Study Of Single Nucleotide Polymorphisms Research Articles

Bacterial N-Acyl Homoserine Lactone Priming Enhances Leaf-Rust Resistance in Winter Wheat and Some Genomic Regions Are Associated with Priming Efficiency.

Leaf rust (Puccinia triticina) is a common disease that causes significant yield losses in wheat. The most frequently used methods to control leaf rust are the application of fungicides and the cultivation of resistant genotypes. However, high genetic diversity and associated adaptability of pathogen populations hamper achieving durable resistance in wheat. Emerging alternatives, such as microbial priming, may represent an effective measure to stimulate plant defense mechanisms and could serve as a means of controlling a broad range of pathogens. In this study, 175 wheat genotypes were inoculated with two bacterial strains: Ensifer meliloti strain expR+ch (producing N-acyl homoserine lactone (AHL)) or transformed E. meliloti carrying the lactonase gene attM (control). In total, 21 genotypes indicated higher resistance upon bacterial AHL priming. Subsequently, the phenotypic data of 175 genotypes combined with 9917 single-nucleotide polymorphisms (SNPs) in a genome-wide association study to identify quantitative trait loci (QTLs) and associated markers for relative infection under attM and expR+ch conditions and priming efficiency using the Genome Association and Prediction Integrated Tool (GAPIT). In total, 15 QTLs for relative infection under both conditions and priming efficiency were identified on chromosomes 1A, 1B, 2A, 3A, 3B, 3D, 6A, and 6B, which may represent targets for wheat breeding for priming and leaf-rust resistance.

Inside the genome: understanding genetic influences on oxidative stress.

Genetics is a key factor that governs the susceptibility to oxidative stress. In the body, oxidative burden is regulated by the balance between the prooxidant genes that orchestrate processes that produce oxidant species, while the antioxidant genes aid those involved in scavenging these species. Together, the two components aid in maintaining the oxidative balance in the body. Genetic variations can influence the expression and activity of the encoded proteins which can then affect their efficiency in regulating redox processes, thereby increasing the risk of oxidative stress. This review studies single nucleotide polymorphisms (SNPs) that bear relevance to oxidative stress by exploring the variations in the prooxidant genes, such as XDH, CYBA, CYP1A1, PTGS2, NOS, and MAO and antioxidant genes including SOD, CAT, GPX, GSS, GLUL, GSR, GSTM1, GSTM5, GSTP1, TXN and HMOX1. Early identification of individuals at the increased risk of oxidative stress is possible from the assessment of sequence of these genes. Integrating genetic insights into oxidative stress management measures can pave the way for personalized medicine that tailors' healthcare approaches to individual genetic profiles. Effective genetic assessment along with routine quantification of biological markers can improve and monitor treatment strategies, enhancing mitigation approaches that maintain cellular health and promote longevity.

Association of fat mass and obesity associate (FTO) single nucleotide polymorphisms in the first intron and obesity risk among Indonesians

Obesity is one of the global pandemics characterized by an excessive fat buildup due to disruption of energy homeostasis in the body. As obesity is a risk factor for many other non-communicable diseases such as diabetes and coronary heart disease, it is crucial to understand the risk factors that contribute to the pathogenesis of obesity. Although obesity is mainly caused due to unhealthy lifestyles, genetic predisposition also plays a part in the pathogenesis of obesity. Individuals who carry risk alleles for genes that control energy balance in the body have a greater risk of developing obesity. Fat mass and obesity associate (FTO) is a gene strongly correlated with obesity and is widely expressed in the hypothalamus. This gene is predicted to have 89 common variations that affect obesity-related phenotypes. Among Indonesians, the three most studied single nucleotide polymorphisms (SNPs) in the first intron of the FTO gene are rs1421085, rs17817449, and rs9939609. They are strongly associated with obesity’s related traits such as weight gain, fat mass, body mass index (BMI), waist, and hip sizes. rs993609 is the most studied among diverse ethnicities in Indonesia, with AA genotype and allele A as a risk allele.

Novel regulators of islet function identified from genetic variation in mouse islet Ca2+ oscillations.

