treatment enhanced low MnSOD activity in TD patients and produced greater improvement in TD symptoms in patients with the Ala allele of the MnSOD Ala-9Val polymorphism.

Linking CDH1 SNPs to gastric cancer risk: a comprehensive analysis of rs16260, rs13689, and rs9929218.

Single nucleotide polymorphisms (SNPs) are linked to carcinogenesis. Pathogenic variants in the CDH1 gene are associated with gastric cancer. This study examines the genotype and allele frequencies of three SNPs (rs16260, rs13689, and rs9929218) in the CDH1 gene and their relationship with gastric cancer risk. The study involved 105 gastric cancer patients with pathology results and 105 healthy controls. Clinical, histopathological, and demographic data were collected and compared between the two groups. No significant differences were found for rs16260 (-160 C > A) and rs9929218 (G > A) between patients and controls (p > 0.05). For rs13689 (T > C), the T allele frequency was 90% in patients versus 69% in controls, while the C allele frequency was 10% in patients versus 31% in controls. A significant difference was observed for this SNP, with a higher T allele frequency in patients (OR = 4.03 CI95% 2.4-6.7, p < 0.0001) compared with controls, suggesting a fourfold increased risk of gastric cancer. Genotype frequencies were 80% wild-type (TT) and 20% heterozygous-type (TC) in patients, and 58% TT, 22% TC, and 20% mutant-type (CC) in controls (p < 0.0001). The frequencies of non-C allele carriers (TT) were present in 80% of patients versus 58.1% of controls (OR = 2.88 CI95% 1.56-5.34, p = 0.0006). This study is the first to link the rs13689 SNP's T allele and TT genotype with increased gastric cancer risk. Our results suggest that thers13689 T allele may contribute significantly to disease susceptibility, while thers16260 CC genotype and rs9929218 GG genotype may influence risk in smokers.

A Meta-Analysis of Association Between Interleukin Polymorphisms (rs4073, rs1800925, rs1179251, rs1179246, rs2227485, rs17855750, and rs153109) and Colorectal Cancer Risk.

Interleukins (ILs) play a significant role in triggering the inflammatory response in blood vessels and immune cells. A systematic review and meta-analysis were conducted to investigate the relationship between IL-8 (rs4073), IL-13 (rs1800925), IL-22 (rs1179251, rs1179246, and rs2227485), and IL-27 (rs17855750 and rs153109) polymorphisms and the risk of developing colorectal cancer (CRC). Four databases were searched up until October 13, 2023, without any restrictions, to find relevant studies. The association was evaluated using crude odds ratios (ORs) and 95% confidence intervals in five genetic models. A total of twenty-three articles were entered into the meta-analysis. The pooled ORs (p-values) for the IL-8 (rs4073) polymorphism were 0.98 (0.63), 0.93 (0.44), 0.89 (0.13), 0.94 (0.38), and 0.99 (0.90) for studies following HWE without heterogeneity, and for all studies with high heterogeneity were 1.03 (0.69), 1.30 (0.07), 1.04 (0.71), 1.12 (0.20), and 1.23 (0.06). For the IL-13 (rs1800925) polymorphism, the pooled ORs were 1.44 (0.06), 2.58 (0.0004), 1.72 (0.16), 1.82 (0.09), and 2.37 (0.001) in AHHDR models, respectively. The pooled ORs of IL-22 (rs1179251) polymorphism for AHHDR models were 0.97 (0.92), 0.92 (0.90), 0.98 (p = 0.95), 1.08 (0.87), and 0.96 (0.82), respectively. The pooled ORs of IL-22 (rs1179246) polymorphism for AHHDR models were 0.98 (0.67), 0.97 (0.80), 0.92 (0.36), 0.93 (0.42), and 1.02 (0.84), respectively. The pooled ORs of IL-22 (rs2227485) polymorphism for AHHDR models were 1.47 (0.02), 2.03 (0.02), 1.28 (0.29), 1.52 (0.06), and 1.70 (0.04), respectively. The pooled ORs of IL-27 (rs17855750) polymorphism for AHHDR models were 0.53 (0.46), 0.19 (0.28), 1.10 (0.60), 0.55 (0.58), and 0.27 (p = 0.05), respectively. The pooled ORs of IL-27 (rs153109) polymorphism for AHHDR models were 1.28 (0.007), 1.45 (0.002), 1.40 (0.0002), 1.41 (< 0.0001), and 1.20 (0.09), respectively. The results reported that just the TT genotype of IL-13 (rs1800925), the T allele and TT genotype of IL-22 (rs2227485), and the G allele and GG, AG and GG + AG genotypes of IL-27 (rs153109) polymorphisms had an elevated risk in CRC patients.

ABC Family Gene Polymorphisms and Cognitive Functions Interact to Influence Antidepressant Efficacy.

