Role Of Single Nucleotide Polymorphisms Research Articles

Investigation of IL-4, IL-10, and HVEM polymorphisms with esophageal squamous cell carcinoma: a case-control study involving 1929 participants.

It is believed that an individual’s hereditary factors may be involved in the development of esophageal cancer (EC). The present study recruited 721 esophageal squamous cell carcinoma (ESCC) cases and 1208 controls and explored the roles of single nucleotide polymorphisms (SNPs) in the interleukin-4 (IL-4), IL-10, and herpesvirus entry mediator (HVEM) genes in contributing to ESCC risk. IL-4, IL-10, and HVEM SNPs were analyzed by employing an SNPscan method. After adjustment for body mass index (BMI), smoking, drinking, age and gender, we identified that the rs2070874 T>C locus in IL-4 gene decreased the risk of ESCC (CC vs. TT: P=0.008; CC vs. TT/TC: P=0.010). After a stratified analysis, we suggested that the IL-4 rs2070874 T>C variants might be a protective factor for ESCC in male, ≥63 years old, never smoking, drinking and BMI < 24 kg/m2 subgroups. In addition, we identified that the rs2243263 G>C polymorphism in IL-4 gene was a risk factor for ESCC development in the BMI ≥ 24 kg/m2 subgroup (GC vs. GG: P=0.030 and GC/CC vs. GG: P=0.018). We identified an association of the IL-4 rs2070874 T>C SNP with the decreased susceptibility of ESCC in stage I/II subgroup. Finally, we found an association of the IL-10 rs1800872 T>G SNP with a worse differentiation (TG vs. TT: P=0.048 and GG/TG vs. TT: P=0.032). In conclusion, the findings indicate a potential importance of IL-4 rs2070874 T>C, IL-4 rs2243263 G>C and IL-10 rs1800872 T>G SNPs in the development of ESCC.

A role of single nucleotide polymorphism in TNF, NOS3 and MMP9 genes at the risk of developing neonatal pneumonia

Neonatal pneumonia is one of the most common causes of infant mortality. Moreover, the diagnosis of this pathology represents a difficult task and requires to seek for additional solutions in clinical and laboratory practice. One of the current and promising ways to diagnose rerlies on search of predictive markers among the innate and adaptive immunity genes involved in disease pathogenesis. We used bioinformatics analysis to select genes playing essential role developing neonatal pneumonia. Next, cord blood samples collected from 234 newborns were examined by real-time polymerase chain reaction for nine polymorphic markers in the TNF, IL10, IL17A, IL17F, IL6, NOS3, and MMP9 genes. The results of statistical analysis showed that heterozygous genotypes in the MMP9 and TNF genes were associated with the risk of developing early neonatal pneumonia, and also the protective role of homozygotes AA in the MMP9 gene and GG in the TNF gene. A search for associations with a risk of intrauterine pneumonia revealed an unfavorable role for heterozygous genotypes in the NOS3 and MMP9 genes. Thus, due to difficulties in diagnosis or in case of developing neonatal pneumonia, it may be recommended to add genetic analysis for assessing polymorphic markers in the MMP9 (rs17576), TNF (rs1800629) and NOS3 (rs1549758) genes along with standard test assays.

Association between single nucleotide polymorphisms (SNPs) of IL1, IL12, IL28 and TLR4 and symptoms of congenital cytomegalovirus infection

Congenital cytomegalovirus (cCMV) infection is the most common intrauterine infection. A non-specific immune response is the first line of host defense mechanism against human cytomegalovirus (HCMV). There is limited data on associations between Single Nucleotide Polymorphisms (SNPs) in genes involving innate immunity and the risk and clinical manifestation of cCMV infection. The aim of the study was to investigate association between selected SNPs in genes encoding cytokines and cytokine receptors, and predisposition to cCMV infection including symptomatic course of disease and symptoms. A panel of eight SNPs: IL1B rs16944, IL12B rs3212227, IL28B rs12979860, CCL2 rs1024611, DC-SIGN rs735240, TLR2 rs5743708, TLR4 rs4986791, TLR9 rs352140 was analyzed in 233 infants (92 cCMV-infected and 141 healthy controls). Associations between genotyped SNPs and predisposition to cCMV infection and symptoms were analyzed. The association analysis was performed using SNPStats software. No statistically significant association was found between any genotyped SNPs and predisposition to cCMV infection and symptomatic course of disease. In relation to particular symptoms, polymorphism of IL12B rs3212227 was linked to decreased risk of prematurity (OR = 0.37;95%CI,0.14-0.98;p = 0.025), while polymorphism of IL1B rs16944 was linked to reduced risk of splenomegaly (OR = 0.36;95%CI,0.14-0.98; p = 0.034) in infants with cCMV infection. An increased risk of thrombocytopenia was associated with IL28B rs12979860 polymorphism (OR = 2.55;95%CI,1.03-6.32;p = 0.042), while hepatitis was associated with SNP of TLR4rs4986791 (OR = 7.80;95%CI,1.49-40,81; p = 0.024). This is the first study to demonstrate four new associations between SNPs in selected genes (IL1B, IL12B, IL28B, TLR4) and particular symptoms in cCMV disease. Further studies on the role of SNPs in the pathogenesis of cCMV infection and incorporation of selected SNPs in the clinical practice might be considered in the future.

