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Relevance. Currently, the number of percutaneous coronary interventions continues to increase, which leads to an increase in the absolute number of restenosis cases, which is the main complication of the long-term postoperative period. The search for risk factors responsible for restenosis and artery re-narrowing mechanisms in order to prevent this complication is an important goal in interventional cardiology. Risk factors for the restenosis development include clinical, angiographic and genetic factors. An active search for biomolecular markers associated with the coronary artery restenosis is currently underway. Objective: to study the role of polymorphic variants C-174G of the IL6 gene and C-819T of the IL10 gene as a risk factor for the development of restenosis in patients after stent implantation. Materials and Methods : The study included 113 patients with stable coronary artery disease, who had previously undergone balloon angioplasty and implantation of drug-eluting stents, and 62 patients with intact arteries that were included to the control group. Statistical data processing was carried out using the R-language program and the SPSS Statistics 20 software package. Results: GG genotype for IL6 gene was associated with the development of coronary artery disease. In the subgroup of patients over 65 years of age and instent restenosis, the GG genotype was significantly less frequent. The homozygous CC genotype for IL10 gene was associated with rapid angiographic in-stent restenosis progression.

The association of glutathione S-transferase (GST) enzymes with vitiligo is inconclusive. To evaluate tissue expressions of GST isoenzymes in vitiligo patients and to compare these expressions with healthy controls, we used 26 active depigmented patches on the trunk of vitiligo patients and 20 healthy sex and age matched controls. Punch biopsies were taken from the lesioned or normal skin. Tissue expression of GST isoenzymes were analyzed immunohistochemically. Tissue expression of GSTT1, GSTA1 and GSTP1 was significantly higher in the patient group than controls. Tissue expression of GSTM1 was not significantly different between the two groups. The increased tissue expression of GSTT1, GSTA1 and GSTP1 may represent a response to excess free radical formation in vitiligo and may support the role of oxidative stress in the pathogenesis of vitiligo. WOS:000698255600001 2-s2.0-85115232607 PubMed: 34547977

The occurrence and severity of chemotherapy-induced nausea and vomiting (CINV) are influenced by many factors; this includes therapeutic factors, such as the dose, administration mode, and chemotherapeutic agent emetogenicity, as well as patient-related risk factors, such as the gender, age, alcohol consumption history, and anxiety level. However, these factors cannot fully explain the individual CINV differences. In recent years, the correlation between gene polymorphism and CINV has been a hot research topic; the present paper reviews current research on CINV-related gene polymorphisms, and the results indicate that the use of gene polymorphism for the optimization of CINV efficacy is of important clinical significance.

Previous studies have reported that the single nucleotide polymorphisms (SNPs) of SAMM50-rs738491, PARVB-rs5764455 and PNPLA3-rs738409 are associated with nonalcoholic fatty liver disease (NAFLD). However, no studies have examined the effect of interactions between these three genotypes to affect liver disease severity. We assessed the effect of these three SNPs on nonalcoholic steatohepatitis (NASH) and also examined the gene-gene interactions in a Chinese population with biopsy-confirmed NAFLD.

Introduction: Cervical cancer is the fourth most common form of cancer among women. Smoking tobacco seems to be a risk factor for the development of cervical intra-epithelial neoplasia (CIN) and cervical cancer, but the exact role of smoking in the process of cervical carcinogenesis is not known. The aim of this study is to investigate the relationship between smoking and the development of CIN and cervical cancer. Areas covered: We searched Embase, Medline, Cochrane Central, Web of Science, and Google Scholar for studies on smoking and CIN and cervical cancer, published between 2009 and 2018. The following were the outcomes: CIN3 alone, CIN2 and CIN3 combined, CIN2+, CIN3+, and cervical cancer alone. We included 49 studies in our review and 45 in our meta-analyses. Expert opinion: Based on the available evidence it can be – cautiously – concluded that smoking increases the risk of cervical abnormalities. However, the high risk of bias indicates that for future studies, it will be important to adjust for relevant predictors, to separate CIN from cervical cancer as outcome measures, and to report research methods in detail.

Aldehyde dehydrogenase 2 (ALDH2) is a key enzyme of alcohol metabolism and it is involved in the cellular mechanism of alcohol liver disease. ALDH2 gene mutations exist in about 8% of the world’s population, with the incidence reaching 45% in East Asia. The mutations will result in impairment of enzyme activity and accumulation of acetaldehyde, facilitating the progression of other liver diseases, including non-alcoholic fatty liver diseases, viral hepatitis and hepatocellular carcinoma, through adduct formation and inflammatory responses. In this review, we seek to summarize recent research progress on the correlation between ALDH2 gene polymorphism and multiple liver diseases, with an attempt to provide clues for better understanding of the disease mechanism and for strategy making.

Background: The relationship between bone metabolism-related gene polymorphisms and low bone mineral density (BMD) risk factors in female athletes is unclear. This study aimed at investigating whether the sensitivity of low BMD risk factors to BMD depends on estrogen receptor α (ERα) gene polymorphisms in Japanese female athletes. Materials and Methods: This study included 280 collegiate female athletes from 12 competitive sports (age, 19.2 ± 1.3 years). Data on sports participation, age at menarche, menstrual cycles, prior stress fractures, and prior eating disorders were obtained through a questionnaire-type survey. Sports types were classified into endurance, esthetic, aquatic, ball, and high load in consideration of exercise load characteristics. ERα gene PvuII (rs2234693) and XbaI (rs9340799) polymorphisms were analyzed by TaqMan® assay. The total body BMD was measured by dual-energy X-ray absorptiometry. Results: On multiple regression analysis, sports types, body mass index (BMI), menarche, and XbaI polymorphism remained robust independent predictors of BMD. However, prior stress fractures and menstrual cycles were excluded. In athletes carrying the XX+Xx genotype of XbaI polymorphism, sports types and BMI were associated with BMD. However, in athletes carrying the xx genotype of XbaI polymorphism, sports types, BMI, and menarche were associated with BMD. These results indicated that athletes carrying the xx genotype with delayed menarche had low BMD. Conclusions: In collegiate female athletes, participation in endurance, esthetic, and aquatic sports types and a low BMI are associated with low BMD. In addition, delayed menarche may negatively affect BMD in athletes carrying the xx type of ERα gene XbaI polymorphism.

Both excessive production of reactive oxygen species (ROS) and impaired antioxidant function are found in patients with chronic kidney disease (CKD). Therefore, individual susceptibility towards CKD can be induced by functional variations of genes encoding antioxidant regulatory (nuclear factor erythroid 2 - related factor 2 (Nrf2)) and catalytic (superoxide dismutase (SOD2) and glutathione peroxidase (GPX1)) proteins. Several types of single nucleotide polymorphisms (SNPs) have been found within the genes encoding these proteins, with Nrf2 (-617C/A), SOD2 (Ala16Val) and GPX1 (Pro198Leu) conferring impaired catalytic activity. The most unexplored gene polymorphism in CKD susceptibility, progression and survival, with only two original studies published, is the Nrf2 (-617C/A) polymorphism. The results of these studies showed that there was no individual impact of this polymorphism on the susceptibility towards end stage renal disease (ESRD) development, oxidative phenotype and mortality. However, Nrf2 had a significant role in ESRD risk and survival, when combined with other antioxidant genes. The results regarding the impact of SOD2 (Ala16Val) and GPX1 (Pro198Leu) polymorphisms on either CKD or ESRD are still inconclusive. Namely, some studies showed that patients having variant SOD2 (Val) or GPX1 (Leu) allele were at increased risk of CKD development and progression, while other studies reported only weak or no association between these polymorphisms and CKD. Surprisingly, the only study that reported an association of GPX1 polymorphism with overall/cardiovascular survival in ESRD patients showed a significant impact of low activity GPX1 (Leu/Leu) genotype on better survival. In this review, we comprehensively and critically appraise the literature on these polymorphisms related to oxidative stress in CKD patients, in order to identify gaps and provide recommendations for further clinical research and translation. New developments in the field of antioxidant polymorphisms in CKD patients could lead to better stratification of CKD patients, based on a prognostic antioxidant gene panel, and provide a more personalised medicine approach for the need of antioxidant therapy in these patients.