The importance of identifying relevant indicators of antidepressant efficacy is highlighted by the low response rates to antidepressant treatment for depression. The ABC gene family, encoding ATP-dependent transport proteins facilitating the transport of psychotropic drugs, has drawn attention. This study delved into the relationship between antidepressant efficacy and seven single nucleotide polymorphisms of ABCB1 and ABCB6 genes. A total of 549 depressed patients participated in the study, and all completed a 6-week course of antidepressant treatment. Cognitive function was assessed at baseline and post-treatment. Patients were categorized based on post-treatment HAMD-17 scores (with HAMD≤7 indicating remission), and comparisons were made between different groups in terms of allelic gene frequencies and genotypes. Logistic regression was used to explore the interaction between cognitive function and genotype on efficacy. Dual-luciferase reporter assays were performed to compare the regulatory effects of rs1109866 allele variants on the ABCB6 promoter. There were no notable differences in allelic gene frequencies and genotypes between the remission and non-remission groups. Nonetheless, a significant interaction was identified between the rs1109866 genotype and language fluency-related indicators concerning efficacy (p=0.029) before correction. The dual-luciferase reporter assays demonstrated markedly higher fluorescence intensity of rs1109866-C compared to that of rs1109866-T (p<0.001). Relying solely on genetic polymorphisms of ABC family genes as predictors of antidepressant treatment response may not be sufficient. However, the interaction between the rs1109866 and cognition plays a pivotal role. The potentially enhanced transcriptional activity of rs1109866-C might offer insight into its impact on antidepressant efficacy.

Signal Transducer and Activator of Transcription 4 (STAT4) Association with Pituitary Adenoma

Background/Objectives: This study aims to investigate whether Signal Transducer and Activator of Transcription 4 (STAT4) influences the anti-tumor immune response and is possibly involved in the initiation or relapse of pituitary adenomas (PAs) by examining STAT4 polymorphisms and serum levels. This research seeks to uncover potential connections that could inform future therapeutic strategies and improve our understanding of PA pathogenesis. Materials and Methods: This study was conducted at the Laboratory of Ophthalmology, Lithuanian University of Health Sciences. DNA was extracted from peripheral venous blood samples, and the genotyping of four STAT4 SNPs (rs7574865, rs10181656, rs7601754, and rs10168266) was performed using real-time PCR with TaqMan® Genotyping assays. The serum STAT4 levels were measured via ELISA, and the optical density was read at 450 nm. Genotype frequencies, allele distributions, and serum STAT4 levels were statistically analyzed to assess associations with pituitary adenoma occurrence. Results: A binary logistic regression revealed that the STAT4 rs7574865 GT + GG genotypes vs. TT were associated with 1.7-fold increased odds of PA occurrence under the dominant genetic model (p = 0.012). The stratification by gender showed no significant associations in females; however, in males, the STAT4 rs10168266 CC + CT genotypes compared to TT were linked to 2.5-fold increased odds of PA under the dominant genetic model (p = 0.005). STAT4 rs10181656, rs7574865, rs7601754, and rs10168266 were analyzed to evaluate the associations with the pituitary adenoma size. We found that the STAT4 rs7574865 GG genotype was statistically significantly less frequent in the macro PA group compared to in the reference group (p = 0.012). For PA relapse, the rs7574865 G allele was less frequent in the PA group without relapse (p = 0.012), and the GT + GG genotypes were associated with a 1.8-fold increase in the PA group without relapse occurrence (p = 0.008). The serum STAT4 levels were higher in the PA patients compared to those of the reference group (p &lt; 0.001). Elevated STAT4 serum levels were observed in PA patients with the STAT4 rs10181656 CC or CG genotypes (CC: p = 0.004; CG: p = 0.023), and with the rs7574865 GG or GT genotypes (GG: p = 0.003; GT: p = 0.021). The PA patients with the STAT4 rs7601754 AA genotype exhibited higher serum levels compared to those of the reference group (p &lt; 0.001). Similarly, higher serum levels were found in the PA patients with the STAT4 rs10168266 CC or CT genotypes (CC: p = 0.004; CT: p = 0.027). A haplotype frequency analysis revealed no statistically significant results. Conclusions: The STAT4 genotypes were significantly associated with the PA occurrence, size, and relapse. Elevated serum STAT4 levels were observed in the PA patients, highlighting its potential role in PA pathogenesis.