Modulatory Role of Single Nucleotide Polymorphisms of Distinct Genetic Pathways on Clinical Behavior of Medullary Thyroid Carcinoma.

Role of RET proto-oncogene as predisposing gene for Medullary Thyroid Carcinoma is well established which provides the basis for clinical management of patients. However clinical behavior of MTC varies considerably among patients. Several studies have investigated whether SNPs in low penetrance genes could modulate the clinical behavior of MTC but with conflicting or inconclusive results. The present study aimed to investigate the modifier effect of 13 SNPs of three distinct genetic pathways -Detoxification, Cell cycle regulation and RET on the clinico-pathological features of hereditary and sporadic MTC. SNPs were genotyped using RFLP or TaqMan method. The genotypes were correlated with various clinico-pathological parameters (age and calcitonin levels at MTC diagnosis, tumor volume, nodal and distant metastasis). Nodal metastasis was the only clinico-pathological parameter showing significant association with any SNP. In the hereditary MTC group (n=77), incidence of nodal metastases was significantly higher in wild type allele for Cyp1A1m1, CDKN2A and CDKN2C (p=0.01 for all three). In sporadic MTC group (n=361) CDKN2C wild type allele had higher nodal metastasis (p=0.03). In this largest MTC cohort with comprehensive analysis of modulatory role of 13 most frequently studied SNPs with MTC clinical outcome, we observed a statistically significant association of few SNPs with nodal metastasis. However as these SNPs did not show association with any other clinico-pathological parameters like tumor volume or Calcitonin, they may not be true modifier of MTC. Additional large cohort studies with clinico-pathological details and long-term follow-up are needed to identify genetic modifiers of MTC behavior.

Single Nucleotide and Copy-Number Variants in IL4 and IL13 Are Not Associated with Asthma Susceptibility or Inflammatory Markers: A Case-Control Study in a Mexican-Mestizo Population

Background: Asthma is a complex and chronic inflammatory airway disease. Asthma’s etiology is unknown; however, genetic and environmental factors could affect disease susceptibility. We designed a case-control study aimed to evaluate the role of single-nucleotide polymorphisms (SNP), and copy-number variants (CNV) in the IL4 and IL13 genes in asthma susceptibility and their participation in plasma cytokine levels depending on genotypes Methods: We include 486 subjects, divided into asthma patients (AP, n = 141) and clinically healthy subjects (CHS, n = 345). We genotyped three SNP, two in the IL4 and two in the IL13 gene; also, two CNVs in IL4. The IL-4, IL-13 and IgE plasma levels were quantified. Results: Biomass-burning smoke exposure was higher in the AP group compared to CHS (47.5% vs. 20.9%; p < 0.01, OR = 3.4). No statistical differences were found in the genetic association analysis. In both CNV, we only found the common allele. For the analysis of IL-4, IL-13, and IgE measures stratified by genotypes, no significant association or correlation was found. Conclusion: In the Mexican-mestizo population, SNPs neither CNVs in IL4 nor IL13 are associated with asthma susceptibility or involved serum cytokine levels. Biomass-burning smoke is a risk factor in asthma susceptibility.

Predictive role of single nucleotide polymorphism (rs11614913) in the development of breast cancer in Pakistani population.