Insufficient insulin secretion to meet metabolic demand results in diabetes. The intracellular flux of Ca2+ into β-cells triggers insulin release. Since genetics strongly influences variation in islet secretory responses, we surveyed islet Ca2+ dynamics in eight genetically diverse mouse strains. We found high strain variation in response to four conditions: (1) 8 mM glucose; (2) 8 mM glucose plus amino acids; (3) 8 mM glucose, amino acids, plus 10 nM glucose-dependent insulinotropic polypeptide (GIP); and (4) 2 mM glucose. These stimuli interrogate β-cell function, α- to β-cell signaling, and incretin responses. We then correlated components of the Ca2+ waveforms to islet protein abundances in the same strains used for the Ca2+ measurements. To focus on proteins relevant to human islet function, we identified human orthologues of correlated mouse proteins that are proximal to glycemic-associated single-nucleotide polymorphisms in human genome-wide association studies. Several orthologues have previously been shown to regulate insulin secretion (e.g. ABCC8, PCSK1, and GCK), supporting our mouse-to-human integration as a discovery platform. By integrating these data, we nominate novel regulators of islet Ca2+ oscillations and insulin secretion with potential relevance for human islet function. We also provide a resource for identifying appropriate mouse strains in which to study these regulators.

Novel regulators of islet function identified from genetic variation in mouse islet Ca2+ oscillations

Insufficient insulin secretion to meet metabolic demand results in diabetes. The intracellular flux of Ca2+ into β-cells triggers insulin release. Since genetics strongly influences variation in islet secretory responses, we surveyed islet Ca2+ dynamics in eight genetically diverse mouse strains. We found high strain variation in response to four conditions: (1) 8 mM glucose; (2) 8 mM glucose plus amino acids; (3) 8 mM glucose, amino acids, plus 10 nM glucose-dependent insulinotropic polypeptide (GIP); and (4) 2 mM glucose. These stimuli interrogate β-cell function, α- to β-cell signaling, and incretin responses. We then correlated components of the Ca2+ waveforms to islet protein abundances in the same strains used for the Ca2+ measurements. To focus on proteins relevant to human islet function, we identified human orthologues of correlated mouse proteins that are proximal to glycemic-associated single-nucleotide polymorphisms in human genome-wide association studies. Several orthologues have previously been shown to regulate insulin secretion (e.g. ABCC8, PCSK1, and GCK), supporting our mouse-to-human integration as a discovery platform. By integrating these data, we nominate novel regulators of islet Ca2+ oscillations and insulin secretion with potential relevance for human islet function. We also provide a resource for identifying appropriate mouse strains in which to study these regulators.

NEAT-seq: simultaneous profiling of intra-nuclear proteins, chromatin accessibility and gene expression in single cells.

In this work, we describe NEAT-seq (sequencing of nuclear protein epitope abundance, chromatin accessibility and the transcriptome in single cells), enabling interrogation of regulatory mechanisms spanning the central dogma. We apply this technique to profile CD4 memory T cells using a panel of master transcription factors (TFs) that drive T cell subsets and identify examples of TFs with regulatory activity gated by transcription, translation and regulation of chromatin binding. We also link a noncoding genome-wide association study single-nucleotide polymorphism (SNP) within a GATA motif to a putative target gene, using NEAT-seq data to internally validate SNP impact on GATA3 regulation.

The BDNF Val66Met Polymorphism (rs6265) Modulates Inflammation and Neurodegeneration in the Early Phases of Multiple Sclerosis

The clinical course of multiple sclerosis (MS) is critically influenced by the interplay between inflammatory and neurodegenerative processes. The brain-derived neurotrophic factor (BDNF) Val66Met polymorphism (rs6265), one of the most studied single-nucleotide polymorphisms (SNPs), influences brain functioning and neurodegenerative processes in healthy individuals and in several neuropsychiatric diseases. However, the role of this polymorphism in MS is still controversial. In 218 relapsing–remitting (RR)-MS patients, we explored, at the time of diagnosis, the associations between the Val66Met polymorphism, clinical characteristics, and the cerebrospinal fluid (CSF) levels of a large set of pro-inflammatory and anti-inflammatory molecules. In addition, associations between Val66Met and structural MRI measures were assessed. We identified an association between the presence of Met and a combination of cytokines, identified by principal component analysis (PCA), including the pro-inflammatory molecules MCP-1, IL-8, TNF, Eotaxin, and MIP-1b. No significant associations emerged with clinical characteristics. Analysis of MRI measures evidenced reduced cortical thickness at the time of diagnosis in patients with Val66Met. We report for the first time an association between the Val66Met polymorphism and central inflammation in MS patients at the time of diagnosis. The role of this polymorphism in both inflammatory and neurodegenerative processes may explain its complex influence on the MS course.