Association of a non-synonymous variant of MLH3 gene involved in meiotic recombination with conception rate of Japanese Black cattle

Context Conception rate, which is an important parameter to evaluate female fertility, has been gradually decreasing in Japanese Black cattle during the past decades. Meiosis is an essential biological process in gamete formation and meiotic failure could be a cause of infertility or reduced fertility in mammals. Of note, single nucleotide polymorphisms (SNPs) in the MLH3 gene involved in meiotic recombination were reported to affect the genome-wide recombination rate of meiosis in cattle. Aims The present study was conducted to investigate the association of SNPs in the MLH3 gene with conception rate in Japanese Black cattle. Methods On the basis of the reproductive data of 2045 Japanese Black cattle born from 1990 to 2009, we selected two groups of the reproductive females with high conception rate (n = 103) and low conception rate (n = 109). Then, we genotyped the SNPs in MLH3 gene in both reproductive groups by sequencing and polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP). The significant association of SNPs with conception rate in Japanese Black cattle was estimated by Fisher’s exact test, by using R commander. Key results We found the presence of five SNPs of MLH3 gene in Japanese Black cattle, including non-synonymous variants of MLH3 N408S that has been reported to be involved in meiotic recombination rate and MLH3 S591G newly identified in the present study. Comparison of genotype distributions and allele frequencies of the MLH3 N408S between high and low conception-rate groups indicated a significant difference between these groups, suggesting that this SNP is associated with conception rate. However, there is no significant difference between MLH3 S591G with conception rate in Japanese Black cattle. Conclusions We found a significant association between a non-synonymous variant of MLH3 N408S and conception rate, suggesting that this SNP can be a potential marker for selecting the Japanese Black cattle for improving fertility. We also identified a novel non-synonymous variant of MLH3 S591G in Japanese Black cattle. Implications These findings will be informative for future marker-assisted selection to improve the fertility of Japanese Black cattle. This is the first report of a genetic variant implicated in meiotic recombination being linked to female fertility in cattle.

The impact of CTLA-4 gene polymorphism on the content of organ-specific antibodies in patients with autoimmune thyroiditis among the population of Azerbaijan

BACKGROUND: The risk of developing immune tolerance to self-antigens in autoimmune thyroiditis is largely associated with a mutation in the CTLA-4 gene, the product of which negatively regulates T-cell activity. AIM: To study the A49G (rs231775) CTLA-4 polymorphism in patients with autoimmune thyroiditis in a sample of Azerbaijani residents and the effect of the frequency of identified alleles and genotypes on the level of antibodies to thyroid peroxidase and thyroglobulin. MATERIAL AND METHODS: A study was conducted in 2021–2023 involving 170 patients with autoimmune thyroiditis and 65 individuals without thyroid pathology or other autoimmune diseases, who formed a comparison group. The groups were matched by gender and age. Based on the patient history, thyroid status study results, thyroid ultrasound data, and organ-specific antibody assessment, the patients were diagnosed with autoimmune thyroiditis. The routine thyroid status study results in the comparison group were within normal limits. Genotyping of the A49G (rs231775) polymorphism was performed using polymerase chain reaction followed by digestion of the reaction product with PspEI restriction endonuclease. The results of the quantitative studies were presented as the median (Me) and interquartile range (25th quartile; 75th quartile). The correspondence of genotype frequencies to the Hardy–Weinberg equilibrium was assessed using the χ2 criterion. RESULTS: The results revealed a statistically significant increase in the frequency of the G allele (48%) compared to the control group [33.8%; p=0.039, χ2=4.27, odds ratio (OR) 1.865, 95% confidence interval (CI) 1.028–3.382] and a decrease in the frequency of the A allele (51.2%) relative to the control group (66.1%; p=0.0389, χ2=4.27, OR=0.536, CI=0.296–0.973). In 22.4% of patients with the GG genotype (p=0.005, χ2=7.86, OR=0.237, 95% CI=0.088–0.635) and 55.6% of patients with the G allele (p=0.0012, χ2=10.43, OR=0.360, 95%, CI=0.192–0.674), thyroglobulin antibody titers were more than 100 IU/ml. Thyroid peroxidase antibody levels of 100 IU/ml or more were recorded in 22.7% of study participants with the GG genotype (p=0.030) and 50.0% with the G allele (p=0.048). CONCLUSION: Elevated titers of antibodies to thyroid peroxidase and thyroglobulin were detected in patients from the population of Azerbaijan with the G allele and homozygous genotype GG of the +49A/G polymorphism of the CTLA-4 gene.

Allele frequencies and genotype distribution of three metformin transporter polymorphisms in Mexican population and their application in pharmacogenomics of type 2 diabetes

Allele frequencies and genotype distribution of three metformin transporter polymorphisms in Mexican population and their application in pharmacogenomics of type 2 diabetes

Protective Effect of EBF Transcription Factor 1 (EBF1) Polymorphism in Sporadic and Familial Spontaneous Preterm Birth: Insights from a Case-Control Study.