Aim:miRNAs play an important role in breast cancer (BC). Variations in miRNAs influence their maturation, expression and consequently regulation of their target genes. Materials & methods: In this study, single nucleotide polymorphism rs11614913 was genotyped in BC patients (n=300) and 230 controls by employing tetra primer amplification refractory mutation system PCR and Sanger sequencing (Macrogen Korea). Results: A significant difference was observed in the genotypes through co-dominant(χ2.#x00A0;=42.03; p<0.0001), additive(odds ratio [OR] =0.6441 [0.4887-0.8490, 95% confidence interval]; p<0.0019), dominant (OR=0.3996 [0.2809-0.5686], p<0.0001) and recessive (OR=0.2993 [0.1220-0.7347], p<0.009) statistical models showed decreased risk association of C allele with BC. Conclusion: Females having CT genotype are at higher risk of BC as compared with those having CC genotype.

Hepcidin gene polymorphisms and iron overload in \u03b2-thalassemia major patients refractory to iron chelating therapy

Backgroundβ Thalassemia is one of the most common groups of hereditary haemoglobinopathies. Affected people with thalassemia major are dependent on regular blood transfusion which on the long term leads to iron overload. Hepcidin is a peptide hormone and an important regulator of iron homeostasis, especially in thalassemia. Expression of this hormone is influenced by polymorphisms within the hepcidin gene, HAMP. Several studies emphasized the role of single nucleotide polymorphisms (SNPs) located in the promoter region of the gene. This study aimed to analyze the association between three SNPs in promoter of HAMP, c.-582A > G, c.-443C > T, and c.-153C > T, with iron overload in β-thalassemia major patients.MethodsA total of 102 samples from β thalassemia major patients were collected. Genomic DNA was extracted and segments of DNA encompassing rs10421768 and rs142126068 were sequenced. Statistical analysis was performed by SPSS Statistics 23 using independent t test and Fisher’s exact test.ResultsA total of 102 adult β-thalassemia major patients were genotyped for three SNPs in the promoter region of HAMP gene by PCR and direct sequencing. Most of the patients (71.3%) were iron overloaded (based on plasma ferritin > 1000 ng/ml) in spite of receiving regular iron-chelating therapy. Our analysis revealed a statistically significant difference between the level of cardiac iron accumulation and c.-582A > G variant (p = 0.02). For c.-443C > T statistical analysis was on the edge of the significant relationship between the minor allele and serum ferritin (p = 0.058). All samples were homozygous for allele C of c.-153C > T.ConclusionsDespite chelating therapy, iron overload is still one of the main complications of thalassemia. Our findings and others emphasize the role of hepcidin -582A > G polymorphism as a key component of iron homeostasis in these patients.

Diagnostic and therapeutic value of micro-RNAs in inflammatory bowel disease

Inflammatory bowel disease (IBD) is a heterogeneous chronic idiopathic inflammatory disease that includes ulcerative colitis (UC) and Crohn's disease with uncertain etiology and pathogenesis. The prevalence of IBD has steadily increased worldwide, affecting numerous groups of people in both developed and developing countries. Current guidelines are being re-defined with the aim for patients with established IBD to achieve mucosal healing and complete morphological figures with minimal drug toxicity, to diminish the likelihood of extra-intestinal manifestations and dysplasia/ colorectal cancer, and to prevent the need for surgery. Many patients with established IBD may require conventional treatment, as well as alternative treatment, due to non-response, loss of response, or intolerance to treatment regimen. In this context, stratification of risk and management of IBD could be based on personified strategy predominantly allocated to core components of pathogenesis of the disease. MicroRNAs (miRNAs) are defined as non-coding short RNAs which are involved in various stages of the natural evolution of IBD. Recent animal and clinical studies have shown the role of single nucleotide polymorphisms (SNPs) and signature of miRNAs in susceptibility to IBD, risk of clinical and histological exacerbation, and remission. The aim of the review is to summarize the knowledge regarding use of miRNAs as biomarkers and molecular targets in IBD.&#x0D;

NOTCH3 T6746C and TP53 P72R Polymorphisms Are Associated with the Susceptibility to Diffuse Cutaneous Systemic Sclerosis