Полиморфизмы гена фибулина-5 (FBLN5) и истмико-цервикальная недостаточность

Objective. To study the role of fibulin-5 (FBLN5) gene polymorphisms in the genesis of cervical insufficiency (CI). Patients and methods. This observational retrospective study included 49 patients with clinical manifestations of CI and 31 patients without history of CI. Four most studied single-nucleotide polymorphisms (SNPs) in the FBLN5 gene were selected: rs2284337, rs2018736, rs2474028, rs12589592. DNA was extracted from whole venous blood, and genotyping was performed by polymerase chain reaction (PCR). STATISTICA 12.0 and SNPstats software packages were used for statistical data processing. Results. It was found that the rs2474028(T) allele of the FBLN5 gene is associated with a risk of developing CI (p = 0.0019). In addition, a comparison of a high-risk CI subgroup and a control group revealed that carriage of the heterozygous rs2018736(A/C) or the heterozygous rs12589592(A/G) genotypes of the FBLN5 gene is protective and reduces the risk of developing CI (p = 0.019 and p = 0.0021, respectively). Conclusion. The presence of single-nucleotide polymorphisms in the FBLN5 gene is associated with the development of CI. Key words: cervical insufficiency, pathogenesis, fibulin-5, FBLN5, SNP

Association of specific haplotype of tumor necrosis factor-α and interleukin-1β polymorphisms with Helicobacter pylori infection and gastric carcinogenesis.

The Helicobacter pylori infection and cytokine-mediated inflammatory responses play significant roles in the pathogenesis of gastric cancer (GC). This study was performed to determine the association between the risk of GC and genetic polymorphisms in interleukin (IL)-1β and tumor necrosis factor-alpha (TNF-α). The polymorphisms of IL-1β and TNF-α genes were analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in 290 patients who underwent endoscopy. Infection with H. pylori was diagnosed by histological analysis, rapid urease test, and PCR of gastric biopsy samples. Quantitative real-time PCR was performed to determine the relative mRNA expression levels. No significant difference was detected in allele frequency and genotype of all studied polymorphisms between chronic gastritis (CG), GC and healthy individuals. IL-1β mRNA was down-regulated in both gastritis (relative quantification (RQ)=0.447) and the GC groups (RQ=0.151). In contrast, the expression of TNF-α was up-regulated in the GC group (RQ=2.817) compared to the gastritis group (RQ=0.861). The studied single-nucleotide polymorphisms are not risk factors for development of CG and GC. However, H. pylori infection causes a huge increase in the TNF-α expression in GC patients.

Molecular Analysis of Single-Nucleotide Polymorphisms of TRAF5 Gene in Patients with Behçet's Disease from the Azeri Population of Northwest Iran

Background: Behçet's disease (BD) is a chronic inflammatory disease with unknown causes. The geographical distribution is mostly consistent with the historic Silk Road. The role of tumor necrosis factor receptor-associated factor 5 (TRAF5) gene in the inflammation signaling pathway leads more attention to the potency of different polymorphisms of the TRAF5 gene, in the development of BD. Methods: This was a case-control study conducted among the Azeri Turk ethnic group (50 BD patients and 50 persons with no history of autoimmune disease), Tabriz, Iran. Four different TRAF5 gene polymorphisms were assessed via the Polymerase Chain Reaction-Restriction Fragment Length Polymorphism technique. Data were analyzed by SPSS Version 20. Results: Genotypic distributions of four studied Single nucleotide polymorphisms (SNPs) had no significant difference between case and control groups (rs6540679 (p=0.50), rs12569232 (p=0.86), rs10863888 (p=0.14), and rs7514863 (p=0.24). There were also found no significant differences in SNP allelic frequencies between cases and controls