This study investigated the potential role of specific single-nucleotide polymorphisms (SNPs) in the genes Astrotactin 1 (ASTN1), EBF Transcription Factor 1 (EBF1), Eukaryotic Elongation Factor, Selenocysteine-tRNA Specific (EEFSEC), Microtubule-Associated Serine/Threonine Kinase 1 (MAST1), and Tumor Necrosis Factor Alpha (TNF-α) to assess whether these genetic variants contribute to the risk of spontaneous preterm birth (sPTB). A case-control study was conducted involving 573 women from Croatia and Slovenia: 248 with sporadic sPTB (positive personal and negative family history of sPTB before 37 weeks' gestation), 44 with familial sPTB (positive personal and family history of sPTB before 37 weeks' gestation), and 281 control women. The analysis of ASTN1 rs146756455, EBF1 rs2963463, EBF1 rs2946169, EEFSEC rs201450565, MAST1 rs188343966, and TNF-α rs1800629 SNPs was performed using TaqMan real-time PCR. p-values were Bonferroni-adjusted for multiple comparisons. EBF1 SNP rs2963463 was significantly associated with sPTB (p adj = 0.03). Women carrying the CC genotype had a 3-4-times lower risk of sPTB (p adj < 0.0001). In addition, a significant difference in the frequency of the minor C allele was observed when comparing familial sPTB cases with controls (p adj < 0.0001). All other associations were based on unadjusted p-values. The minor T allele of EBF1 SNP rs2946169 was more frequent in sPTB cases overall than in controls, especially in sporadic sPTB (p = 0.045). Similarly, the CC genotype of ASTN1 SNP rs146756455 was more frequent in sporadic sPTB cases compared to controls (p = 0.019). Finally, the TNF-α SNP rs1800629 minor A allele and AA genotype were more common in the familial sPTB group compared to sporadic sPTB and controls (p < 0.05). The EBF1 SNP rs2963463 polymorphism showed a protective effect in the pathogenesis of sPTB, particularly in women carrying the CC genotype. Moreover, EBF1 SNP rs2946169 and ASTN1 SNP rs146756455, as well as TNF-α SNP rs1800629, were associated with an increased risk of sPTB, representing suggestive potential risk factors for sporadic and familial sPTB, respectively.

The association of serum level and polymorphisms of IFN-γ (rs2069705) with the susceptibility to cutaneous leishmaniasis

Leishmaniasis, a broad range of parasitic diseases, caused by Leishmania which is a flagellated intracellular protozoan parasite of the family Trypanosomatidae. The severity of leishmaniasis diseases ranges from minor cutaneous lesions to severe visceral illnesses that can be disfiguring and life-threatening. Cytokines are glycoprotein molecules produced by various cells in response to various immunological triggers. They regulate the body’s innate and adaptive immunological responses. The aim of this study was to clarify the association of serum level and polymorphisms of IFN-γ with susceptibility to cutaneous leishmaniasis (CL). The whole blood 200 samples were collected from patients and controls from Diyala Governorate/ Iraq from October 2022 to February 2023 which were used to measure IFN-γ polymorphisms using High Resolution Melting technique. Enzyme-linked immunosorbent assay was used to detect the serum level of IFN-γ. The findings of this investigation showed that the IFN-γ serum concentration elevated significantly in patients compared to controls (P < 0.01). Also, the study found that the highest mean level IFN-γ concentrations were found in adults aged 46–55 years old for patients compared with controls with significant differences (P < 0.01). While, no significant differences were observed in the rest age groups except children aged 5–15 years old. Additionally, significant differences between patients and controls were revealed by polymorphisms data in all genetic models for genotypes GA, AA, (GA + AA) and allele A with (P < 0.01) and OR > 1. However, the distribution of IFN-γ serum levels by SNP (rs2069705) demonstrated no differences between genotypes except GG genotype which has significant differences for patients comparing to the same genotype in controls. Taking together, the SNP for IFN-γ (rs2069705) could be a risk factor for susceptibility infection with CL. Also, considered the mutant allele A as a risk allele and genotype AA in codominant genetic model as more risk factor than the genotype GA.

Distribution of genotypes by the growth diferential factor 9 (GDF-9) gene locus in the romanov breed sheep population

The FecG gene, also known as GDF-9 (growth factor differentiation factor 9), plays an important role in regulating reproductive function in mammals. This paper presents the results of a study of a point mutation in the differential growth factor gene in Romanov breed sheep. Mutations in exon 1 of the GDF-9 gene can lead to disturbances in ovarian development and ovulation, resulting in infertility or reduced reproductive capacity in animals. The object of the study was Romanov breed sheep in a sample of 30 individuals. For DNA extraction, venous blood samples were taken from the jugular vein. In Romanov breed sheep for the GDF-9 gene, it was found that at the G1 locus of this gene there are two alleles – G and A. Three genotypes were also identified: GG (254 bp/117 bp), AG (410bp/254/117 bp) and AA (410 bp/410 bp). The observed χ2 criterion was less than expected, therefore, the empirical and theoretical frequencies do not differ significantly, and deviations from the distribution according to the Hardy-Weinberg law are not observed. The observed heterozygosity index (Ho) was 0.27. Allele frequencies were 0,8 for G and 0,2 for A. For genotypes the following were obtained: GG – 0,66, GA – 0,27 and AA – 0,07.It can be noted that the data on the frequencies of alleles and genotypes in the population of Romanov breed sheep differ from the results for the Kulunda fine-wool, Dagestan mountain, Salsk, Lacaune and Merino breeds. The research results can be used to monitor changes in allele frequencies and genotypes in sheep during the selection process.