This study aimed to explore the roles of ERCC1/XPF gene polymorphisms in the occurrence of breast cancer in the Uygur and Han ethnic groups in Xinjiang, China. Single nucleotide polymorphisms (SNPs) were detected by TaqMan real‐time PCR. The rs11615 G>A and rs2276466 C>G variant frequencies were higher in Uygur patients with breast cancer than in Han patients, while the frequency of rs2298881 C>A was higher in Han patients. We found that rs2298881 C>A (CA vs. CC: OR = 0.35, 95% CI = 0.20‐0.60; AA vs. CC: OR = 0.13, 95% CI = 0.04‐0.34; CA + AA vs. CC: OR = 0.33, 95% CI = 0.18‐0.51; AA vs. CA + CC: OR = 0.24, 95% CI = 0.08‐0.62; CA vs. AA + CC: OR = 0.49, 95% CI = 0.29‐0.82) was associated with a reduced breast cancer risk and rs3212986 C>A (AA vs. CC: OR = 4.80, 95% CI = 1.79‐15.29,; CA+AA vs. CC: OR = 1.71, 95% CI = 1.06‐2.77; AA vs. CA+CC: OR = 4.12, 95% CI =1.58‐12.89) and rs11615 G > A (AA vs. GG: OR = 3.49, 95% CI =1.54‐8.55; GA + AA vs. GG: OR = 1.98, 95% CI = 1.21‐3.27; AA vs. GA+GG: OR = 2.87, 95% CI = 1.30‐6.85) were associated with an elevated breast cancer risk among Uygur individuals. In addition, Uygur patients with breast cancer with 2‐3 combined risk genotypes of ERCC1 had a higher risk than patients with 0‐1 risk genotypes (OR = 2.91; 95% CI = 1.54‐5.71, p = 0.001). However, we failed to detect a statistically significant association between ERCC1/XPF polymorphisms and breast cancer risk in five genetic models among Han individuals. Our results showed that ERCC1/XPF gene polymorphisms predispose Uygur individuals to breast cancer; this finding should be verified by further large‐scale analyses., Distribution of ERCC1/XPF gene polymorphisms in Han and Uygur women with breast cancer was different. ERCC1/XPF gene polymorphisms predispose Uygur individuals to breast cancer.

Background: Whether polymorphisms in VDR gene affect the risk of postmenopausal osteoporosis or not remain unclear. Thus, the authors performed a meta-analysis to more robustly assess associations between polymorphisms in VDR gene and the risk of postmenopausal osteoporosis by integrating the results of previous literature. Methods: Medline, Embase, Wanfang, VIP and CNKI were searched comprehensively for eligible literature, and 67 genetic association studies were finally selected to be included in this meta-analysis. Results: We found that ApaI rs7975232 (dominant comparison: OR = 0.77, P = 0.007; allele comparison: OR = 0.81, P = 0.04), BsmI rs1544410 (dominant comparison: OR = 0.69, P = 0.002; allele comparison: OR = 0.78, P = 0.008) and TaqI rs731236 (recessive comparison: OR = 1.32 , P = 0.01) polymorphisms were significantly associated with the risk of postmenopausal osteoporosis in Caucasians, whereas FokI rs10735810 polymorphism was significantly associated with the risk of postmenopausal osteoporosis in Asians (dominant comparison: OR = 0.61, P = 0.0001; recessive comparison: OR = 2.02, P = 0.001; allele comparison: OR = 0.68, P = 0.002). Conclusions: This meta-analysis shows that ApaI rs7975232, BsmI rs1544410 and TaqI rs731236 polymorphisms may affect the risk of postmenopausal osteoporosis in Caucasians, while BsmI rs1544410 polymorphism may affect the risk of postmenopausal osteoporosis in Asians.

Background Childhood obesity represents a serious global health crisis. Apelin and its receptor system are widely distributed throughout the central nervous system and have been demonstrated to serve a role modulating feeding behaviour and energy homeostasis. The purposes of this study were to examine apelin concentrations and anthropometric-cardiometabolic parameters in obese and non-obese children and to identify associations of APLN T-1860C and APLNR G212A polymorphisms with apelin levels and obesity among Thai children. Methods This case-control study included an analysis of 325 Thai children: 198 children with obesity and 127 healthy non-obese children. Anthropometric-cardiometabolic variables and apelin concentration were measured. Genotyping of APLN T-1860C and APLNR G212A was performed using the polymerase chain reaction-restriction fragment length polymorphism technique. Results The obese group had significantly lower apelin and HDL-C levels but significantly higher triglycerides and glucose (TyG) index values, TG/HDL-C ratio and TC/HDL-C ratio than the non-obese group (p p APLN T-1860C polymorphism (OR = 4.39, 95% CI = 1.25–15.28) and apelin concentration (OR = 0.45, 95% CI = 0.23–0.92) were significantly associated with obesity among female children (p APLNR G212A polymorphism showed no significant relationship with apelin concentration or obesity. Conclusion These findings in Thai children suggest that apelin concentrations are related to obesity and cardiometabolic parameters. Furthermore, the APLN T-1860C polymorphism may influence susceptibility to obesity among female children.

Aims Peripartum cardiomyopathy (PPCM) is a life-threatening heart disease occurring in previously heart-healthy women. A common pathomechanism in PPCM involves the angiostatic 16 kDa-prolactin (16 kDa-PRL) fragment, which via NF-κB-mediated up-regulation of microRNA-(miR)-146a induces vascular damage and heart failure. We analyse whether the plasminogen activator inhibitor-1 (PAI-1) is involved in the pathophysiology of PPCM. Methods and results In healthy age-matched postpartum women (PP-Ctrl, n = 53, left ventricular ejection fraction, LVEF > 55%), PAI-1 plasma levels were within the normal range (21 ± 10 ng/mL), but significantly elevated (64 ± 38 ng/mL, P Conclusion In PPCM patients, circulating and cardiac PAI-1 expression are up-regulated. While circulating PAI-1 may add 16 kDa-PRL to induce vascular impairment via the uPAR/NF-κB/miR-146a pathway, experimental data suggest that cardiac PAI-1 expression seems to protect the PPCM heart from fibrosis. Thus, measuring circulating PAI-1 and miR-146a, together with an uPAR/NF-κB-activity assay could be developed into a specific diagnostic marker assay for PPCM, but unrestricted reduction of PAI-1 for therapy may not be advised.

Background The relationships between polymorphisms in interleukin-10 (IL-10) gene and the risk of viral hepatitis remain inconclusive. Therefore, the authors conducted so far the very first meta-analysis to robustly assess the relationships between polymorphisms in IL-10 gene and the risk of viral hepatitis by integrating the results of previous works. Methods Medline, Embase, Wanfang, VIP and CNKI were searched throughly for eligible studies, and 76 genetic association studies were finally included in this meta-analysis. Results We noticed that rs1800871 (− 819 C/T), rs1800872 (− 592 C/A) and rs1800896 (− 1082 G/A) polymorphisms were all significantly associated with the risk of viral hepatitis in Asians, whereas only rs1800896 (− 1082 G/A) polymorphism was significantly associated with the risk of viral hepatitis in Caucasians. In further analyses by disease subtypes, we noticed that the three investigated polymorphisms were all significantly associated with the risk of both HBV and HCV. Conclusions This meta-analysis demonstrates that rs1800871 (− 819 C/T), rs1800872 (− 592 C/A) and rs1800896 (− 1082 G/A) polymorphisms may influence the risk of viral hepatitis in Asians, while only rs1800896 (− 1082 G/A) polymorphism may influence the risk of viral hepatitis in Caucasians. In further analyses by disease subtypes, we noticed that the three investigated polymorphisms may influence the risk of both HBV and HCV.

Summary Vogt–Koyanagi–Harada (VKH) disease is an autoimmune disease leading to visual impairment. Its pathogenic mechanisms remain poorly understood. Our purpose was to investigate the distinctive protein and metabolic profiles of sweat in patients with VKH disease. In the present study, proteomics and metabolomics analysis was performed on 60 sweat samples (30 VKH patients and 30 normal controls) using liquid chromatography tandem mass spectrometry. Parallel reaction monitoring (PRM) analysis was used to validate the results of our omics analysis. In total, we were able to detect 716 proteins and 175 metabolites. Among them, 116 proteins (99 decreased and 17 increased) were observed to be significantly different in VKH patients when compared to controls. Twenty-one differentially expressed metabolites were identified in VKH patients, of which 18 included choline, L-tryptophan, betaine and L-serine were reduced, while the rest were increased. Our multi-omics strategy reveals an important role for the amino acid metabolic pathway in the pathogenesis of VKH disease. Significant differences in proteins and metabolites were identified in the sweat of VKH patients and, to some extent, an aberrant amino acid metabolism pathway may be a pathogenic factor in the pathogenesis of VKH disease.