Cytotoxic T Lymphocyte Antigen 4 (CTLA4) Single Nucleotide Polymorphisms Do Not Impact Outcomes After Unrelated Donor Transplant: A Center For International Blood and Marrow Transplant Research Analysis

Cytotoxic T Lymphocyte Antigen 4 (CTLA4) is a critical T cell molecule that inhibits T cell activation and plays an essential role in T cell homeostasis and immune responses. Genetic variations in the CTLA4 gene have been hypothesized to be possible biologic markers that are predictive of transplant outcomes. Previous investigators have studied single nucleotide polymorphisms (SNPs) of the CTLA4 gene and its impact on hematopoietic cell transplantation (HCT) outcomes with discordant results. AA and AG genotypes in the donor CTLA4 regulatory region involving SNP rs4553808 in patients after unrelated donor (URD) HCT have recently been shown to be an independent predictor of improved relapse free survival (RFS) and overall survival (OS) compared to the GG genotype. To validate these preliminary findings, a Center for International Blood and Marrow Research (CIBMTR) study was performed in a larger, more homogenous cohort of patients.Adult patients with acute myeloid leukemia (AML) and advanced myelodysplastic syndrome (MDS) undergoing a first 8/8 or 7/8 HLA matched URD HCT after myeloablative, non-myeloablative, or reduced intensity conditioning from 2002 to 2007 in first or second complete remission with available donor research samples from the National Marrow Donor Program research repository were included. The primary goal was to evaluate the impact of SNP rs4553808 on RFS, OS, and NRM and the cumulative incidence of acute graft-versus-host disease (aGVHD), and chronic graft-versus-host disease (cGVHD). Any GVHD prophylaxis could be used except in vitro T-cell depletion or use of in vivo/in vitro alemtuzumab. Patients receiving T cell depletion with anti-thymocyte globulin (ATG) were oversampled to allow analysis of any effects on outcomes. An exploratory analysis of 9 other tagSNPs that encompass the entire CTLA4 gene (rs231775, rs231779, rs11571315, rs231777, rs3087243, rs16840252, rs231725, rs10197010, rs11571316) was performed to evaluate for any additional potential associations with clinical outcomes.Each SNP was analyzed in multivariable models adjusting for clinically significant variables using the Cox proportional hazards model. Due to multiple testing, p-values <0.005 were considered significant. The interaction with CTLA4 SNPs and use of ATG was also specifically analyzed. The final analysis included 780 patients with a median followup of 63 months. Median age of recipients and donors was 50 and 34, respectively. 90% of recipients were identified to be of Caucasian descent (N=709). 80% of patients had AML (N=624) and 20% MDS (N=156). Conditioning was 61% ablative, 28% reduced intensity and 11% non-myeloablative, with 74% receiving peripheral blood grafts. 75% were HLA-matched and 25% single locus mismatched. Tacrolimus with methotrexate or mycophenolate mofetil GVHD prophylaxis was given to 62%, cyclosporine-based prophylaxis to 15% while 23% received other regimens. By design, 50% of patients received ATG. Genotyping showed that 552 (71%) were AA, 208 (27%) were AG and 19 (2%) were GG (AG, and particularly GG, were associated with worse outcomes in the prior study). Multivariable analysis adjusting for significant donor and recipient characteristics showed no significant association between SNP rs4553808 and OS (p=0.07), RFS (p=0.41), NRM (p=0.25), and incidence of acute and chronic GVHD (Figure 1). Multivariable analysis of the other 9 tagSNPs also showed no association with transplant outcomes (p>0.005). No interaction was found between the CTLA4 SNPs and use of ATG on outcomes. These results indicate that CTLA4 SNPS do not have impact on outcomes. Other genomic or cellular biomarkers need to be studied to risk stratify patients at high risk of negative clinical events, especially as therapies targeting CTLA4 and PD-1 evolves. [Display omitted] [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Mortality after Allogeneic Stem Cell Transplantation Associates with Gene Polymorphisms in CD40L and Thrombomodulin in the Absence of Statins