Genotype distribution and allele frequency of thioester-containing protein 1(Tep1) and its effect on development of Plasmodium oocyst in populations of Anopheles arabiensis in Ethiopia.

Thioester-containing protein 1 (TEP1) is a crucial component of mosquitoes' natural resistance to parasites. To effectively combat malaria, there is a need to better understand how TEP1 polymorphism affects phenotypic traits during infections. Therefore, the purpose of this study was to determine the Tep1 genotype frequency in malaria vector populations from south-western Ethiopia and investigate its effect on Plasmodium oocyst development in Anopheles arabiensis populations. Using standard dippers, Anopheles mosquito larvae were collected from aquatic habitats in Asendabo, Arjo Dedessa, and Gambella in 2019 and 2020. Collected larvae were reared to adults and identified morphologically. Female An. gambiae s.l. were allowed to feed on infected blood containing the same number of gametocytes obtained from P. falciparum and P. vivax gametocyte-positive individuals using indirect membrane feeding methods. Polymerase Chain Reaction (PCR) was used to identify An. gambiae s.l. sibling species. Three hundred thirty An. gambiae s.l. were genotyped using Restricted Fragment Length Polymorphism (RFLP) PCR and sub samples were sequenced to validate the TEP1 genotyping. Among the 330 samples genotyped, two TEP1 alleles, TEP1*S1 (82% frequency) and TEP1*R1 (18% frequency), were identified. Three equivalent genotypes, TEP1*S1/S1, TEP1*R1/R1, and TEP1*S1/R1, had mean frequencies of 65.15%, 2.12%, and 32.73%, respectively. The nucleotide diversity was ranging from 0.36554 to 0. 46751 while haplotype diversity ranged from 0.48871 to 0.63161, across all loci. All sample sites had positive Tajima's D and Fu's Fs values. There was a significant difference in the TEP1 allele frequency and genotype frequency among mosquito populations (p < 0.05), except populations of Anopheles arabiensis from Asendabo and Gambella (p > 0.05). In addition, mosquitoes with the TEP1 *RR genotype were susceptible and produced fewer Plasmodium oocysts than mosquitoes with the TEP1 *SR and TEP1 *SS genotypes. The alleles identified in populations of An. arabiensis were TEP1*R1 and TEP1*S1. There was no significant variation in TEP1*R1 allele frequency between the high and low transmission areas. Furthermore, An. arabiensis carrying the TEP1*R1 allele was susceptible to Plasmodium infection. Further studies on vector-parasite interactions, particularly on the TEP1 gene, are required for vector control techniques.

The Evaluation of the Genetic Polymorphisms of TERT (rs2736100) and MUC5B (rs35705950) in Idiopathic Pulmonary Fibrotic patients

Background: Polymorphisms of the TERT and MUC5B genes have been consistently associated with idiopathic pulmonary fibrosis (IPF) in recent genome-wide genetic studies. In Iraq, we did not find research on the role of these polymorphisms in respiratory disorders, so we conducted this study to evaluate the genetic polymorphisms of TERT (rs2736100) and MUC5B (rs35705950) in IPF patients in Iraq. Method: The current study was a case-control study that included 70 patients who were diagnosed with IPF, in addition to, 70 healthy control groups who had no history or clinical evidence of IPF or asthma. blood samples from participants were obtained for DNA extraction, and T-ARMS-PCR was used to determine genetic polymorphisms of TERT (rs2736100) and MUC5B (rs35705950). Result: Current study showed that the mutant/minor homogenous genotype AA and allele A of TERT (rs2736100) appeared at a higher rate in patients (47% and 87% respectively) compared to control (38.5% and 53% respectively), as this indicator appeared as an effective factor (EF = 0.139 and 0.242 respectively), while the wild/major homogenous genotype CC and allele C were appeared in control at a rate of 38.5% and 50% respectively and in patients at rate 23% and 50% respectively. The results of MUC5B (rs35705950) G/T polymorphism showed that the mutant/minor TT genotype and T allele were associated with the occurrence of the disease (EF = 0.177 and 0.192 respectively) while the wild /major GG genotype and G allele appeared as a protective factor (PF= 0.243 and 0.375 respectively) for the control group. Moreover, most of the smoking patients were carriers of the mutant homogenous genotypes of TERT (rs2736100) and MUC5B (rs35705950). Conclusion: TERT (rs2736100) and MUC5B (rs35705950) polymorphisms are significantly associated with IPF, especially among smokers patients.