Jing Gao,1,* Tanja Törölä,1,* Chuan-Xing Li,2 Steffen Ohlmeier,3 Tuula Toljamo,4 Pentti Nieminen,5 Noboru Hattori,6 Ville Pulkkinen,1 Hiroshi Iwamoto,6 Witold Mazur1 1Heart and Lung Centre, Department of Pulmonary Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; 2Pulmonomics Group, Respiratory Medicine Unit, Department of Medicine & Centre for Molecular Medicine, Karolinska Institute, Stockholm, Sweden; 3Proteomics Core Facility, Biocentre Oulu, Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland; 4Department of Pulmonary Medicine, Lapland Central Hospital, Rovaniemi, Finland; 5Medical Informatics and Statistics Group, University of Oulu, Oulu, Finland; 6Department of Molecular and Internal Medicine, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan*These authors contributed equally to this workCorrespondence: Jing GaoHeart and Lung Centre, Department of Pulmonary Medicine, University of Helsinki and Helsinki University Hospital, FinlandTel +358417071559Email jing.gao@helsinki.fi, HelsinkiIntroduction: The vitamin D binding protein (VDBP, also known as GC-globulin) and vitamin D deficiency have been associated with chronic obstructive pulmonary disease (COPD). rs7041 and rs4588 are two single nucleotide polymorphisms of the VDBP gene, including three common allelic variants (GC1S, GC1F and GC2). Previous studies primarily assessed the serum levels of vitamin D and VDBP in COPD. However, less is known regarding the impact of the local release of VDBP on COPD lung function. Thus, we examined the association of sputum and plasma VDBP with lung function at baseline and at four years, and examined potential genetic polymorphism interactions.Methods: The baseline levels of sputum VDBP, plasma VDBP and plasma 25-OH vitamin D, as well as the GC rs4588 and rs7041 genotypes, were assessed in a 4-year Finnish follow-up cohort (n = 233) of non-smokers, and smokers with and without COPD. The associations between the VDBP levels and the longitudinal decline of lung function were further analysed.Results: High frequencies of the haplotypes in rs7041/rs4588 were homozygous GC1S/1S (42.5%). Higher sputum VDBP levels in stage I and stage II COPD were observed only in carriers with GC1S/1S genotype when compared with non-smokers (p = 0.034 and p = 0.002, respectively). Genotype multivariate regression analysis indicated that the baseline sputum VDBP and FEV1/FVC ratio at baseline independently predicted FEV1% at follow-up.Discussion and Conclusion: The baseline sputum VDBP expression was elevated in smokers with COPD among individuals with the GC1S/1S genotype, and predicted follow-up airway obstruction. Our results suggest that the GC polymorphism should be considered when exploring the potential of VDBP as a biomarker for COPD.Keywords: vitamin D binding protein, VDBP, genotype, COPD, prospective study, sputum

This study aimed to explore whether the polymorphisms of CYP4F2 and CYP3A5 are correlated with the risk of lung cancer development. A case–control study was conducted among 510 patients with pathologically confirmed lung cancer as the case group and 504 healthy individuals as the control group. Four single-nucleotide polymorphisms of the CYP4F2 and CYP3A5 genes were genotyped, and their correlations with the risk of lung cancer were examined using Chi-square test and logistic regression analysis. Stratified analysis found that the rs3093105 and rs3093106 loci of CYP4F2 gene were significantly associated with lower risk of lung cancer (P = 0.012, OR 0.64, 95% CI 0.45–0.91). The correlation was related to patients’ age and sex and pathological type of lung cancer. Similarly, the rs10242455 loci of CYP3A5 gene showed a statistical significance between the case group and the control group (P = 0.018, OR 0.71, 95% CI 0.53–0.94), which also was associated with reduced risk of squamous cell lung cancer in the dominant and additive models (dominant: OR 0.66, 95% CI 0.46–0.94, P = 0.021; additive: OR 0.71, 95% CI 0.53–0.95, P = 0.023). CYP4F2 and CYP3A5 gene polymorphisms are associated with the reduced risk of non-small cell lung cancer, and its correlation is related to patients’ age and sex and pathological type of lung cancer.

Background. Identification of predictive molecular markers of triple-negative breast cancer (TNBC) will enable the evaluation of the efficacy of neoadjuvant chemotherapy (NACT) and define optimum approaches for the prognosis of the disease course in TNBC patients. The aim of the study was to examine the correlation between the expression of the epidermal growth factor receptor (EGFR), its gene’s polymorphic variants and the neoadjuvant chemotherapy (NACT) efficacy in triple-negative breast cancer (TNBC) patients. Materials and methods. The study included 70 patients with triple-negative breast cancer, who had received 2-4 cycles of FAC and CAX regimens. The efficacy of the neoadjuvant chemotherapy was assessed according to the RECIST scale. The EGFR expression level in tumors before and after the NACT was evaluated with the help of immunohistochemistry. Genotypes for EGFR (rs2227983 and rs1468727) were detected by a real-time PCR. Results. It was found that NCT significantly decreases the EGFR expression level in the tumor ( p = 0.000). The research associates the objective clinical response as well as the pathological complete response with the low EGFR expression level ( p = 0.007 and p = 0.000 respectively). Patients carrying the EGFR CC mutant genotype of rs1468727 did not achieve a pathological complete response ( p = 0.042). In addition, patients with EGFRCC mutant genotype are more likely to have tumors with a high EGFR expression compared to EGFRTT wild-type genotype patients ( p = 0.047). Conclusion . The EGFR expression level in tumor tissue and the polymorphic variants of its gene in the rs1468727 locus can be considered as potential molecular markers with predictive significance in relation to the NACT efficacy in triple-negative breast cancer patients.

Introduction Previous studies found that vitamin D receptor (VDR) TaqI, BsmI, FokI and ApaI gene polymorphisms are associated with several inflammatory diseases. However, the relationship between VDR gene polymorphisms and chronic spontaneous urticaria (CSU) is not clear. Aim The purpose of our study was to explore the relationship between the polymorphism of VDR and the incidence of chronic spontaneous urticaria in the Chinese Han population. Meanwhile, the vitamin D levels in patients with chronic spontaneous urticaria were also detected and the effects of VDR gene polymorphism on vitamin D levels were detected. Material and methods The genotypes of four VDR polymorphisms (TaqI, BsmI, ApaI, and FokI) were studied using allele-specific PCR analysis in 90 CSU patients and 90 healthy controls. Results Compared to the control group, the mutant allele (C) of FokI were more common in patients with CSU (57.2% vs. 45%, p = 0.020, odds ratio (OR) = 0.612, 95% confidence interval (CI): 0.403-0.928). We found that serum vitamin D levels were significantly lower in CSU patients than in healthy controls (p = 0.023). However, the effect of VDR gene polymorphism on vitamin D levels was not found in patients of CSU. Conclusions We first reported the effect of VDR gene FokI (rs2228570) polymorphism on the incidence of chronic spontaneous urticaria in the Chinese Han population.

Oral carcinoma is the sixth most common malignancy worldwide, with survival rates of approximately 50%. The major type of oral cancer, present in 90% of the cases, is oral squamous cell carcinoma (OSCC). The genetic background predisposing an individual to OSCC is complex and largely unknown. Studies have suggested that endothelial nitric oxide synthase (eNOS) gene polymorphisms modulate the cancer risk, prompting us to assess the impact of three functional eNOS gene polymorphisms on OSCC risk. The present study included 50 patients with OSCC and 110 controls. Polymerase chain reaction and restriction fragment length polymorphism analysis were used for genotyping of single-nucleotide polymorphisms -786 T/C (rs2070744) and 894 G/T (rs1799983) and variable number of tandem repeats (VNTR) intron 4b/a polymorphism. Homozygous carriers of -786 T/C and intron 4b/a VNTR variant alleles paired with a significant increase of oral cancer risk [odds ratio (OR): 3.63, 95% confidence interval (CI): 1.08-12.21; P = 0.045 and OR: 11.29, 95% CI: 2.71-47.11; P < 0.001, respectively]. When combined, CC and 4b4a genotypes together led to a 21-fold OSCC risk increase (OR: 21, 95% CI: 2.07-213.29; P = 0.006). Haplotype analysis showed that the C-G-4b haplotype conferred an 11-fold increase in OSCC risk. In conclusion, eNOS polymorphisms considerably influence levels of OSCC risk in the Serbian population.

Background. A variety of biological processes regulated by differential gene expression are required to maintain a normal gestation and accordingly, the mutations and polymorphisms in such genes may cause miscellaneous biological disorders that eventually result in early pregnancy loss. Many studies reported that aberrant fetal DNA methylation as well as embryonic chromosome abnormalities may lead to impairment of fetal early growth and development. Therefore, we have aimed to genotype several gene polymorphisms might be involved in the above-mentioned biological disorders to screen their prevalence in Russian population. Materials and methods. 81 Russian women without previous history of normal pregnancy or early abortion were recruited into this population study to determine the genotype and allele frequencies through genotyping using RFLP-PCR method for DNMT3B rs2424913, DNMT3B rs1569686, DNMT3A rs7590760, DNMT1 rs2228611, DNMT1 rs8101626, DNMT3L rs2276248, and DNMT3L rs2070565, allele-specific PCR for SYCP3 T657C, and real-time PCR for MTHFR rs1801133, MTHFR rs1801131, MTR rs1805087, and MTRR rs1801394. Results. Minor homozygous genotypes and minor alleles of the polymorphisms DNMT3B rs2424913 (TT: 11.1%, T: 37.05%), DNMT1 rs2228611 (GG: 18.5%, G: 40.75%), and DNMT1 rs8101626 (GG: 16.0%, G: 40.1%) were quite prevalent in Russian women and as frequent as those of the well-studied polymorphisms: MTRR rs1801394 (GG: 27.2%, G: 50.65%), MTHFR rs1801131 (CC: 17.3%, C: 40.15%), and MTHFR rs1801133 (TT: 11.1%, T: 29.0%).The heterozygous genotype of SYCP3 T657C (CT: 12.3%, T: 6.15%) was also quite frequent. Conclusion. Based on our study and literature data, we suggest that DNMT3B rs2424913, DNMT1 rs2228611, DNMT1 rs8101626, and SYCP3 T657C polymorphisms along with the common folate cycle gene polymorphisms can be potential genetic predictors for early pregnancy loss in Russian women.