Purpose:Endothelial vulnerability is a novel concept to understand complications after allogeneic stem cell transplantation (alloSCT). The concept is based on genetic polymorphisms in the recipients' thrombomodulin gene (THBD) and endothelial related serum markers prior to conditioning therapy. These parameters predict outcome of alloSCT. CD40 ligand (CD40L) is a key orchestrator of immune responses. Its expression on endothelial cells led us to study single nucleotide polymorphisms (SNPs) in the recipients' CD40L gene on outcome after alloSCT.Patients and methods:Three CD40L gene SNPs (rs3092920, rs30929252, rs3092936) were correlated with outcome endpoints in 342 alloSCT recipients. The SNPs had at least 10% minor allele frequency and tagged additional 21 polymorphisms encompassing 30 kb region of gene locus. The chosen three polymorphisms are in linkage disequilibrium with CD40LG haplotype (TGGC) of rs975379, rs3092952, rs3092933 and rs3092929 polymorphisms that was associated with increased circulating soluble CD40 ligand in inflammatory disorders.Overall survival (OS), non-relapse mortality (NRM), acute GVHD-related mortality, and transplant-associated microangiopathy (TAM) were analyzed. The genotype relevant to outcome was subsequently tested in an independent cohort (n=364) and merged into a genetic risk score with established THBD polymorphisms (rs1962, rs1042579 and rs1042580 (Rachakonda, et al., JCO 2014)). Validation of this risk score was attempted in the independent cohort. Finally, the score was evaluated in 375 independent, non-randomized patients taking statin-based endothelial prophylaxis.Results:While rs3092920 and rs30929252 had no impact on any endpoint, rs3092936 CC/CT genotype was associated with an increased risk of TAM (HR 4.83, p=0.001, 95%CI, 1.89-12.37), NRM (HR 2.24, p=0.019, 95%CI, 1.15-4.40) and acute GVHD-related mortality (HR 3.02, p=0.005, 95%CI, 1.39-6.56) (Figure 1). The combined genetic high risk score (CD40L and THBD) predicted OS and NRM in uni- and multivariable analyses (Multivariable analysis, training cohort, OS: HR 1.50, 95% CI 1.07-2.01, p=0.018; NRM: HR 2.52, 95% CI 1.54-4.13, p=0.0003; validation cohort, OS: HR 1.51, 95% CI 1.05-2.17, p=0.025; NRM: HR 2.17, 95% CI 1.25-3.78, p=0.006). In order to confirm and validate the prognostic impact of the genetic risk score on NRM in patients without statin therapy, the cause-specific Cox model was fitted to the validation cohort with an offset equal to the effect of the genetic risk score in the training cohort. The effect of THBD+CD40L score in the validation cohort was not significantly different from the effect in the training cohort.The predictive impact of the genetic risk score was completely lost in patients taking statins.Conclusion:The rs3092936C allele in the recipients' CD40L gene independently associates with NRM and risk of TMA. A combined genetic score based on THBD and CD40L polymorphisms strongly predicted outcome, but only in the absence of a statin based endothelial protection. Our results support the hypothesis that endothelial vulnerability can be defined prior to allogeneic stem cell transplantation by genetic markers in the recipient's genome. The normalization of mortality risk in patients treated with statins suggests a way of overcoming the negative impact of high risk genotypes and warrants further clinical validation. [Display omitted] DisclosuresLuft:Alexion: Consultancy; Neovii: Research Funding. Dreger:AbbVie: Consultancy, Other: Travel grants, Speakers Bureau; AbbVie: Consultancy, Other: Travel grants, Speakers Bureau; AbbVie: Consultancy, Other: Travel grants, Speakers Bureau; AbbVie: Consultancy, Other: Travel grants, Speakers Bureau; AbbVie: Consultancy, Other: Travel grants, Speakers Bureau; AbbVie: Consultancy, Other: Travel grants, Speakers Bureau; Riemser: Consultancy, Research Funding; Riemser: Consultancy, Research Funding; Riemser: Consultancy, Research Funding; Jansen: Consultancy; Gilead: Consultancy, Speakers Bureau; Riemser: Consultancy, Research Funding; Riemser: Consultancy, Research Funding; AbbVie: Consultancy, Other: Travel grants, Speakers Bureau; Riemser: Consultancy, Research Funding; Riemser: Consultancy, Research Funding; Riemser: Consultancy, Research Funding; Jansen: Consultancy; Riemser: Consultancy, Research Funding; AbbVie: Consultancy, Other: Travel grants, Speakers Bureau; Riemser: Consultancy, Research Funding; Jansen: Consultancy; AbbVie: Consultancy, Other: Travel grants, Speakers Bureau; Riemser: Consultancy, Research Funding; AbbVie: Consultancy, Other: Travel grants, Speakers Bureau; Jansen: Consultancy; Jansen: Consultancy; AbbVie: Consultancy, Other: Travel grants, Speakers Bureau; Jansen: Consultancy; Gilead: Consultancy, Speakers Bureau; AbbVie: Consultancy, Other: Travel grants, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Jansen: Consultancy; Riemser: Consultancy, Research Funding; Gilead: Consultancy, Speakers Bureau; Jansen: Consultancy; Jansen: Consultancy; medac: Other: Travel grants; medac: Other: Travel grants; medac: Other; medac: Other; medac: Other; Gilead: Consultancy, Speakers Bureau; Jansen: Consultancy; Gilead: Consultancy, Speakers Bureau; Jansen: Consultancy; Gilead: Consultancy, Speakers Bureau; medac: Other: Travel grants; Jansen: Consultancy; Gilead: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; medac: Other: Travel grants; Gilead: Consultancy, Speakers Bureau; medac: Other: Travel grants; medac: Other: Travel grants; medac: Other.