Introduction. NOTCH pathway and TP53 protein are involved in the development of fibrosis and autoimmune disorders, respectively. The aim of this study was to evaluate the role of single nucleotide polymorphisms (SNPs) of NOTCH3 and TP53 genes and serum anti-TP53 antibodies with the susceptibility, clinical subset of systemic sclerosis (SSc), and clinical profile of SSc patient, particularly with lung involvement and disease activity. Objects and Methods. 124 white Polish SSc patients (101 with limited cutaneous SSc–lcSSc, and 23 with diffuse cutaneous SSc–dcSSc) and 100 healthy individuals were included in the study. Patients were assessed for the presence of autoantibodies and interstitial lung disease. Two SNPs at position 6746 of NOTCH3 and TP53 genes and serum anti-TP53 antibodies with the susceptibility, clinical subset of systemic sclerosis (SSc), and clinical profile of SSc patient, particularly with lung involvement and disease activity. Results The genotypic frequencies of the NOTCH3 and p=0.03; χ2 = 4.63). There was no significant difference between SSc patients and the control population in allele frequencies of both SNPs. The CT + CC genotypes of NOTCH3 and p=0.03; p=0.03; p=0.03; TP53 genes and serum anti-TP53 antibodies with the susceptibility, clinical subset of systemic sclerosis (SSc), and clinical profile of SSc patient, particularly with lung involvement and disease activity. p=0.03; Conclusion The CT + CC genotypes of NOTCH3 gene and PR + RR genotypes of the TP53 gene increased the risk of dcSSc development. Moreover, genotypes of CT + CC were associated with the active form of SSc suggesting the role of the NOTCH pathway in the pathogenesis of this disease.NOTCH3 and TP53 genes and serum anti-TP53 antibodies with the susceptibility, clinical subset of systemic sclerosis (SSc), and clinical profile of SSc patient, particularly with lung involvement and disease activity.

Potential pathological role of single nucleotide polymorphism (c.787T>C) in alkaline phosphatase (ALPL) for the phenotypes of hypophosphatasia.

Hypophosphatasia (HPP; OMIM 241510, 241500, and 146300) is an inherited metabolic disease characterized by defects of bone and tooth mineralization, which is caused by loss-of-function mutations in the ALPL gene encoding tissue non-specific alkaline phosphatase (TNSALP). In the last three decades, several studies have focused on the genotype-phenotype correlation in hypophosphatasia (HPP). In particular, functional tests based on in vitro analysis for the residual enzymatic activities of mutations have revealed a clear but imperfect genotype-phenotype correlation, suggesting that multiple potential factors modulate the phenotype. One of the missense variants identified in the tissue non-specific alkaline phosphatase (ALPL) gene, c.787T>C, has been considered as a benign polymorphism in HPP; however, its pathogenicity and role in disease manifestation remain controversial. We here report our recent experience of three unrelated families harboring the c.787T>C variant, suggesting clinical implications regarding the controversial pathogenicity of c.787T>C. First, despite the lack of obvious clinical phenotypes, homozygous c.787T>C would decrease the serum level of ALP activity. Second, c.787T>C might deteriorate phenotypes of a patient harboring another ALPL variant, especially one that has thus far presumed to be benign, e.g., the c.1144G>A variant. These cases contribute to the recent advances in understanding HPP to facilitate clinical recognition of more subtle phenotypes, further providing insights into the pathogenesis of HPP.

The Role of SNPs in IL1RL1 and IL1RAP Genes in Age-related Macular Degeneration Development and Treatment Efficacy.

Age-related macular degeneration (AMD) affects the central part of the retina and causes blindness. In developed countries, AMD occurs in people over 50 years old. Important factors for AMD pathogenesis are an immune response, inflammation, and genetic factors. This study aimed to determine the impact of IL1RL1 rs1041973 and IL1RAP rs4624606 single nucleotide polymorphisms (SNPs) on the occurrence of AMD and the outcome of treatment with aflibercept and bevacizumab. 563 patients with AMD and 281 healthy candidates were evaluated. Patients with exudative AMD were treated with intravitreal bevacizumab and aflibercept and, after 6 months based on the changes in best-corrected visual acuity and central macular thickness, were classified as 'responders' or 'poor-responders'. Genotyping of IL1RL1 rs1041973 and IL1RAP rs4624606 was accomplished using real-time PCR. Age was compared using the Mann-Whitney U-test. Categorical data (gender, genotype, and allele distributions) compared between groups using the χ2 test or the Fisher's exact test. Associations of gene polymorphisms were calculated using logistic regression analysis with adjustment for age in exudative and atrophic AMD analysis. An adjusted significance threshold for multiple comparisons α=0.025 was applied. Statistically significant differences in the distribution of IL1RAP rs4624606 genotypes (TT, TA and AA) were found between males with atrophic AMD and controls: 50%, 42.9% and 7.1% vs. 69.7%, 30.3% and 0%, respectively, p=0.015. Moreover, we found that 'responders' had a significantly better best-corrected visual acuity than 'poor-responders' before treatment (p=0.032). The central macular thickness was significantly lower in exudative AMD patients with IL1RL1 rs1041973 AA genotype than in wild type and heterozygous (CC+CA) genotype carriers before treatment (p=0.017). IL1RAP rs4624606 may be associated with atrophic AMD in males while IL1RL1 rs1041973 may play a protective role against macular thickening in exudative AMD patients.