Cytokines are key modulators of immune response, and dysregulated production of proinflammatory and anti-inflammatory cytokines contributes to the pathogenesis of influenza A(H1N1)pdm09 virus infection. Cytokine production is impacted by single nucleotide polymorphisms (SNPs) in the genes coding for them. In the present study, SNPs in the IL6, TNFA, IFNG, IL17A, IL10, and TGFB were investigated for their association with disease severity and fatality in influenza A(H1N1)pdm09-affected patients with mild disease (n = 293) and severe disease (n = 86). Among those with severe disease, 41 patients had fatal outcomes. In a subset of the patients, levels of IL-2, IL-4, IL-6, IL-10, TNF, IFN-γ, and IL-17 were assayed in the plasma for their association with severe disease. The frequency of TNFA rs1800629 G/A allele was significantly higher in severe cases and survived severe cases group compared to that of those with mild infection (OR with 95% for mild vs. severe cases 2.95 (1.52–5.73); mild vs. survived severe cases 4.02 (1.84–8.82)). IL10 rs1800896-rs1800872 G-C haplotype was significantly lower (OR with 95% 0.34 (0.12–0.95)), while IL10 rs1800896-rs1800872 G-A haplotype was significantly higher (OR with 95% 12.11 (2.23–76.96)) in fatal cases group compared to that of the mild group. IL-6 and IL-10 levels were significantly higher in fatal cases compared to that of survived severe cases. IL-6 levels had greater discriminatory power than IL-10 to predict progression to fatal outcome in influenza A(H1N1)pdm09 virus-infected patients. To conclude, the present study reports the association of TNFA and IL10 SNPs with severe disease in Influenza A(H1N1)pdm09 virus-infected subjects. Furthermore, IL-6 levels can be a potential biomarker for predicting fatal outcomes in Influenza A(H1N1)pdm09 virus infected subjects.

Background Chronic kidney Failure (CKD), particularly End-Stage Renal Disease (ESRD), may be serious ill-health related to a high death rate. Uremic syndrome leads to increased oxidative stress, inflammation, and dyslipidemia. Our study aimed at identifying the association of NOS3 (rs 2070744) and SOD2 Val16Ala (rs4880) gene polymorphisms within ESRD Egyptian patients. Methods This work was conducted on 100 ESRD and 16 CKD Egyptian patients who were compared to 100 healthy controls. DNA was genotyped for these variants using the (T-ARMS-PCR) technique. Results ESRD patients showed a significant association of the genotype of NOS3 gene polymorphism compared with healthy controls (P = 0.032). In the contrast, the present study revealed that no statistically significant differences were found among the CKD, ESRD, and control groups as regards the SOD2 genotypes (P = 0.064). Conclusions Our findings indicated a significant association between NOS3 (rs 2070744) gene polymorphism and increased risk of ESRD and CKD among Egyptian patients.

Our study aimed to evaluate the distribution of genotypes and allele frequencies of IL-6 597A/G (rs1800797) and 174G/C (rs1800795) polymorphisms in HPV infected and uninfected healthy women and cervical cancer patients. A PCR based Multiplex HPV genotyping test kit was used for in vitro detection and differentiation of high risk HPV genotypes. Genotyping of two polymorphisms, IL-6 597A/G (rs1800797) and 174G/C (rs1800795), was performed using the KASP genotyping assay kit. Cervical cancer patients were more likely to be HPV positive than control patients. Allele C of IL-6 rs1800795 was associated with a higher risk of cervical cancer by 2.26-fold and genotype CC by 5.37-fold. Genotype CC of IL-6 rs1800795 was more frequent in the HPV positive group compared with the HPV negative group (p = 0.002). Allele G of IL-6 rs1800797 was more frequently found in women with HPV16/HPV18 compared to other HPV types (p = 0.045). Women with AA genotypes of IL-6 rs1800797 were less frequently infected with HPV16/HPV18 compared to other HPV types (p = 0.045). The major finding of the study is the significant association of C allele and CC genotype of IL-6 1800795 gene with cervical cancer in the Lithuanian population. Genotype CC of IL-6 rs1800795 has a significant association with HPV infection as well.

The development, progression, diagnosis and treatment of autoimmune diseases, such as multiple sclerosis (MS), are convoluted processes which remain incompletely understood. Multiple studies demonstrated that the interleukin (IL)-2 – IL-2 receptor (IL-2R) pathway plays a pivotal role within these processes. The most striking functions of the IL-2 – IL-2R pathway are the differential induction of autoimmune responses and tolerance. This paradoxical function of the IL-2 – IL-2R pathway may be an attractive therapeutic target for autoimmune diseases such as MS. However, the exact mechanisms that lead to autoimmunity or tolerance remain to be elucidated. Furthermore, another factor of this pathway, the soluble form of the IL-2R (sIL-2R), further complicates understanding the role of the IL-2 – IL-2R pathway in MS. The challenge is to unravel these mechanisms to prevent, diagnose and recover MS. In this review, first, the current knowledge of MS and the IL-2 – IL-2R pathway are summarized. Second, the key findings of the relation between the IL-2 – IL-2R pathway and MS have been highlighted. Eventually, this review may launch broad interest in the IL-2 – IL-2R pathway propelling further research in autoimmune diseases, including MS., Highlights • The IL-2 – IL-2R pathway determines the balance between immunity and tolerance. • The IL-2 – IL-2R pathway is involved in the pathogenesis of multiple sclerosis. • The role of soluble IL-2R is controversial and requires further investigation.

Publisher Copyright: © 2021 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics This study aimed to analyze associations between genetic variants and the occurrence of clinical outcomes in dabigatran, apixaban, and rivaroxaban users. This was a retrospective real-world study linking genotype data of three Finnish biobanks with national register data on drug dispensations and healthcare encounters. We investigated several single-nucleotide variants (SNVs) in the ABCG2, ABCB1, CES1, and CYP3A5 genes potentially associated with bleeding or thromboembolic events in direct oral anticoagulant (DOAC) users based on earlier research. We used Cox regression models to compare the incidence of clinical outcomes between carriers and noncarriers of the SNVs or haplotypes. In total, 1,806 patients on apixaban, dabigatran, or rivaroxaban were studied. The ABCB1 c.3435C>T (p.Ile1145=, rs1045642) SNV (hazard ratio (HR) 0.42, 95% confidence interval (CI), 0.18-0.98, P = 0.044) and 1236T-2677T-3435T (rs1128503-rs2032582-rs1045642) haplotype (HR 0.44, 95% CI, 0.20-0.95, P = 0.036) were associated with a reduced risk for thromboembolic outcomes, and the 1236C-2677G-3435C (HR 2.55, 95% CI, 1.03-6.36, P = 0.044) and 1236T-2677G-3435C (HR 5.88, 95% CI, 2.35-14.72, P < 0.001) haplotypes with an increased risk for thromboembolic outcomes in rivaroxaban users. The ABCB1 c.2482-2236G>A (rs4148738) SNV associated with a lower risk for bleeding events (HR 0.37, 95% CI, 0.16-0.89, P = 0.025) in apixaban users. ABCB1 variants are potential factors affecting thromboembolic events in rivaroxaban users and bleeding events in apixaban users. Studies with larger numbers of patients are warranted for comprehensive assessment of the pharmacogenetic associations of DOACs and their relevance for clinical practice.

Background and Objectives: The age-related macular degeneration (AMD) pathophysiology is multifactorial, as it consists of interactions between aging, genetic, and environmental factors. We aimed to determine a relationship between AMD and the genes controlling lipid metabolism, and to assess its association with treatment results. The purpose was to find the ABCA1 rs1883025 and CYP4F2 rs2108622 gene polymorphisms in patients with exudative AMD (eAMD) treated with anti-VEGF. Materials and Methods: The study enroled 104 patients with eAMD and 201 healthy persons in a control group. The genotyping of rs1883025 and rs2108622 was performed using the RT-PCR method. The best-corrected visual acuity (BCVA) and central retinal thickness (CRT) were measured before anti-VEGF therapy, then at three and six months during the therapy, using optical coherence tomography (OCT). The patients were grouped to responders and non-responders according to the changes in BCVA and CRT. Results: The T allele at rs1883025 was more frequent in non-responder eAMD patients compared to responder eAMD patients (41.7% vs. 21.1%, p = 0.009). The analysis of rs2108622 gene polymorphism did not reveal any differences in the distribution of C/C, C/T, and T/T genotypes between the eAMD group and the control group (56.35%, 39.78%, and 3.87% in the eAMD group and 53.33%, 39.05% and 7.62% in the control group, respectively, p = 0.286). The comparison of CRT and BCVA between the rs2108622 genotypes revealed statistically significant differences: CRT was thicker for the CC carriers than for those with CT and TT genotypes (p = 0.030). Conclusion: The rs1883025 T allele was found to play a more significant role in non-responder eAMD patients compared to responder eAMD patients. The rs2108622 genotypes revealed statistically significant differences: CRT was thicker for the CC carriers than for those with CT and TT genotypes.