A clinical case of multiple primary cancers in a carrier of rare SDK2 and NOTCH2 gene mutations

BackgroundGenetic predisposition is one of the risk factors for the development of multiple primary cancers (MPCs), the frequency of which increases and ranges from 2 to 17%. This study describes a combination of rare mutations, rs746551843 in the NOTCH2 gene and rs144933006 in the SDK2 gene, in a woman with breast cancer and leiomyosarcoma without a clearly burdened family history.Case presentationA 55-year-old Caucasian woman received complex treatment on the basis of the National Medical Research Centre for Oncology for left breast cancer and leiomyosarcoma of soft tissues of the left thigh. The patient was referred for consultation with a geneticist. Among direct relatives, a maternal aunt with a history of kidney cancer was not a carrier of the studied single nucleotide polymorphisms (SNPs). The healthy son of the patient inherited both mutations.ConclusionThus, perhaps in the described case, there is a synergistic effect of two alleles of moderate and low penetrance, which led to the phenotype of multiple primary cancers.

Integrative analysis of eosinophilic esophagitis genome-wide association study single-nucleotide polymorphisms

Eosinophilic esophagitis (EoE) is a multifactorial, complex allergic disorder of the esophagus. GWAS have identified potential causal loci, however overall these are associated with modest increases in disease risk. This study integrates gene expression and epigenetic data with GWAS to more completely characterize the molecular basis of EoE.

Association between VEGF single nucleotide polymorphism and breast cancer in the Northern China Han population.

To investigate the associations of four commonly studied single nucleotide polymorphisms (SNP) of the vascular endothelial growth factor (VEGF), including -460T/C (rs833061), - 634G/C (rs2010963), - 2578C/A (rs699947), and +936T/C (rs3025039), with the incidence, aggressiveness, and tumor markers expression of breast cancer in the Northern China Han population. Followed the genomic DNA extraction, a total of 259 patients with breast cancer (case group) and 273 healthy women (control group) underwent genotyping by PCR-LDR SNP assays. The associations between VEGF gene polymorphisms and the incidence, aggressiveness, and tumor markers expression of breast cancer were analyzed. Significant differences were observed in allele frequency and genotype distribution of - 634G/C between breast cancer cases and healthy controls (p = 0.006, 0.013). Individuals who carry the G allele more likely had a lower risk of breast cancer (OR, 0.866, 95% CI 0.782-0.959). Compared with CC genotype carriers, women who had the CG and GG genotypes demonstrated a relatively lower risk (OR, 0.860, 95% CI 0.757-0.978, p = 0.022; OR, 0.778, 95% CI, 0.656-0.924, p = 0.004, respectively). When we stratified the group of patients according to the status of tumor markers, a significant association of - 634G/C SNP and Ki-67 expression was observed. The CC genotype carriers were more likely to be characterized by high expression of Ki-67 (p = 0.031). Further analysis showed that the - 460T/-634C/-2578C/+936C haplotype was more associated with a higher risk of breast cancer (OR, 1.445, 95% CI 1.123-1.859, p = 0.004), whereas the - 460T/- 634G/- 2578C/+936C one was associated with a lower risk (OR, 0.736, 95% CI 0.563-0.963, p = 0.025). In the present study, we concluded that VEGF gene - 634G/C polymorphism is related to the incidence of breast cancer in the Han population in Northern China and also might be associated with tumor proliferation index Ki-67.