The Role of Single-Nucleotide Polymorphisms in Pituitary Adenomas Tumorigenesis.

Pituitary adenomas (PAs) are among the most common intracranial neoplasms, but despite their histologically benign nature, these tumors sometimes grow large enough to cause symptoms of mass effect such as vision loss, headaches, or hypopituitarism. When they get this large, surgery will unfortunately not be curative and, other than prolactinomas, medical options are limited, and radiation has variable efficacy in controlling growth. Understanding the genetic perturbations, such as single nucleotide polymorphisms (SNPs), that promote the formation or growth of functional and nonfunctional PAs is important because such genetic insights could improve the diagnosis and subsequent classification of PAs as well as unlock potential therapeutic targets outside contemporary standard of care. While there have been great strides in the research of SNPs as drivers of PA formation and maintenance, a comprehensive discussion of these genetic mutations has not been undertaken. In the present article, and with the goal of providing scientists and clinicians a central review, we sought to summarize the current literature on SNPs and their relationship to PA formation. Across multiple tumor types, such as nonfunctioning PAs, prolactinomas, corticotroph adenomas, somatotroph adenomas, thyrotropic adenomas, and gonadotroph adenomas, SNPs in cell surface receptors implicated in proliferation can be appreciated. Polymorphisms found in tumor suppressors and cell cycle regulators have also been identified, such as p53 SNPs in nonfunctioning PAs or cyclin D1 in prolactinomas. While the translational relevance of SNPs in the formation of PAs is still in the early stages, the use of wide-scale genomic analysis to identify patients at risk for developing PAs could yield therapeutic benefit in the future.

An in silico approach to characterize nonsynonymous SNPs and regulatory SNPs in human TOX3 gene

Cancer is one of the deadliest complex diseases having multigene nature where the role of single-nucleotide polymorphism (SNP) has been well explored in multiple genes. TOX high mobility group box family member 3 (TOX3) is one such gene, in which SNPs have been found to be associated with breast cancer. In this study, we have examined the potentially damaging nonsynonymous SNPs(nsSNPs) in TOX3 gene using in silico tools, namely PolyPhen2, SNP&GO, PhD-SNP and PROVEAN, which were further confirmed by I-Mutant, MutPred1.2 and ConSurf for their stability, functional and structural effects. nsSNPs rs368713418 (A266D), rs751141352 (P273S, P273T), rs200878352 (A275T) have been found to be the most deleterious that may have a vital role in breast cancer. Premature stop codon producing SNPs (Q527STOP), rs1259790811 (G495STOP), rs1294465822 (S395STOP) and rs1335372738 (G8STOP) were also found having prime importance in truncated and malfunctional protein formation. We also characterized regulatory SNPs for its potential effect on TOX3 gene regulation and found nine SNPs that may affect the gene regulation. Further, we have also designed 3D models using I-TASSER for the wild type and four mutant TOX3 proteins. Our study concludes that these SNPs can be of prime importance while studying breast cancer and other associated diseases as well. They are required to be studied in model organisms and cell cultures, and may have potential importance in personalized medicines and gene therapy.

Recent developments and highlights in allergic rhinitis.

Allergic rhinitis (AR) is a disease with high prevalence all over the world and therefore needs to be thoroughly investigated and treated accordingly. The mechanisms underlying the pathology and treatment of AR have been widely studied, but many aspects remain unclear and warrant further investigations. This review presents an overview of recently published papers highlighting the risk factors, mechanisms, and treatment of AR. Additionally, recent studies discussing the role of single nucleotide polymorphism, DNA methylation, regulatory B cells, group 2 innate lymphoid cells, immunotherapy, and biologics in AR are also covered.