This article is part of the thesis: Analysis of genetic variants associated with response to bisoprolol in patients with acute coronary syndrome with percutaneous coronary intervention with stent, within the doctoral program in Pharmacy at the University of Granada, to whom we thank for their collaboration. We would like to thank Dr. T. Eschenhagen and Dr. K. Kontula for sharing with us detailed information from their articles [16,22] which have allowed us to perform the meta-analysis., β-blockers are commonly prescribed to treat multiple cardiovascular (CV) diseases, but, frequently, adverse drug reactions and intolerance limit their use in clinical practice. Interindividual variability in response to β-blockers may be explained by genetic differences. In fact, pharmacogenetic interactions for some of these drugs have been widely studied, such as metoprolol. But studies that explore genetic variants affecting bisoprolol response are inconclusive, limited or confusing because of mixed results with other β-Blockers, different genetic polymorphisms observed, endpoint studied etc. Because of this, we performed a systematic review in order to find relevant genetic variants affecting bisoprolol response. We have found genetic polymorphism in several genes, but most of the studies focused in ADRB variants. The ADRB1 Arg389Gly (rs1801253) was the most studied genetic polymorphism and it seems to influence the response to bisoprolol, although studies are inconclusive. Even, we performed a meta-analysis about its influence on systolic/diastolic blood pressure in patients treated with bisoprolol, but this did not show statistically significant results. In conclusion, many genetic polymorphisms have been assessed about their influence on patients´ response to bisoprolol and the ADRB1 Arg389Gly (rs1801253) seems the most relevant genetic polymorphism in this regard but results have not been confirmed with a meta-analysis. Our results support the need of further studies about the impact of genetic variants on bisoprolol response, considering different genetic polymorphisms and conducting single and multiple SNPs analysis, including other clinical parameters related to bisoprolol response in a multivariate study.

Trait anxiety is a vulnerable personality factor for anxiety and depression. High levels of trait anxiety confer an elevated risk for the development of anxiety and other psychiatric disorders. There is evidence that 5-hydroxytryptamine receptor 1B (5-HT1B) gene polymorphisms play an important role in emotional disorders. Genotyping for four single-nucleotide polymorphisms (SNP) (rs11568817, rs130058, rs6297, and rs13212041) was conducted for 388 high trait anxious (HTA) individuals and 463 low traitanxious (LTA) individuals in Chinese Han college subjects. The results showed that the frequencies of the C-allele and TC + CC genotype of rs13212041 in the LTA individuals were higher than that in the HTA individuals (p = 0.025 and p = 0.014, respectively). Both the C-allele and TC + CC genotype were associated with trait anxiety decreasing (OR = 0.771 and OR = 0.71, respectively). Furthermore, different gene model analysis also showed that the C allele was a protective factor for trait anxiety in Chinese Han college subjects. These findings suggest that 5-HT1B rs13212014 may play a role in trait anxiety among China Han college subjects. The rs13212014 polymorphism may be involved in decreasing the risk of trait anxiety. These results also provide a novel insight into the molecular mechanism underlying trait anxiety.

The question of whether cannabis can trigger schizophrenia continues to be a subject of interest. There has been an increasing focus on identifying potential genetic factors that may predispose cannabis users to develop schizophrenia. One such gene identified in many studies codes for a catechol-O-methyltransferase (COMT) enzyme polymorphism. These studies, however, are limited by the inclusion of patients displaying psychotic symptoms during cannabis intoxication and those who continue to display psychotic symptoms after its cessation. The latter is of interest in truly understanding the risk of cannabis triggering schizophrenia and more studies are needed to clarify the potential relationship. We present the case of a 24-year-old female who presented with psychotic symptoms and was diagnosed with schizophrenia after extensive cannabis use. In addition, she had a homozygous valine COMT polymorphism, a genetic variant thought to be associated with a predisposition for schizophrenia in cannabis users. We discuss the significance of our findings in understanding the relationship between cannabis use and the development of schizophrenia in genetically predisposed individuals.

The objective of our clinical study was to identify the relationship between the incidence of persistent pain in the late postoperative period and polymorphisms (SNP) in the COMT and GCH1 genes. Subjects and methods . Following the provision of written informed consent, 102 patients (57 women and 45 men) with ASA physical condition I/II underwent transabdominal radical prostatectomy (n = 45) or hysterectomy (n = 57) for cancer-related pathology. The frequency and intensity of postoperative residual pain in the pelvic and scar areas were assessed by a nurse in all patients using a telephone survey three months after discharge from the clinic. Genotyping was performed in the region Chr14q22.1 and 22q11.21 containing the genes GCH1 and COMT, respectively. We identified five SNP GCH1s that, as shown, had a significant association with pain reactions in a previous study by Tegeder and co-authors: rs752688, rs4411417, rs8007201, rs3783641 and rs8007267, and one SNP COMT-rs4680 G1947A. Results and discussion . In the first three months after discharge from the hospital, 35 patients (34.3%) were diagnosed with moderate and severe pain of varying duration. In this group, 6 (17.1%) patients manifested signs of chronic neuropathic pain. Statistical analysis of 102 patients undergoing surgery on the lower floor of the abdominal cavity showed a statistically significant relationship only between GCH1 rs752688 and the more frequent occurrence of chronic postoperative pain. This relationship was mainly found in the male patient group, which indicated a gender-dependent effect. SNP GCH1rs752688 can be used as a clinical "marker" of chronic pain.

Identifying biomarkers which can be used as a diagnostic tool is a major objective of pharmacogenetic studies. Most mental and many neurological disorders have a compiled multifaceted nature, which may be the reason why this endeavor has hitherto not been very successful. This is also true for tardive dyskinesia (TD), an involuntary movement complication of long-term treatment with antipsychotic drugs. The observed associations of specific gene variants with the prevalence and severity of a disorder can also be applied to try to elucidate the pathogenesis of the condition. In this paper, this strategy is used by combining pharmacogenetic knowledge with theories on the possible role of a dysfunction of specific cellular elements of neostriatal parts of the (dorsal) extrapyramidal circuits: various glutamatergic terminals, medium spiny neurons, striatal interneurons and ascending monoaminergic fibers. A peculiar finding is that genetic variants which would be expected to increase the neostriatal dopamine concentration are not associated with the prevalence and severity of TD. Moreover, modifying the sensitivity to glutamatergic long-term potentiation (and excitotoxicity) shows a relationship with levodopa-induced dyskinesia, but not with TD. Contrasting this, TD is associated with genetic variants that modify vulnerability to oxidative stress. Reducing the oxidative stress burden of medium spiny neurons may also be the mechanism behind the protective influence of 5-HT2 receptor antagonists. It is probably worthwhile to discriminate between neostriatal matrix and striosomal compartments when studying the mechanism of TD and between orofacial and limb-truncal components in epidemiological studies.

Introduction: Dental fluorosis is a foremost public health problem in many countries, including India. Very few studies investigated gene polymorphism and risk of dental fluorosis. Genetic polymorphisms in Collagen Type I, alpha 2 (COL1A2) gene, found to be linked with bone pathogenesis, may affect the tooth formation resulting in the vulnerability to dental fluorosis. Aim: To assess the association between COL1A2 (PvuII) gene polymorphism and risk as well as severity of dental fluorosis. Methods: The present case control study was conducted among participants with (n = 60) and without (n = 60) dental fluorosis. Dental fluorosis was assessed using Modified Dean’s fluorosis index (1942). The PvuII polymorphisms (in exon 25) inside the COL1A2 gene were genotyped by Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) procedure. Statistical analysis were carried out with Chi-square test and Odds Ratio (OR) was determined with multivariate logistic regression analysis. Results: The genetic polymorphism in COL1A2 PvuII was found to be associated with the risk of dental fluorosis which was highly significant (p

Background Cytokines were correlated with survival and disease progression in acute myeloid leukemia (AML). We aimed to evaluate the multivariate effect of TNF‐α rs361525, rs1800750, rs1800629, IL‐10 rs1800896, rs1800872, IL‐6 rs1800795, TGF‐β1 rs1800470, IFN‐γ rs2430561 single nucleotide polymorphisms (SNPs) on AML risk, the multivariate effect of SNPs on overall survival (OS) in AML and the association between the investigated SNPs and prognostic factors in AML. Methods All SNPs were genotyped in 226 adult AML cases and 406 healthy individuals. AML patients were investigated for FLT3 (ITD, D835), DNMT3A (R882), and NPM1 type A mutations. Results Univariate analysis revealed that age above 65 years had a negative influence on survival (P 2, lactate dehydrogenase (LDH) level, platelet (PLT) count, We aimed to evaluate the multivariate effect of TNF‐α rs361525, rs1800750, rs1800629, IL‐10 rs1800896, rs1800872, IL‐6 rs1800795, TGF‐β1 rs1800470, IFN‐γ rs2430561 single nucleotide polymorphisms (SNPs) on AML risk, the multivariate effect of SNPs on overall survival (OS) in AML and the association between the investigated SNPs and prognostic factors in AML. A negative association was observed between Eastern Cooperative Oncologic Group Scale status >2, lactate dehydrogenase (LDH) level, platelet (PLT) count