Association of CYP2C19, TNF-α, NOD1, NOD2, and PPARγ polymorphisms with peptic ulcer disease enhanced by Helicobacter pylori infection.

Objectives:To assess the correlation between a number of genetic variations of CYP2C19, TNF-α, NOD1, NOD2, and PPARγ genes with the severity of Helicobacter pylori (H. pylori) infections and peptic ulcers (PU).Methods:A retrospective cross-sectional design was used in this study. Formalin-fixed paraffin-embedded (FFPE) tissue was used to extract genomic DNA that was collected from Jordanian patients who visited endoscopy clinics between 2014 to 2018 at the King Abdullah University Hospital (KAUH), Irbid, Jordan. Genotyping of the studied single nucleotide polymorphisms (SNPs) were applied using the sequencing protocol.Results:A total of 251 patients (mean age: 42.12 ± 16.09 years) and healthy controls (mean age: 52.76 ± 19.45 years) were enrolled in this study. This study showed no significant association between patients and the studied polymorphisms except for rs2075820 of the NOD1 (p=0.0046). It is hypothesized that the heterozygous genotype (TC); 44.8% in patients versus 61.3% in controls has a decreased risk of peptic ulcers (OR: 0.49). The alleles frequency association was insignificant in all studied SNPs with a p-value more than 0.05.Conclusion:This study provided evidence regarding the association of the rs2075820 with H. pylori infections. The other studied SNPs were not statistically significant.

PD-L1 polymorphisms predict survival outcomes in advanced non-small-cell lung cancer patients treated with PD-1 blockade.

We previously reported that PD-L1 polymorphisms are associated with the efficacy and immune-related adverse events of PD-1 blockade with nivolumab. However, the association between PD-L1 polymorphisms and survival outcomes under PD-1/PD-L1 blockade is still uncertain. Here, we aimed to investigate whether PD-L1 polymorphisms are associated with survival outcomes in advanced non-small-cell lung cancer (NSCLC) patients treated with nivolumab. PD-1/PD-L1 polymorphisms and survival outcomes were retrospectively analysed in two independent cohorts (133 patients treated with nivolumab and 96 patients with no treatment history of an immune checkpoint inhibitor (ICI) (the non-ICI cohort)) with advanced NSCLC. Among the 7 studied single-nucleotide polymorphisms, PD-L1 rs822339 and rs1411262 were associated with overall survival (OS) in patients treated with nivolumab. Patients with the A/A genotype of rs822339 had a significantly longer OS than those with A/G or G/G genotypes (not reached versus 12.0 months; hazard ratio (HR), 0.35; 95% confidence interval (CI), 0.18-0.64; p=0.0008). A similar survival benefit with the A/A genotype was observed regardless of driver mutation status. In multivariate analysis, performance status (PS) and PD-L1 rs822339 genotype were independent prognostic factors for OS. In the non-ICI cohort, the PD-L1 rs822339 genotype did not correlate with OS (HR, 0.77; 95% CI, 0.31-1.70; p=0.55). The T/T genotype of rs1411262 also showed a significant prolongation of OS compared to that with the C/T or C/C genotypes in patients treated with nivolumab. PD-L1 polymorphisms are associated with favourable OS in nivolumab-treated NSCLC patients and may be useful predictive biomarkers, regardless of driver mutation status.