B-269 Development and CYP3A4 Characterization of a Population-based Urinary Buprenorphine and Norbuprenorphine Nomogram

Abstract Background Buprenorphine (Bup), routinely prescribed for opioid use disorder, metabolizes to norbuprenorphine (NBup) primarily via cytochrome P450 (CYP) 3A4. Confirmation of urinary Bup and NBup helps monitor patient adherence to therapy and potential misuse. This study aims to develop and characterize a population-based urinary NBup/Bup nomogram using pharmacogenetics (PGx) to facilitate opioid result interpretations. Methods Adult urinary Bup and NBup results between 09/01/2022 and 09/30/2023 at UNC Health were retrieved from the EMR. Results outside the clinically reportable range (CRR; 5-25,000 ng/mL) were assigned the lower or upper CRR value, respectively. A scatterplot of Bup versus NBup/Bup on logarithmic scale was generated using Excel. Buffy coats from 14 EDTA whole blood samples were extracted and isolated using EasySep buffer (StemCell) with centrifugation at 8000rpm for 10 minutes without braking and stored at -80°C until shipment to DHMC. Genomic DNA was extracted using an EZ1 DNA procedure (Qiagen) and libraries (Agilent SureSelect) were prepared by hybridization capture of a custom PGx panel. Paired-end sequencing was performed on a MiSeq prior to diplotype-metabolizer function assignments in AUGMET. 22 CYP3A4 gene hotspots were detected by NGS and analyzed for gene-drug-variant relationships. Results 3593 results from 896 patients were retrieved. The NBup/Bup nomogram revealed 3 subgroups from this population (Figure). CYP3A4 genotyping showed 13 wildtype calls and 1 CYP3A4 *1/*22 star allele genotype, with reduced enzyme activity. Wildtype results corresponded with Bup/NBup in subgroups 1(n=1), 2 (n=11) and 3 (n=1); CYP3A4 *1/*22 result corresponded with subgroup 3. Conclusions We developed a novel NBup/Bup nomogram revealing 3 subgroups in our patient population. Overlap of wildtype CYP3A4 in subgroups 1, 2 and 3 as well as CYP3A4 *1/*22 genotype in subgroup 3 suggest the NBup/Bup subgroups are independent of CYP3A4 phenotype. The characterization of population-based urinary NBup/Bup nomogram shows promise for aiding in opioid result interpretations.

The 14-bp insertion/deletion as a promising gene polymorphism to understand cancer risk: Evidence from a systematic review and comprehensive meta-analysis

BackgroundHLA-G is associated with cancer cell escape. The 3’UTR polymorphism is involved in the regulation of membrane-bound HLA-G and soluble HLA-G proteins. The aim of our study was to assess the association of the HLA-G 14-bp insertion (I)/deletion (D) polymorphism with cancer susceptibility and its interaction with clinicopathological features and environmental factors. MethodsA meta-analysis was performed to investigate the association between the HLA-G 14-bp I/ D polymorphism and different types of cancers according to the Prisma guidelines. ResultsThirty-nine publications that studied the 14-bp I/D polymorphism in cancers met our inclusion criteria. The findings of the meta-analysis showed a significant association between the 14-bp I/D polymorphism and cancer risk under the allelic contrast model D vs. I (OR=1.112, 95% CI= 1.009-1.227, P = 0.033) suggesting that the D allele was a risk factor for cancer susceptibility. Stratification by cancer type demonstrated a significant association of the 14-bp I/D polymorphism with breast cancer under the D vs. I contrast allele model (OR=1.267, 95% CI= 1.028-1.563, P=0.027). No significant association was found for digestive, cervical, haematological and thyroid cancers. A comparison of groups stratified by ethnicity showed a significant association for Caucasians under the D vs. I model (OR=1.147, 95% CI= 1.002-1.313, P=0.047); and for mixed ethnicities under the DD+DI vs. II (OR=1.388, 95% CI= 1.083-1.780, P=0.010) and DI vs. II (OR= 1.402, 95% CI=1.077-1.824, P=0.012) models. A comparison of cancer risks associated with the 14-bp I/D polymorphism according to geographic location revealed significant risks for the D allele and DD genotype in North Africa, the Middle East and South America. However, no significant susceptibility to cancer associated with the 14-bp I/D polymorphism was shown for Europe and North Asia. The findings of a meta-analysis of subgroups by disease stage showed a significant association in both early and advanced stages, with the 14-bp deletion variant being a risk factor. Similarly, a significant cancer risk was shown for the 14-bp deletion variant in both low- and high-grade cancers. Finally, the risk associated with the 14-bp I/D polymorphism was higher in cancers with concomitant viral infection with human papillomavirus (HPV), hepatitis B virus (HBV) or hepatitis C virus (HCV). ConclusionThe findings of the overall meta-analysis showed a significant association between the HLA-G 14-bp I/D polymorphism and cancer susceptibility. The findings stratified analysis and subgroup comparisons showed that the 14-bp I/D deletion variant was associated with an increased risk of breast cancer. The HLA-G 14-bp I/D polymorphism may interact with individual and clinicopathological factors to alter cancer risk. These promising findings for cancer risk provide the basis for further studies that explore 14bp I/D polymorphism in cancer screening and immunotherapeutic approach.