Background Several studies have been performed to investigate the associations between interleukin (IL)-8 rs4073 polymorphism and acute pancreatitis (AP), but the results are inconclusive. We conducted this cumulative meta-analysis for a precise estimate of the relationship between IL-8 rs4073 polymorphism and acute pancreatitis. Methods We searched the electronic databases for relevant studies. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to evaluate the strength of the associations. For a better presentation of how the pooled ORs changed as updated evidence accumulated, we used forest plots from a cumulative meta-analysis method. Results Ten studies involving 1646 AP patients and 1816 controls were finally included in this meta-analysis. Cumulative meta-analyses indicated there is a consistent trend toward association after the initial discovery. Under the allelic, dominant, recessive and homozygous models, the pooled ORs were 1.265 (1.147–1.395, p

The most severe visual impairments due to age-related macular degeneration (AMD) are frequently caused by the occurrence of choroidal neovascularization (CNV). Although photodynamic therapy with verteporfin (PDT-V) is currently a second-line treatment for neovascular AMD, it can be conveniently combined with drugs acting against vascular endothelial growth factor (anti-VEGF) to reduce the healthcare burden associated with the growing necessity of anti-VEGF intravitreal re-injection. Because the common 677 C > T polymorphism of the methylenetetrahydrofolate reductase gene (MTHFR-C677T; rs1801133) has been described as predictor of satisfactory short-term responsiveness of AMD-related CNV to PDT-V, we retrospectively examined the outcomes of 371 Caucasian patients treated with standardized, pro-re-nata, photodynamic regimen for 24 months. Responder (R) and non-responder (NR) patients were distinguished on the basis of the total number of scheduled PDT-V (TN-PDT-V) and change of best-corrected visual acuity (∆-BCVA). The risk for both TN-PDT-V and ∆-BCVA to pass from R to NR group was strongly correlated with CT and TT genotypes of MTHFR-C677T variant resulting, respectively, in odd ratios of 0.19 [95% CI, 0.12–0.32] and 0.09 [95% CI, 0.04–0.21] (P

L-dopa–induced dyskinesias (LID) is a common motor side effect of levodopa therapy of Parkinson’s disease (PD). The identified predictors may only partially account for the risk of developing LID and genetic factors may contribute to this variability. The present study is aimed to investigate whether polymorphisms in the dopamine transporter gene (DAT) are associated with the risk of developing LID. Genotyping of the 40-bp VNTR (rs28363170) and rs393795 (A/C) polymorphisms of the DAT gene was performed in a well-characterized cohort of 181 Italian PD patients in treatment with L-DOPA for 3 years or more. The results of our study show that there is no difference in dyskinesias prevalence among carriers of the two DAT gene polymorphisms. However, the combination of the two genotypes 10R/10R (rs28363170) and A carrier (rs393795) of the DAT gene reduces the risk of LID occurrence during long-term therapy with l -DOPA with respect to the PD subjects who did not carry these alleles (OR = 0.31; 95% CI, 0.09-0.88). Also based on a logistic regression analysis, the 10R/10R and the A carrier allele of the rs393795 polymorphisms of the DAT gene, could reduce the susceptibility to develop LID during levodopa therapy adjusted by demographical and clinical variables (OR = 0.19; 95% CI, 0.05-0.69). Additional studies further investigating the rs28363170 and rs393795 polymorphisms with LID in PD are needed to clarify their role in different ethnicities.

This study investigated the renin-angiotensin-aldosterone system (RAAS) gene polymorphisms as possible genetic risk factors for the restenosis development in patients with drug-eluting stents. 113 participants had coronary artery disease and underwent stenting. The control group consisted of 62 individuals with intact coronary arteries. Patients were divided into two groups: with in-stent restenosis (ISR) and without it. The patients with ISR were classified into subgroups by the terms of the restenosis development and age. Real-time PCR and Restriction Fragment Length Polymorphism-PCR were used to genotype the study participants for RAAS gene polymorphisms. We found that the development of restenosis is generally associated with the minor A allele for renin (REN) rs2368564 and the major TT genotype for angiotensinogen (AGT) rs699. The heterozygous genotype for AGT rs4762 acts as a protective marker. A minor A allele for angiotensin II type 2 receptor (AGTR2) rs1403543 is associated with a risk of restenosis in people under 65 years old. Among patients with the early ISR, heterozygotes for angiotensin II type 1 receptor (AGTR1) rs5186 are more frequent, as well as A allele carriers for AGTR2 rs1403543. A minor homozygous genotype for REN rs41317140 and heterozygous genotype for aldosterone synthase (CYP11B2) rs1799998 are predisposed to the late restenosis. Thus, to choose the effective treatment tactics for patients with coronary artery disease, it is necessary to genotype patients for the RAAS polymorphisms, which, along with age and clinical characteristics, will allow a comprehensive assessment of the risk of the restenosis development after stenting.

Background:Pseudomonas aeruginosa (PA) infection in cystic fibrosis (CF) is associated with poor prognosis. Surfactant protein-D (SFTPD) and mannose-binding lectin (MBL) play a critical role in innate immunity and response to bacterial infections. We investigated serum levels and genetic variants of SFTPD and MBL in CF patients.Method: Thirty-five Caucasian patients homozygous for ΔF508del were genotyped for functional relevant polymorphisms within MBL2 (promoter−221 Y/X, codons 52, 54, and 57) and SFTPD genes (Met11Thr, Ala160Thr, and Ser270Thr). Serum levels of collectins, clinical characteristics, and PA status were correlated with genetic data.Results: Patients age, gender, and PA status did not affect MBL and SFTPD serum concentrations. MBL concentrations were correlated with MBL haplotypes. Patients with chronic Pseudomonas aeroginosa infection (PAC) and MBL insufficiency had a shorter interval between first PA infection and onset of PAC (0.01 vs. 4.6 years, p < 0.04) as well as a lower median age at transition to PAC (9.8 vs. 16.4 years, p < 0.03) compared to MBL sufficient patients with PAC. SFTPD serum level and FEV1% (Spearman r = −0.41, p < 0.03) showed a negative correlation irrespective of PA infection status. The hazard ratio to PA acquisition was increased in carriers of the SFTPD haplotype 11Thr-160Ala-270Ser compared to carriers of the common 11Met-160Thr-270Ser haplotype [HR 3.0 (95%CI: 1.1–8.6), p < 0.04].Conclusion: MBL insufficiency leads to a shorter interval between first PA infection and onset of chronic infection. Susceptibility to PA acquisition is associated with SFTPD genetic variants with 11Thr-160Ala-270Ser as risk haplotype for early PA infection. This may be due to presence of threonine associated with oligomeric structure of SFTPD and binding ability to bacteria.

Background and Aims: Tacrolimus(TAC)-induced nephrotoxicity, which has a large individual variation, may lead to treatment failure or even the end-stage renal disease. However, there is still a lack of effective models for the early prediction of TAC-induced nephrotoxicity, especially in nephrotic syndrome(NS). We aimed to develop and validate a predictive model of TAC-induced tubular toxicity in children with NS using machine learning based on comprehensive clinical and genetic variables.Materials and Methods: A retrospective cohort of 218 children with NS admitted between June 2013 and December 2018 was used to establish the models, and 11 children were prospectively enrolled for external validation. We screened 47 clinical features and 244 genetic variables. The changes in urine N- acetyl- β-D- glucosaminidase(NAG) levels before and after administration was used as an indicator of renal tubular toxicity.Results: Five machine learning algorithms, including extreme gradient boosting (XGBoost), gradient boosting decision tree (GBDT), extremely random trees (ET), random forest (RF), and logistic regression (LR) were used for model generation and validation. Four genetic variables, including TRPC6 rs3824934_GG, HSD11B1 rs846910_AG, MAP2K6 rs17823202_GG, and SCARB2 rs6823680_CC were incorporated into the final model. The XGBoost model has the best performance: sensitivity 75%, specificity 77.8%, accuracy 77.3%, and AUC 78.9%.Conclusion: A pre-administration model with good performance for predicting TAC-induced nephrotoxicity in NS was developed and validated using machine learning based on genetic factors. Physicians can estimate the possibility of nephrotoxicity in NS patients using this simple and accurate model to optimize treatment regimen before administration or to intervene in time after administration to avoid kidney damage.

