Association between ADCY9 Gene Polymorphisms and Ritodrine Treatment Outcomes in Patients with Preterm Labor

The purpose of this study was to investigate the genetic effects of ADCY9 on ritodrine responses in patients with preterm labor. Five single nucleotide polymorphisms (SNPs) of the ADYC9 gene in 163 patients in preterm labor were genotyped: rs879619, rs2601796, rs2531988, rs2531995, and rs2230739. Additionally, rs598961 of the PDE4B gene and rs1042719 of the ADRB2 gene were included for analysis. Patients with CC genotype of ADCY9 rs879619 had a 2.0-fold (95% confidence interval [CI]: 1.3, 3.2) higher hazard of time to delivery than T allele carriers. Patients with combined genotypes of CC in ADCY9 rs879619, AA in PDE4B rs598961, and GC, CC in ADRB2 rs1042719 showed a greater hazard of time to delivery than patients with other combinations (adjusted hazard ratio [AHR] 3.2; 95% CI: 1.7, 6.3), whereas patients carrying the C allele of ADCY9 rs2531995, G allele of PDE4B rs598961, and GG genotype of ADRB2 rs1042719 had a lower hazard of time to delivery than patients carrying other genotypes (AHR 0.4; 95% CI: 0.2, 0.7). Regarding ritodrine-induced adverse drug events (ADEs), height less than 160 cm and CC genotype of ADCY9 rs2531995 showed a greater risk of ADEs. The results of our study suggest that ADCY9 polymorphisms could affect the efficacy and safety of β2-adrenergic agonists.

PSVI-15 Combined effect of C73T × C528T polymorphisms in the leptin gene with quantitative and qualitative indicators of meat productivity

The LEP is a highly polymorphicgene and it is associated with genetic differences in various productivetraits in cattle. The aim of research was to study the combined effect of C73T and C528T polymorphisms in leptin gene on meat productivity and carcass grade in Aberdeen-Angus cows and heifers. Heifers (n = 49) were slaughtered at the age of 20 months and cows (n = 30) after the first calving (3 years). There were seven haplotypes C73T (GenBank AF120500) × C528T (GenBank AB070368) identified in cows with different frequency. The maximum frequency was established in combined genotypes CT/CT (0.37), TT/CC (0.27) and CT/CC (0.13). The most massive carcasses (337.5 kg) were obtained from cows-carriers of the CT/CC haplotype, which exceeded their peers by 14.8–24.7 kg (4.59–7.90%; P >0.05). However, cows carrying the CT/CC genotype had a minimum carcass yield of 49.8%. There were eight haplotypes identified in heifers. The highest frequency was in combinations CT/CT (0.26), TT/CC (0.20), CC/TT (0.20), CC/CT (0.12), TT/CT (0.10). Heifers carrying the TT/CT genotype were characterized by the highest live weight (568.9 kg) and carcass weight (331.2 kg), exceeding the indicators of peers by 8.9–43.5 kg (1.59–8.28%; P < 0.05, P > 0.05) and 10.9–22.2 kg (3.40–7.18%; P < 0.05, P > 0.05), respectively. The maximum carcass yield was recorded in carriers of the CT/CC haplotype (60.7%). The best carcasses grade were observedin heifers with a combination of CC/TT and CT/CT genotypes. The highest categories (Prime and TopChoice) were assigned to 70.0 and 69.2% of carcasses, respectively. The superiority of haplotype CT/CT in the quality of meat raw materials was confirmed in cows. Thus, the combination of C73T and C528T polymorphisms in the leptin gene is associated with intra-breed variability in live weight, carcass weight and yield, and carcass grade in Aberdeen-Angus cattle. This research was performed with financial support from the project 0526-2021-0001 of RAS.

Association of the Pro12Ala, C161-T polymorphisms in the PPARγ2 gene with obesity in Han nationality of Yunnan Plateau in Southwest China