Strong associations between the FGF-2 gene and productivity traits of Holstein-Friesian dairy cattle

Sustainability in dairy cattle farms depends on the efficiency of milk yield and reproductive traits. Thus, this study aimed to investigate the effect of the FGF-2/Csp6I gene and major environmental factors on these traits in Holstein-Friesian cattle. A total of 212 whole blood samples were collected from the Vena coccygea of cattle and the data obtained from these samples were used in all statistical analyses. Then, the restriction fragment length polymorphism (RFLP) method (determination of genotypes) was conducted and programs including PopGene (allele and genotype frequencies), Minitab (association analyses) and MTDFREML (variance components and genetic parameters) were used. Alleles A (0.4269) and G (0.5731) as well as genotypes AA (0.174), AG (0.505) and GG (0.321) were found, indicating that the population is polymorphic and in Hardy-Weinberg equilibrium (P > 0.05). The effect of the Csp6I polymorphism of FGF-2 gene on peak milk yield (PMY) (P < 0.01); lactation milk yield (LMY), milking time (MT), 305-day and 200-day lactation milk yield (LMY305 and LMY200), average daily milk yield (ADMY) (P < 0.05); 100-day lactation milk yield (LMY100), age of using in first breeding (AUFB) and number of inseminations per conception (NIPC) (P < 0.10) were significant. The heritability of milk yield traits and the correlation between direct and maternal heritability for reproductive traits were high. Furthermore, the breeding value of PMY was higher for the AA genotype (0.745 ± 0.292) than for the AG genotype (−0.268 ± 0.171) (P < 0.05). As a result, the A allele and AA genotype for the FGF-2/Csp6I gene had an increasing effect on milk yield without compromising reproductive performance in Holstein-Friesian dairy cattle.

MOIRE: a software package for the estimation of allele frequencies and effective multiplicity of infection from polyallelic data.

Malaria parasite genetic data can provide insight into parasite phenotypes, evolution, and transmission. However, estimating key parameters such as allele frequencies, multiplicity of infection (MOI), and within-host relatedness from genetic data is challenging, particularly in the presence of multiple related coinfecting strains. Existing methods often rely on single nucleotide polymorphism (SNP) data and do not account for within-host relatedness. We present Multiplicity Of Infection and allele frequency REcovery (MOIRE), a Bayesian approach to estimate allele frequencies, MOI, and within-host relatedness from genetic data subject to experimental error. MOIRE accommodates both polyallelic and SNP data, making it applicable to diverse genotyping panels. We also introduce a novel metric, the effective MOI (eMOI), which integrates MOI and within-host relatedness, providing a robust and interpretable measure of genetic diversity. Extensive simulations and real-world data from a malaria study in Namibia demonstrate the superior performance of MOIRE over naive estimation methods, accurately estimating MOI up to seven with moderate-sized panels of diverse loci (e.g. microhaplotypes). MOIRE also revealed substantial heterogeneity in population mean MOI and mean relatedness across health districts in Namibia, suggesting detectable differences in transmission dynamics. Notably, eMOI emerges as a portable metric of within-host diversity, facilitating meaningful comparisons across settings when allele frequencies or genotyping panels differ. Compared to existing software, MOIRE enables more comprehensive insights into within-host diversity and population structure. MOIRE is available as an R package at https://eppicenter.github.io/moire/.

Inflammatory Factor Interleukin-6 and its Correlation with Rheumatoid Arthritis: A Meta-analysis