Sequence Variation in the DDAH1 Gene Predisposes for Delayed Cerebral Ischemia in Subarachnoidal Hemorrhage.

Delayed cerebral ischemia (DCI) often causes poor long-term neurological outcome after subarachnoidal hemorrhage (SAH). Asymmetric dimethylarginine (ADMA) inhibits nitric oxide synthase (NOS) and is associated with DCI after SAH. We studied single nucleotide polymorphisms (SNPs) in the NOS3, DDAH1, DDAH2, PRMT1, and AGXT2 genes that are part of the L-arginine–ADMA–NO pathway, and their association with DCI. We measured L-arginine, ADMA and symmetric dimethylarginine (SDMA) in plasma and cerebrospinal fluid (CSF) of 51 SAH patients at admission; follow-up was until 30 days post-discharge. The primary outcome was the incidence of DCI, defined as new infarctions on cranial computed tomography, which occurred in 18 of 51 patients. Clinical scores did not significantly differ in patients with or without DCI. However, DCI patients had higher plasma ADMA and SDMA levels and higher CSF SDMA levels at admission. DDAH1 SNPs were associated with plasma ADMA, whilst AGXT2 SNPs were associated with plasma SDMA. Carriers of the minor allele of DDAH1 rs233112 had a significantly increased relative risk of DCI (Relative Risk = 2.61 (1.25–5.43), p = 0.002). We conclude that the DDAH1 gene is associated with ADMA concentration and the incidence of DCI in SAH patients, suggesting a pathophysiological link between gene, biomarker, and clinical outcome in patients with SAH.

Analysis of Single Nucleotide Polymorphisms in HLA-DRA, IL2RA , and HMGB1 Genes in Multiple Sclerosis.

Multiple sclerosis (MS) is a common demyelinating neurodegenerative disorder with significant heritability. Previous studies have associated genetic variants in human leukocyte antigen (HLA) complex, IL2RA , and HMGB1 genes with the pathophysiology of MS. In order to investigate the gene association in the Iranian population, we performed a genotyping study of 36 variants in the mentioned genes using Sanger sequencing in 102 MS patients and 113 healthy controls. Our results identified significant associations as well as significant allele frequency differences in some of the studied single-nucleotide polymorphisms including rs4935356, rs3177928, and rs7197 from HLA-DRA gene, and rs12722489 and rs12722490 variants from IL2RA gene (p< 0.05). Moreover, the strong linkage disequilibrium of two common haplotypes was estimated from the HLA-DRA gene. This association study may suggest the role of these polymorphisms in the genetic susceptibility of MS in the Iranian population and would facilitate the recognition of causative variants in this disease.

The FGF-21 genetic variants rs838133 and rs838145 are associated with high salt intake in the Emirati population

Food predilection is linked to variants in the hepatokine “Fibroblast Growth Factor-21” gene (FGF21); with rs838133 linked to the sweet tooth in Caucasians. The effect of FGF21 variants on food intake is still unclear in other populations. A cohort of 196 healthy Emirati subjects was investigated [age: 30.34 ± 9.75yrs (44.4% males)]. The FGF21 rs838133 and rs838145 were genotyped. The daily intake was calculated based on a 61-item food frequency questionnaire. Multivariate analysis was performed using in house R script that implements two-way unsupervised hierarchical clustering to detect the association of the studied single-nucleotide polymorphisms (SNPs) and related SNPs in linkage disequilibrium, using data from the 1000 genome project. Both SNPs were in Hardy-Weinberg Equilaribium (HWE). BMI positively correlated with age (p = 0.002), but not with caloric intake. Salt intake was significantly higher in subjects homozygous (A: rs838133) and (G:rs838145),(p = 0.03 and 0.01, respectively). An interaction was observed between both SNPs; significantly associated with high salt intake. Using publicly available data, both SNPs fall within a region transmitted in Iberians which has a profile closely similar to Caucasians, but far from Chinese population. In conclusion, the minor alleles of FGF21 rs838145 and rs838133 are associated with high salt intake in Emiratis and may suggest neuro-metabolic link to dietary preference across different populations.