Background Obesity is considered a major public health problem in the world. At present, the association of single nucleotide polymorphisms (SNPS) Pro12Ala and C161-T in peroxisome proliferator-activated receptor gamma 2 (PPARγ2) gene with obesity is still controversial. The aim of this study is to evaluate the relationship between the Pro12Ala and C161-T polymorphisms of PPARγ2 gene and obesity among Han nationality of Yunnan Plateau in Southwest China. Methods The genotypes of 284 extremely overweight patients, 475 obese patients and 759 normal controls from Yongsheng County of Yunnan Province (China) were analyzed. The Pro12Ala and C161-T genotypes of PPARγ2 were detected by SNaPshot genotyping assay. The data were analyzed statistically. Results The overall prevalence of obesity was 4.99% and the overweight rate was 23.93% among Han nationality in Yongsheng, Yunnan Province. Statistical analysis showed that there were no significant differences in the Pro12Ala genotype, C161-T genotype and the two combined genotypes between the extremely overweight and the control 1, either between the obesity and the control 2 (P > 0.05). Further, the alleles of Pro12Ala and C161-T did not exhibit any signifificant association with extreme overweight or obesity among the complete sample population (P > 0.05). However, conditional logistic regression analysis showed that there was a statistically significant association between the two combined genotype of “CC + TT” and the extreme overweight after adjusting for covariates (Calculated with the combined genotype of “CC + CC ” as the reference category; P = 0.014; OR = 4.04; 95%CI = 1.33–12.33). Conclusions Our study indicates that the combined genotypes "CC + TT" of PPARγ2 Pro12Ala and C161-T were associated with an increased risk of extreme overweight, however, Pro12Ala and C161-T polymorphisms may not be the main cause of obesity in Han nationality of the Yunnan Plateau in Southwest China.

Reflection of P53 Phenotype in Tumor Tissue by Genotypic Variants in Glutathione S-Transferases: An Association with DNA Damage in Lung Adenocarcinoma

Background: Genetic deficiency of glutathione S-transferase (GST) enzymes results in accumulating carcinogens from tobacco smoke. Consequently, the elevated risk of lung carcinoma (LC) is due to increased DNA damage and mutational frequency of the P53 caretaker gene.Objective: To determine GST gene variants association with LUAD susceptibility and the relative risk of these variations developing the P53 mutation and DNA damageMethods: We analyzed genetic polymorphisms in GST-M1 (+/-), T1 (+/-), and P1 (Ile 105 Val) genes using restriction fragment length PCR. The P53 phenotype was categorized as the mutant type (>50% and 2-3 + intensity in IHC) in M1 (+/-), T1 (+/-), and P1 (Ile105Val) variants. Lymphocytic DNA damage was assessed using the comet assay. Results: The M1 (-/-) and P1 Val/Val (GG) genotypes were significantly associated with the risk of the P53 mutant phenotype (RR: 1.81, p=0.03) and (RR: 2.23, p=0.05), respectively. In contrast, GSTT1 was not associated with the P53 phenotype. GSTM1 (-/-)/ GSTP1 Ile/Ile (AA) combined genotypes showed a significant synergistic effect on the P53 phenotype (RR: 8.50, p=0.01). DNA damage was significantly associated with GST-M1 (-/-), T1 (-/-), and P1 Val/Val (GG) genotypes and smoking (p=0.001) as compared to GST-T1 (+/+)/M1 (+/+)/P1 Ile/Ile (AA) genotypes. However, P53 expression was not associated with DNA damage. Conclusion: The GSTM1 (-/-) and GSTT1 (-/-) null genotypes act as risk modifiers for LUAD and increase DNA damage. The GSTM1 (-/-)/ GSTP1 Ile/Ile (AA) combined genotype amplified 8-fold the risk of a P53 mutant phenotype.

Temporal evolution of sulfadoxine-pyrimethamine resistance genotypes and genetic diversity in response to a decade of increased interventions against Plasmodium falciparum in northern Ghana

Background Anti-malarial drug resistance remains a key concern for the global fight against malaria. In Ghana sulfadoxine-pyrimethamine (SP) is used for intermittent preventive treatment of malaria in pregnancy and combined with amodiaquine for Seasonal Malaria Chemoprevention (SMC) during the high malaria season. Thus, surveillance of molecular markers of SP resistance is important to guide decision-making for these interventions in Ghana. Methods A total of 4469 samples from uncomplicated malaria patients collected from 2009 to 2018 was submitted to the Wellcome Trust Sanger Institute, UK for DNA sequencing using MiSeq. Genotypes were successfully translated into haplotypes in 2694 and 846 mono infections respectively for pfdhfr and pfdhps genes and the combined pfhdfr/pfdhps genes across all years. Results At the pfdhfr locus, a consistently high (> 60%) prevalence of parasites carrying triple mutants (IRNI) were detected from 2009 to 2018. Two double mutant haplotypes (NRNI and ICNI) were found, with haplotype NRNI having a much higher prevalence (average 13.8%) than ICNI (average 3.2%) across all years. Six pfdhps haplotypes were detected. Of these, prevalence of five fluctuated in a downward trend over time from 2009 to 2018, except a pfdhps double mutant (AGKAA), which increased consistently from 2.5% in 2009 to 78.2% in 2018. Across both genes, pfdhfr/pfdhps combined triple (NRNI + AAKAA) mutants were only detected in 2009, 2014, 2015 and 2018, prevalence of which fluctuated between 3.5 and 5.5%. The combined quadruple (IRNI + AAKAA) genotype increased in prevalence from 19.3% in 2009 to 87.5% in 2011 before fluctuating downwards to 19.6% in 2018 with an average prevalence of 37.4% within the nine years. Prevalence of parasites carrying the quintuple (IRNI + AGKAA or SGEAA) mutant haplotypes, which are highly refractory to SP increased over time from 14.0% in 2009 to 89.0% in 2016 before decreasing to 78.9 and 76.6% in 2017 and 2018 respectively. Though quintuple mutants are rising in prevalence in both malaria seasons, together these combined genotypes vary significantly within season but not between seasons. Conclusions Despite high prevalence of pfdhfr triple mutants and combined pfdhfr/pfdhps quadruple and quintuple mutants in this setting SP may still be efficacious. These findings are significant as they highlight the need to continuously monitor SP resistance, particularly using deep targeted sequencing to ascertain changing resistance patterns.