Introduction: at present, there are inconsistent research findings regarding the precise relationship between IL-6 gene polymorphisms (GPMs) and rheumatoid arthritis (RA). This work employed meta-analysis (MA) methodology to systematically evaluate the correlation between IL-6 GPMs and susceptibility to RA. Material and Methods: this study comprehensively searched multiple databases from inception to March 31, 2024. The search utilized keywords including “IL-6,” “Interleukin-6,” “Cytokines,” “Autoimmune diseases,” “Arthritis,” “rheumatoid arthritis,” “Inflammation,” “genetic polymorphism,” and “genetic variation.” Included studies focused on patients diagnosed with rheumatoid arthritis (RA), with healthy individuals or those without RA-related diseases as controls. The study designs encompassed cohort studies and case-control studies. Genetic frequency distributions of IL-6 gene rs1800795 (G-174C), rs1800796 (G-572C), and rs1800797 (G-597A) polymorphic sites were statistically analyzed. Quality of included studies was assessed. The preliminary assessment of literature heterogeneity was conducted. Quantitative assessment of heterogeneity results was performed using the I2 statistic in RevMan5.3. Publication bias (PB) assessment was conducted. Result: the study included a total of 21 articles, comprising 9,772 participants, with 4,679 cases diagnosed with RA and 5,093 individuals in the control (CT) group. The IL-6 gene allelic model (G vs C) exhibited a notable association with RA [OR=0.66, 95%CI: 0.51∼0.87, Z=3.02, P=0.003]. In Southeast Asian populations, IL-6 gene rs1800795 (G-174C) genotype (CC) demonstrated a considerable correlation with RA [OR=15.23, 95%CI: 3.53∼65.67, P=0.00003]. IL-6 gene rs1800795 (G-174C) genotype (CG) was associated with RA [OR=1.54, 95%CI: 1.10∼2.17, Z=2.48, P=0.01], with only the Asian population showing an observable correlation [OR=6.55, 95%CI: 1.28∼33.45, P=0.02]. Additionally, IL-6 rs1800795 (G-174C) genotype (GG) was associated with RA [OR=0.66, 95%CI: 0.49∼0.91, Z=2.55, P=0.01], with notable associations observed in the Asian [OR=0.17, 95%CI: 0.03∼0.83, P=0.03] and mixed populations [OR=1.29, 95%CI: 1.011.65, P=0.04]. No correlation was found between rs1800796 (G-572C) and rs1800797 (G-597A) GPMs and RA (P>0.05). ConclusionIL-6 gene rs1800795 (G-174C) allelic model and genotypes (CC, CG, GG) were all associated with susceptibility to RA, with the G allele model being susceptible in Southeast Asian populations, and genotypes (CG and GG) being susceptible in Asian populations. However, there was neglectable correlation between rs1800796 (G-572C) and rs1800797 (G-597A) GPMs and susceptibility to RA.

Genetic Signatures: CD44 Single-Nucleotide Polymorphisms Affect Cell Surface Expression and Elevate Risk in Head and Neck Squamous Cell Carcinoma.

This study aimed to investigate the impact of single-nucleotide polymorphisms (SNPs) in the CD44 gene, specifically in the 3'UTR region (rs13347) and intronic region (rs187115), on the cell surface expression of CD44 protein and the risk of development of head and neck squamous cell carcinoma (HNSCC). The study involved analysis of 85 samples and 85 healthy controls. Immunohistochemistry (IHC) and flow cytometry were used to assess cell surface protein expression using CD44 antibody. DNA from formalin-fixed paraffin-embedded tissue sections was isolated and amplified using targeted primers. Sanger sequencing of the resultant amplified products was performed to determine the genotypes of the CD44 rs13347 and rs187115 SNPs. GTEx and RegulomeDB were queried to evaluate the genotypic effects of these variants on target gene expression and regulation. A comparison between patients with HNSCC and healthy controls revealed a significant association between CD44 rs13347 and an increased risk of HNSCC in all the analyzed models, especially the TT genotype showed a significantly higher risk with an odds ratio of 8.69 (95% CI, 2.35 to 32.09; P = .0003). However, no significant association was found between CD44 rs187115 and HNSCC in any of the models analyzed (all P > .05). Other notable findings included significant associations between CD44 rs13347 genotype and age (P = .031), number of CD44-positive tumor cells (P = .049), CD44 staining intensity (SI; P = .039), and CD44 immunoreactivity score (IRS) status (P = .019). The T allele and homozygous TT genotype of CD44 rs13347 SNP were associated with increased susceptibility to HNSCC and decreased proportion of CD44-positive tumor cells, low SI, and reduced IRS.

Variants in the N-acetyltranferase 2 gene, acetylator phenotypes and their association with tuberculosis: Findings in Peruvian patients

BackgroundTuberculosis (TB) is a highly prevalent chronic infectious disease in developing countries, with Peru being one of the most affected countries in the world. The variants of the N-acetyltransferase 2 (NAT2) gene are related to xenobiotic metabolism and have potential usefulness in TB studies. AimTo determine whether NAT2 gene variants and acetylator phenotypes are associated with active TB in Peruvian patients. MethodsThis study included cases (patients with TB) and controls (population-based data). First, DNA isolation and the rs1799929, rs1799930, and rs1799931 variants of the NAT2 gene were identified using sequencing methods. Subsequently, the acetylator phenotypes, namely slow (SA), intermediate (IA), and rapid acetylation (RA), were also analyzed. ResultsThe comparison of the frequencies of the rs1799931 variant in the cases and controls revealed significant differences. Risk factors were found for both the A allele (p = 0.00; odds ratio [OR] = 3.04, 95 % confidence interval [CI]: 1.88–4.9) and AG genotype (p = 0.00; OR = 5.94, 95 % CI: 3.17–11.09). In addition, the non-rapid acetylator phenotype (SA + IA) was also found to be a risk factor (p = 0.016; OR = 3.16, 95 % CI: 1.29–7.72). ConclusionThe A allele, GA heterozygous genotype of the rs1799931 variant of the NAT2 gene, and SA + IA acetylator phenotype showed an association with increased risk for the development of TB. In addition to xenobiotic metabolism, other metabolic and immunological functions of NAT2 have also been postulated to confer susceptibility to TB in the Peruvian population owing to its characteristic high Native American component.