Qing Shu,1,* Qingqing Fan,1,* Bingzhu Hua,2 Hang Liu,1 Shiying Wang,2 Yunxing Liu,1 Yao Yao,1 Han Xie,1 Weihong Ge1 1Department of Pharmacy, Nanjing Drum Tower Hospital, Nanjing, 210008, People’s Republic of China; 2Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, Nanjing, 210008, People’s Republic of China*These authors contributed equally to this workCorrespondence: Weihong GeDepartment of Pharmacy, Nanjing Drum Tower Hospital, Nanjing, 210008, People’s Republic of ChinaEmail 6221230@sina.comIntroduction: Mycophenolate mofetil (MMF), a new type of immunosuppressant, has emerged as a frontline agent for treating autoimmune diseases. Mycophenolic acid (MPA) is an active metabolite of MMF. MPA exposure varies greatly among individuals, which may lead to adverse drug reactions such as gastrointestinal side effects, infection, and leukopenia. Genetic factors play an important role in the variation of MPA levels and its side effects. Although many published studies have focused on MMF use in patients after organ transplant, studies that examine the use of MMF in patients with autoimmune diseases are still lacking.Methods: This study will not only explore the genetic factors affecting MPA levels and adverse reactions but also investigate the relationships between UGT1A9 − 118(dT)9/10, UGT1A9 - 1818T>C, UGT2B7 802C>T, SLCO1B1 521T>C, SLCO1B3 334T>G, IMPDH1 − 106G>A and MPA trough concentration (MPA C0), along with adverse reactions among Chinese patients with autoimmune diseases. A total of 120 patients with autoimmune diseases were recruited. The MPA trough concentration was detected using the enzyme multiplied immunoassay technique (EMIT). Genotyping was performed using a real-time polymerase chain reaction (PCR) system and validated allelic discrimination assays. Clinical data were collected for the determination of side effects.Results: SLCO1B1 521T>C demonstrated a significant association with MPA C0/d (p=0.003), in which patients with the CC type showed a higher MPA C0/d than patients with the TT type (p=0.001) or the CT type (p=0.000). No significant differences were found in MPA C0/d among the other SNPs. IMPDH1 − 106G>A was found to be significantly related to infections (p=0.006). Subgroup analysis revealed that UGT2B7 802C>T was significantly related to Pneumocystis carinii pneumonia infection (p=0.036), while SLCO1B1 521T>C was associated with anemia (p=0.029).Conclusion: For Chinese autoimmune disease patients, SLCO1B1 521T>C was correlated with MPA C0/d and anemia. IMPDH1 − 106G>A was significantly related to infections. UGT2B7 802C>T was significantly related to Pneumocystis carinii pneumonia infection.Keywords: mycophenolic acid, gene polymorphisms, adverse drug reactions, infections, anemia, autoimmune diseases

Factor V Leiden G1691A (FVL) and Factor II prothrombin G20210A (PGM) mutations are the leading causes of thrombophilia. In this study, we have investigated the prevalence of the FVL G1691A and PGM G20210A single nucleotide polymorphisms (SNPs) among Libyan deep vein thrombosis (DVT) and myocardial infarction (MI) patients. SNP genotyping was performed using high-resolution melt analysis (HRM) and DNA sequencing. Biochemical parameters conducted on 112 males and 93 females showed no significant difference in means between the control group and the deep vein thrombosis and myocardial infarction groups. For Factor V Leiden, 40 samples were genotyped. Of the 40 samples, 6 (15.0%) of them were heterozygous and no one was homozygous. As for Factor II SNP, 59 samples were genotyped and only 2 (3.3%) were heterozygous. All the heterozygous samples showed 100% concordance between the HRM-PCR and DNA sequence analysis. Our study showed, for the first time, that both the FVL and PGM mutations are present among Libyan DVT and MI patients and that the FVL mutation is significantly associated with DVT but not with MI. However, our results do not support the association of PGM G20210A mutation with DVT or MI.

Diabetic kidney disease (DKD) is one of the most serious complications of both type 1 (T1DM) and type 2 diabetes mellitus (T2DM). Current guidelines recommend a personalized approach in order to reduce the burden of DM and its complications. Recognizing sex and gender- differences in medicine is considered one of the first steps toward personalized medicine, but the gender issue in DM has been scarcely explored so far. Gender differences have been reported in the incidence and the prevalence of DKD, in its phenotypes and clinical manifestations, as well as in several risk factors, with a different impact in the two genders. Hormonal factors, especially estrogen loss, play a significant role in explaining these differences. Additionally, the impact of sex chromosomes as well as the influence of gene–sex interactions with several susceptibility genes for DKD have been investigated. In spite of the increasing evidence that sex and gender should be included in the evaluation of DKD, several open issues remain uncovered, including the potentially different effects of newly recommended drugs, such as SGLT2i and GLP1Ras. This narrative review explored current evidence on sex/gender differences in DKD, taking into account hormonal, genetic and clinical factors.

Purpose: The present study aimed to investigate the potential impact of age, gender, baseline strength, and selected candidate polymorphisms on maximal strength training (MST) adaptations. Methods: A total of 49 subjects (22 men and 27 women) aged 20–76 years, divided into five age groups, completed an 8 weeks MST intervention. Each MST session consisted of 4 sets with 4 repetitions at ∼85–90% of one-repetition maximum (1RM) intensity in leg-press, three times per week. 1RM was tested pre and post the intervention and blood samples were drawn to genotype candidate polymorphisms ACE I/D (rs1799752), ACTN3 R577X (rs1815739), and PPARGC1A Gly482Ser (rs8192678). Results: All age groups increased leg-press 1RM (p < 0.01), with a mean improvement of 24.2 ± 14.0%. There were no differences in improvements between the five age groups or between male and female participants, and there were no non-responders. Baseline strength status did not correlate with 1RM improvements. PPARGC1A rs8192678 T allele carriers had a 15% higher age- and gender corrected baseline 1RM than the CC genotype (p < 0.05). C allele carriers improved 1RM (%) by 34.2% more than homozygotes for the T allele (p < 0.05). Conclusion: To the best of our knowledge, this is the first study to report improvement in leg-press maximal strength regardless of gender, baseline strength status in all age groups. The present study is also first to demonstrate an association between the PPARGC1A rs8192678 and maximal strength and its trainability in a moderately trained cohort. MST may be beneficial for good health and performance of all healthy individuals. Copyright © 2021 Kittilsen, Goleva-Fjellet, Freberg, Nicolaisen, Støa, Bratland- Sanda, Helgerud, Wang, Sæbø and Støren. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

Gastroenterology; Pharmacogenetics Gastroenterologia; Farmacogenètica Gastroenterología; Farmacogenética Bleeding in non-steroidal anti-inflammatory drug (NSAID) users limited their prescription. This first multicenter full case–control study (325 cases and 744 controls), explored the association of e-NOS intron 4 variable number tandem repeat (VNTR) polymorphism with upper gastrointestinal hemorrhage (UGIH) in NSAID exposed and unexposed populations and assessed any interaction between this polymorphism and NSAIDs. NSAID users carrying e-NOS intron 4 wild type genotype or VNTR polymorphism have higher odds of UGIH than those unexposed to NSAIDs [Odds Ratio (OR): 6.62 (95% Confidence Interval (CI): 4.24, 10.36) and OR: 5.41 (95% CI 2.62, 11.51), respectively], with no effect modification from VNTR polymorphism-NSAIDs interaction [Relative Excess Risk due to Interaction (RERI): −1.35 (95% CI −5.73, 3.03); Synergism Index (S): 0.77 (95% CI 0.31, 1.94)]. Similar findings were obtained for aspirin exposure. Non-aspirin NSAID users who carry e-NOS intron 4 VNTR polymorphism have lower odds of UGIH [OR: 4.02 (95% CI 1.85, 8.75) than those users with wild type genotype [OR: 6.52 (95% CI 4.09, 10.38)]; though the interaction estimates are not statistically significant [RERI: −2.68 (95% CI −6.67, 1.31); S: 0.53 (95% CI 0.18, 1.55)]. This exploratory study suggests that the odds of UGIH in NSAID or aspirin users does not modify according to patient´s e-NOS intron 4 genotype. This work was supported by a grant from Instituto de Salud Carlos III [PI12/02414]/Plan Estatal de I + D + I 2012–2016; Fondo Europeo de Desarrollo Regional (FEDER); the Novartis, Pfizer and Dr Esteve pharmaceutical companies; the Health Research Fund/Fondo de Investigación Sanitaria [PI021512, PI021364, PI020661, PI021572]; Ministry of Health & Consumer Affairs, Spain [SAF2002-04057]; Galician Regional Authority, Spain [PGIDIT03PXIC20806PN]; Department of Health of the Basque Country [03/11092 and 11/111103]; and Fundacion vasca de innovacin e investigacin sanitarias [OSIBG19/002 and OSIBG18/105]. The genotyping service was carried out at CEGEN-PRB3-ISCIII; Instituto de Salud Carlos III and ERDF [PT17/0019, of the PE I + D + I 2013–2016].