Distributive characteristics of the CYP2C9 and AGTR1 genetic polymorphisms in Han Chinese hypertensive patients: a retrospective study

Background There is an individual variation in response to antihypertensive effect of the angiotensin II receptor antagonist. This study aimed to determine the allele and genotype frequencies of CYP2C9 and AGTR1 genetic polymorphisms and explore the potential role of these polymorphisms in guiding the selection of angiotensinIIreceptor antagonist in Han Chinese hypertensive patients. Methods Totally 2419 Han Chinese hypertensive patients and 126 normotensive controls were recruited in this study. Venous blood samples were collected from each patient, and the genetic polymorphisms of CYP2C9 and AGTR1 were assessed using a gene chip platform. The allele and genotype frequency of each gene and the combined genotypes in this study were analyzed respectively. Results The gene chip analysis identified an allelic frequency of 96.51% for CYP2C9*1 and 3.49% for CYP2C9*3 in the cohort of Han Chinese hypertensive patients. Statistical analysis showed that the frequency of wild-type homozygous for CYP2C9*1/*1 was 93.30%, while the frequency of heterozygous for *1/*3 or mutant homozygous for *3/*3 was 6.41% or 0.29%. Meanwhile, we detected allelic frequencies of 95.06% and 4.94% for the A and C allele of AGTR1, respectively. While the genotype frequency of wild-type homozygous for AA was 90.41%, the frequency of heterozygous for AC or mutant homozygous for CC was 9.30% or 0.29%. Notably, we observed that 84.66% (2048/2419) of the subjects exhibited a combined genotype of CYP2C9 and AGTR1 as *1/*1 + AA, while the combined genotypes *3/*3 + AC or *3/*3 + CC were not detected in hypertension patients. Besides, no significant association was found between normotensive controls and hypertensive patients, or among the three grades of hypertensive patients. Conclusions These data revealed the polymorphisms characteristics of CYP2C9 and AGTR1 in Han Chinese hypertensive patients, providing valuable information for genotype-based antihypertension therapy in prospective clinical studies in the future.

Polymorphisms of the GSTT1 and GSTM1 genes in polycystic ovary syndrome

SUMMARY BACKGROUND: This study aimed to investigate the deletion polymorphisms of the genes of the glutathione S-transferase family GSTT1 and GSTM1 in patients with Polycystic Ovarian Syndrome (PCOS), comparing them with a control population. METHODS: Blood was collected from 219 women (110 with PCOS and 109 controls) and genomic DNA was extracted. For the analysis of polymorphisms, the technique used was multiplex PCR. In the statistical analysis, the chi-square test and multiple logistic regression were used. RESULTS: There is no association between the GSTM1 null and GSTT1 null genotypes with PCOS when analyzed separately (P = 0.616 and P = 0.188). The analysis of the combined genotypes showed differences between the groups (P < 0.05), evidencing that the genotypic combination GSTT1 positive and GSTM1 negative is more frequent among patients. In the multivariate analysis, smoking was more frequent in the control group (OR = 0.22; 95% CI - 0.87-0.57; P = 0.002) while the presence of a family history of PCOS (OR = 2, 96; 95% CI - 1.54-5.68; P = 0.001) was more frequent in women with PCOS. CONCLUSIONS: In the studied sample, the deletion polymorphisms of the GSTT1 and GSTM1 genes isolated are not associated with PCOS, but in combination, they may be implicated in the etiology of the condition.