The role of single-nucleotide polymorphism (SNPs) in toxicity of induction chemotherapy based on cisplatin and paclitaxel in patients with advanced head and neck cancer

BackgroundInduction chemotherapy in locally-advanced head and neck squamous cell carcinoma (LAHNSCC) patients is potentially associated to serious adverse events. Biomarkers associated with toxicity could tailor its indication. This study evaluated the association between single-nucleotide polymorphisms (SNPs) in metabolic genes and toxicity to induction chemotherapy. Methods59 LAHNSCC phase II clinical trial patients (NCT00959387) were assessed regarding 47 metabolic genes (366 SNPs). Toxicities were graded (CTCAE 3.0) and statistical analysis was performed. ResultsThe SNPs rs8187710 (ABCC2) and rs1801131 (MTHFR) were associated to increased risk of gastrointestinal toxicity, whereas the SNPs rs3788007 (ABCG1) and rs4148943 (CHST3) were associated to decreased risk. Two other SNPs, rs2301159 (SLC10A2) and rs2470890 (CYP1A2), were associated with increased risk of hematological toxicity. Nevertheless, these SNPs did not remain significant after adjusting for multiple comparisons. ConclusionsThis study could not demonstrate relationship between SNPs and toxicity to induction chemotherapy in LAHNSCC patients. The small number of patients may have affected the results.

The association between polymorphisms in tankyrase gene and telomere length in omethoate–exposed workers

Peripheral blood leukocyte telomere length in omethoate–exposed workers is related to environmental exposure and single nucleotide polymorphisms (SNPs) in genes including p21, GSTM1, miR-145, etc. However, the roles of SNPs in tankyrase (TNKS) gene in telomere length are still unknown. The aim of this study was to explore the association between SNPs in TNKS gene and telomere length in omethoate–exposed workers. Telomere length in peripheral blood leukocyte DNA from 180 omethoate-exposed workers and 115 healthy controls was measured using Real-time quantitative polymerase chain reaction (PCR). Genotyping of the selected functional and susceptible SNPs was performed by the flight mass spectrometry based on PCR and single-base extension. The analysis of covariance was performed to find effects of SNPs on telomere length. Generalized linear models were used to analyze the environment, gene, and interaction on telomere length. The results showed that telomere length in the CG + CC genotypes in rs1055328 in TNKS gene was significantly longer than that in the wild homozygous GG genotype both in exposure group (P = 0.017) and in control group (P = 0.038) after adjusting the covariates. The variables kept in the generalized linear models included omethoate-exposure (β = 0.580, P = 0.001) and rs1055328 (CG + CC) in TNKS gene (β = 0.339, P = 0.002). The study suggests that the prolongation of telomere length is associated with omethoate-exposure and the CG + CC genotypes in rs1055328 in TNKS gene.

Long noncoding RNA PVT1: A highly dysregulated gene in malignancy.

Recent studies have verified the contribution of several long noncoding RNAs (lncRNAs) in the carcinogenesis. Among the highly acknowledged lncRNAs is the human homolog of the plasmacytoma variant translocation gene, which is called PVT1. PVT1 resides near Myc oncogene and regulates the oncogenic process through modulation of several signaling pathways, such as TGF-β, Wnt/ β-catenin, PI3K/AKT, and mTOR pathways. This lncRNA has a circular form as well. Expression analyses and functional studies have appraised the oncogenic roles of PVT1 and circPVT1. Experiments in several cancer cell lines have shown that PVT1 silencing suppresses cancer cell proliferation, whereas its overexpression has the opposite effect. Its silencing has led to the accumulation of cells in the G0/G1 phase and diminished the number of cells in the S phase. Moreover, genome-wide association studies have signified the role of single nucleotide polymorphisms of this lncRNA in conferring risk of lymphoma in different populations. In the current study, we have summarized recent data about the role of PVT1 and circPVT1 in the carcinogenesis process.

Role of the Allelic Variation in the 5-Hydroxytryptamine Receptor 1A (HTR1A) and the Tryptophan Hydroxylase 2 (TPH2) Genes in the Development of PTSD.