Rheumatoid arthritis (RA) is a common autoimmune disease in which many different genetic variants of functional gene polymorphisms may play a culprit role in the underlying pathogenetic mechanism. The recent studies suggest that interleukin-23 receptor (IL-23R) gene polymorphisms may increase susceptibility to the development of various autoimmune diseases. We aimed to examine the possible relationship of nine single nucleotide polymorphisms (SNPs) in the IL-23R gene to susceptibility to rheumatoid arthritis and their associations with disease characteristics in the South Aegean region of Turkey. We enrolled 100 rheumatoid arthritis patients and age- and sex-matched 96 healthy subjects in the study. After deoxyribonucleic acid (DNA) isolation was performed, a 'Restriction Fragment Length Polymorphism' (RFLP) method was used for the investigation of polymorphisms associated with the IL-23R gene. Allele identification and genotyping were obtained from polymerase chain reaction (PCR) products using gel electrophoresis. Allele frequencies and detected genotypes were compared between groups. All statistical analyses were performed using SPSS 25.0 (IBM SPSS Statistics 25 software (Armonk, NY: IBM Corp.)). Continuous variables were defined by the mean +/- standard deviation and categorical variables were defined by number and percent. Logistic Regression Analysis was used for determining which variables affect the presence of RA. Differences between categorical variables were analyzed with Chi-square analysis. Statistical significance was determined as p < 0.05. The mean age was 53.48 +/- 11.7 years in the RA group, whereas 52.55 +/- 12.7 years in the healthy control group. The genotypes of IL-23R with rs11805303(TT), rs10889677(AA), rs1004819(AA), and rs7530511(CT) polymorphisms were seen more often in RA patients than healthy controls. Having the AA genotype of IL-23R rs1004819 and the CT genotype of Il-23R rs7530511 increase the development risk of RA with a statistical significance (OR: 3.416 p = 0.003 and OR: 4.899 p = 0.0001, respectively). RA patients with the CC genotype of Il-23R with rs11805303, the CC genotype with rs10889677, and the TT genotype with rs2201841 of the IL-23R gene had higher erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels than with other genotypes. RA patients with the CC genotype rs11805303 and the GG genotype rs1004819 of the IL-23R gene had more active disease. Our findings suggest that all of the nine analyzed IL-23R gene polymorphisms are seen more frequently than healthy controls in our study population. Besides, some SNPs were related to higher acute phase reactants and higher disease activity scores.

Background: Idiopathic Nephrotic syndrome (INS) is an immune-mediated disease in which a number of cytokines, including IL-4 and IL-13, have been implicated in the pathogenesis. Cytokine gene polymorphisms might affect their levels and activity. Therefore, may affect INS susceptibility and response to treatment. The aim of the study was to determine the association of IL-4 and IL-13 gene polymorphisms and INS susceptibility and their effects on steroid responsiveness in children. Methods: The polymorphisms in IL-4 and IL-13 genes were detected by PCR-RFLP in 155 INS patients and 64 controls. Results: A total of 132 steroid-sensitive (SS) and 23 steroid resistance (SR) INS patients; mean age 7.3 ± 4.0 years, were included. Male: Female ratio was 2:1. No significant statistical differences were detected in the frequency of CC, CT, and TT genotypes of IL-4 gene compared to controls (P = 0.57, 0.61, and 1.00, respectively). There was no significant difference in the T and C-allele frequencies, in SS and SR subgroups. Analysis of IL-13 gene polymorphism also did not show significant statistical differences in the frequency of QQ, RQ, and RR genotypes compared to controls (P = 0.74, 1.00, and 0.68, respectively). No significant difference was found in the Q and R-allele frequency. However, the heterozygous RQ genotype of the IL13 gene was significantly higher in SS INS patients compared to the SR INS cases (P = 0.04). Conclusion: Our findings did not show an association between IL-4 and IL-13 gene polymorphisms and INS susceptibility. However, IL-13 RQ genotype was expressed more in children with INS who are steroid sensitive.

About half of the patients with fibromyalgia (FM) had a lifetime major depression episode and one third had a panic disorder (PD). Because the co-morbidity between bipolar disorder (BD) and PD marks a specific subtype of BD we aimed to investigate if co-morbid BD/PD (comBD/PD) occurs more frequently than the single disorder in FM patients and evaluate the clinical significance and timing of this co-morbidity. Further, we explored the role of co-morbid subthreshold BD and PD. In 118 patients with FM, lifetime threshold and sub-threshold mood disorders and PD were diagnosed with Diagnostic and Statistical Manual of Mental Disorders-IV-Text Revision (DSM-IV-TR) Clinical Interview. Demographic and clinical variables were compared in co-morbid BD/PD (comBD/PD) and not co-morbid BD/PD (nocomBD/PD) subgroups. The co-morbidity BD/PD was seen in 46.6% of FM patients and in 68.6% when patients with minor bipolar (MinBD) and sub-threshold panic were included. These rates are higher than those of the general population and BD outpatients. There were no statistically significant differences between threshold and sub-threshold comBD/PD and nocom-BD/PD subgroups in demographic and clinical parameters. In the majority of patients (78.2%), the onset of comBD/PD preceded or was contemporary with FM. These findings support the hypothesis that comBD/PD is related to the development of FM in a subgroup of patients.

Venous ulcers represent the most frequent ulcers and have a high clinical and socioeconomic significance. Nevertheless, pending questions remain on epidemiology, genetic and biomolecular mechanisms, contraindications and risk factors of compression therapy, role of pharmacological therapy. Overall prevalence in the range of 1-2% and point prevalence of 0.08-0.6% can be reduced if risk factors are identified and treated early. In this context, analysis of factor XIII and hemocromatosis gene polymorphisms, with the C282Y and H63D variants, may be of great importance. Also MMP12 gene polymorphism and the imbalance between matrix metalloproteinases and their tissue inhibitors are able to impair wound healing via deleterious degradation process of extra-cellular matrix. From a therapeutic point of view, conflicting recommendations exist on relative contraindications, risks and adverse events of compression therapy. Some studies showed that the administration of pentoxyphilline, Micronized purified flavonoid fraction (MPFF) and sulodexide was effective in accelerating ulcer healing, but there is no data on the duration of treatment, recurrence rates and cost-effectiveness relationship.

Bacterial meningitis (BM) is a severe disease caused by various bacterial pathogens. Toll-like receptors (TLRs) protect humans from invading pathogens. In this study, we determined whether single nucleotide polymorphisms (SNPs) of TLR4 and TLR9 are associated with susceptibility to and outcome of BM in Angolan children. Samples were taken from 241 patients and 265 age-matched ethnic controls. The SNPs TLR4 rs4986790 (896A &gt, G) and TLR9 rs187084 (&minus, 1486T &gt, C) were determined by high-resolution melting analysis (HRMA). The frequency of variant genotypes in TLR4 was significantly higher in patients with Haemophilus influenzae meningitis than controls (odds ratio (OR), 2.5, 95% confidence interval (CI), 1.2&ndash, 5.4, p = 0.021), whereas the frequency of variant genotypes in TLR9 was significantly lower in patients with H. influenzae meningitis than controls (OR, 0.4, 95% CI, 0.2&ndash, 0.9, p = 0.036). No such differences were found with other causative pathogens, such as Streptococcus pneumoniae and Neisseria meningitidis. At the time of discharge, patients with meningitis caused by Gram-negative bacteria who were carriers of variant TLR4 genotypes had a higher risk of ataxia (OR, 12.91, 95% CI, 1.52&ndash, 109.80, p = 0.019) and other neurological sequelae (OR, 11.85, 95% CI, 1.07&ndash, 131.49, p = 0.044) than those with the wild-type TLR4 genotype. Our study suggests an association between H. influenzae meningitis and genetic variation between TLR4 and TLR9 in Angolan children.

Background: To investigate the correlation between growth arrest-specific transcript 5 (GAS5) gene polymorphism and the risk and prognosis of prostate cancer in Chinese Han population. Methods: Sanger sequencing was used to analyze genotypes at the rs17359906 and rs1951625 loci of the GAS5 gene in 218 prostate cancer patients and 220 healthy controls. The follow-up period was from August 2016 to August 2019, and the relationships between GAS5 gene polymorphisms at the rs17359906 and rs1951625 loci and the recurrence-free survival rate of prostate cancer patients were analyzed. Results: GAS5 A-allele carriers at the rs17359906 locus were 3.44 times more likely to develop prostate cancer than G-allele carriers (95% confidence interval (CI): 2.38–4.96, P A and rs1951625 G > A were associated with high plasma PSA levels. The recurrence-free survival rate of patients with prostate cancer with AA genotype at the rs17359906 locus of GAS5 (66.67%) was significantly lower than that of the GA genotype (76.47%), whereas the GG genotype was the highest (91.96%), and the difference was statistically significant (P = .002). The recurrence-free survival rate of patients with prostate cancer with the AA genotype at the rs1951625 locus of GAS5 (75.00%) was significantly lower than that of the GA genotype (81.82%), whereas the GG genotype was the highest (87.76%) with a statistically significant difference (P = .025). Conclusion: GAS5 rs17359906 G > A and rs1951625 G > A are significantly associated with an increased risk of prostate cancer and a reduction in three-year relapse-free survival.