Disruption of foxc1 genes in zebrafish results in dosage-dependent phenotypes overlapping Axenfeld-Rieger syndrome

The Forkhead Box C1 (FOXC1) gene encodes a forkhead/winged helix transcription factor involved in embryonic development. Mutations in this gene cause dysgenesis of the anterior segment of the eye, most commonly Axenfeld-Rieger syndrome (ARS), often with other systemic features. The developmental mechanisms and pathways regulated by FOXC1 remain largely unknown. There are two conserved orthologs of FOXC1 in zebrafish, foxc1a and foxc1b. To further examine the role of FOXC1 in vertebrates, we generated foxc1a and foxc1b single knockout zebrafish lines and bred them to obtain various allelic combinations. Three genotypes demonstrated visible phenotypes: foxc1a−/− single homozygous and foxc1−/− double knockout homozygous embryos presented with similar characteristics comprised of severe global vascular defects and early lethality, as well as microphthalmia, periocular edema and absence of the anterior chamber of the eye; additionally, fish with heterozygous loss of foxc1a combined with homozygosity for foxc1b (foxc1a+/−;foxc1b−/−) demonstrated craniofacial defects, heart anomalies and scoliosis. All other single and combined genotypes appeared normal. Analysis of foxc1 expression detected a significant increase in foxc1a levels in homozygous and heterozygous mutant eyes, suggesting a mechanism for foxc1a upregulation when its function is compromised; interestingly, the expression of another ARS-associated gene, pitx2, was responsive to the estimated level of wild-type Foxc1a, indicating a possible role for this protein in the regulation of pitx2 expression. Altogether, our results support a conserved role for foxc1 in the formation of many organs, consistent with the features observed in human patients, and highlight the importance of correct FOXC1/foxc1 dosage for vertebrate development.

The association of EGF rs2237051 variant, serum EGF levels and generalized aggressive periodontitis: a preliminary study

Background Epidermal growth factor (EGF) is a pro-inflammatory small peptide that stimulates cell growth, proliferation and differentiation through binding to its receptor. EGF rs2237051 and serum EGF levels have been demonstrated to be related with a variety of diseases, including several tumors and inflammatory diseases. Therefore, this study aims to investigate the association of the EGF rs2237051 variant and serum EGF levels in Chinese patients with generalized aggressive periodontitis (GAgP). Material and Methods A case-control study was conducted among 216 patients with GAgP and 138 healthy controls. The clinical parameters of plaque index, probing depth, attachment loss and bleeding index were recorded. The EGF rs2237051 polymorphism was genotyped using time-of-flight mass spectrometry, and serum EGF levels were determined. Logistic and linear regression models were used to investigate the association between the genotypes of EGF rs2237051, serum EGF levels and GAgP risk. Results The AA genotype of EGF rs2237051 showed higher risk for GAgP than the combined genotypes GG and AG (adjusted OR = 1.65, 95% CI [1.06–2.57]). Increased serum EGF levels were associated with GAgP (adjusted OR = 1.18, 95% CI [1.14–1.22]). Moreover, the serum EGF level for the AA genotype was significantly higher than that for the AG/GG genotypes in patients with GAgP (adjusted β = 4.70, 95% CI [2.09–7.31]). Conclusion We demonstrated that EGF rs2237051 variant and the increased level of serum EGF were associated with the risk of GAgP, the serum EGF was up-regulated in patients with GAgP. It was indicated that serum EGF might be a biomarker of GAgP and EGF rs2237051 may be related to the genetic background of GAgP.

Interaction of miR-181b and IFNA1 Polymorphisms on the Risk of Systemic Lupus Erythematosus

Introduction. A previous work has discovered that chromosome 1q32 locus linked to the risk of systemic lupus erythematosus (SLE) and miR-181b located on the susceptibility site with downregulation inversely correlating to its target molecular interferon alpha 1 (IFNA1). The purpose of this study was to investigate the association of miR-181b and IFNA1 polymorphisms with IS risk. Methods. The miR-181b rs322931, IFNA1 rs1332190, and rs10811543 were genotyped using a Multiplex SNaPshot assay. miR-181b expression levels in plasma of SLE patients and controls were analyzed using quantitative PCR. Results. The rs322931 CT, CT/TT, and T allele exerted an increased trend of SLE risk (CT vs. CC: adjusted OR=1.71, 95% CI 1.16-2.50, P=0.01; CT/TT vs. CC: adjusted OR=1.45, 95% CI 1.08-1.95, P=0.01; T vs. C: adjusted OR=1.38, 95% CI 1.07-1.79, P=0.01). Combined genotypes of the rs322931 CT/TT+rs1332190 TT and the rs322931 CC+rs10811543 AG/AA also revealed an increased risk of SLE. Gene-gene interaction analysis showed that a three-locus model consisting of rs322931, rs1332190, and rs10811543 attributed an increased risk of SLE. Further genotype-phenotype analysis revealed that rs322931 CT/TT carriers displayed lower levels of miR-181b. Conclusions. These findings indicate that the miR-181b rs322931 may be singly and jointly responsible for the etiology of SLE by altering miR-181b expression.