Post-traumatic stress disorder (PTSD) is a stress related disorder which can occur in an individual after exposure to a traumatic event. It most commonly co-occurs with depression. The two disorders share not only overlapping symptoms, but also genetic diathesis. The aim of this study was to investigate the potential role of single nucleotide polymorphisms (SNPs) of the two serotonergic candidate genes 5-hydroxytryptamine receptor 1A (HTR1A) and tryptophan hydroxylase 2 (TPH2) in the pathogenesis of PTSD and comorbid psychopathology. 719 (487 males, 232 females) participants who had experienced war-related trauma between 1991 and 1999 in Bosnia and Herzegovina, Kosovo and Croatia were included in the study. The Sociodemographic questionnaire, Mini International Neuropsychiatric Interview (M.I.N.I.), Clinician Administered PTSD Scale (CAPS) and Brief Symptom Inventory (BSI) were used to collect clinical data. The SNPs rs6295 (HTR1A), rs11178997 and rs1386494 (TPH2) were investigated for their association with PTSD and comorbid psychopathology. A nominal significant association was found between the BSI total score in Lifetime PTSD with the SNP rs6295 of the HTR1A gene. The best result was seen in the dominant model (P=0.018), with the minor allele (C) being the risk allele. Several BSI subscores were also associated with the minor (C) allele in Lifetime PTSD. No association was found for the TPH2 SNPs rs11178997 and rs1386494 in relation to PTSD or comorbid psychopathology. Our findings suggest that rs6295 in the HTR1A gene may contribute to the psychopathology of PTSD.

Abstract 1343: SNPs in the NFKB alternative pathway genes CD40, BAFFR and LTβR in CRC

Abstract We sought to assess the role of single nucleotide polymorphisms (SNPs) in genes of the alternative NF-KB pathway, important in regulating different aspects of immune functions in colorectal cancer (CRC). The study comprised DNA samples from 418 patients with CRC and 299 age-matched healthy individuals. Genotyping was performed with real time PCR followed by high resolution melt curve analysis for the following SNPs: CD40 rs1883832 (C/T), BAFFR rs7290134 (A/G), LTβR rs10849448 (A/G). Genotypes of random samples were confirmed by sequencing. Genotype frequencies differed between CRC and healthy individuals for CD40 rs1883832 and LTβR rs10849448 (p = 0.001 and p = 0.016, respectively) but were similar for BAFFR rs7290134. The LTβR rs10849448 G allele was more frequent in CRC patients compared to healthy controls and increased risk for CRC by 61% (p = 0.024). Moreover, the G allele was found more frequently in stage D patients compared to stages A and C while the A allele was more prevalent in stage B patients (p = 0.007). Additionally, most patients with grade III tumors were G allele carriers whereas the majority of grade I tumors were AA homozygotes (p = 0.019). The CD40 rs1883832 T allele was less frequent in CRC patients and reduced risk for CRC by 71% (p = 0.027). The CD40 rs1883832 SNP proved to be a prognostic factor for PFS with the CC individuals displaying a longer PFS compared to T carriers (p = 0.045). The BAFFR rs7290134 SNP was independent of all clinical parameters evaluated. Primary site was independent of genotypes for all three SNPs. SNPs within genes of receptors of the NF-KB alternative pathway, CD40 rs1883832 and LTβR rs10849448, influence PFS and risk for CRC development. Additionally, particular genotypes correlated with stage and grade. Citation Format: Anna Antonacopoulou, Anastasia Kottorou, Angelos Koutras, Foteinos-Ioannis Dimitrakopoulos, Thomas Makatsoris, Haralabos P. Kalofonos. SNPs in the NFKB alternative pathway genes CD40, BAFFR and LTβR in CRC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1343.

Genetic Variants Associated with the Development of Type 2 Diabetes: Approaches to Their Identification

In the development of type 2 diabetes (T2D), an important role is played by a combination of environmental factors (hypodynamia, hypernutrition, etc.) and genetic variants that predispose the development of the disease. The contribution of inherited traits to the development of T2D can reach 80%, which is confirmed by the results of a number of published studies. At the same time, the multifactorial and polygenetic nature of T2D makes it difficult to establish direct cause-effect relations between individual genetic variants and specific metabolic changes. This explains a large number of studies and a long ongoing search for the most convenient and effective strategy for assessing the role of single nucleotide polymorphisms (SNP), the main type of genetic variation in the human genome. Involvement of specialists from various fields and the emergence of many methods for processing and interpreting data have led to the parallel development of scientific approaches. In this review of the main approaches (except mathematical ones) their characteristics will be described and the results obtained with their help will be evaluated, with special focus on new features of modern methods of genome editing, in particular the CRISPR/Cas9 system, and the future prospects in this area.