Functional Single Nucleotide Polymorphisms Research Articles

Genetic polymorphisms of TLR1, TLR2, TLR3 and TLR4 in patients with recurrent or severe infections.

Toll-like receptors (TLRs) play an important role in innate immunity. Previous studies have shown that single nucleotide polymorphisms (SNPs) in the genes coding for these innate immune molecules can affect susceptibility to and the outcome of certain diseases. The aim of the present study was to examine the clinical relevance of well-studied TLR1-4 SNPs in individuals who are prone to infections. Four functional SNPs, TLR1 rs5743618 (1805C>A, Ser602Ile), TLR2 rs5743708 (2258G>A, Arg753Gln), TLR3 rs3775291 (1234C>T, Leu412Phe) and TLR4 rs4986790 (896A>G, Asp299Gly), were analysed in 155 patients with recurrent respiratory infections (n=84), severe infections (n=15) or common variable immunodeficiency (n=56), and in 262 healthy controls, using the High Resolution Melting Analysis method. Polymorphisms of TLR2 rs5743708 (odds ratio [OR] 3.16; 95% confidence interval [CI] 1.45-6.83, p=.004, ap=.016) and TLR4 rs4986790 (OR 1.8; 95% CI 1.05-3.12, p=.028, ap=.112) were more frequent in patients with recurrent or severe infections than in controls. Interestingly, seven patients were found to carry both variant genotypes of TLR2 and TLR4, whereas none of the control group carried such genotypes (p≤.0001). Moreover, TLR2 polymorphism was associated with increased risk for acute otitis media episodes (OR, 3.02; 95% CI 1.41-6.47; p=.012). This study indicates that children and adults who are more prone to recurrent or severe respiratory infections carry one or both variant types of TLR2 and TLR4 more often than control subjects. Genetic variations of TLRs help explain why some children are more susceptible to respiratory infections.

A Pilot Study of Detecting RS920778 and RS1899663 Genetic Variants of HOTAIR in A Cohort of Sporadic Breast Cancer Patients in Sri Lanka

Background: Some functional single nucleotide polymorphisms (SNPs) on the HOTAIR gene are potent to elevate breast cancer risk where rs920778 and rs1899663 are associated with the expression and function of the HOTAIR gene, and these SNPs were detected in the current study. Methods: A cohort of nine sporadic cancer patients and five healthy controls were screened for selected HOTAIR variants using direct sequencing. Results: Among patients, seven were with TT genotype, and other 2 with CT genotype for rs920778 C>T while two healthy controls showed TT, another two were with CT, and the remaining with CC genotypes. Among the cohort, the rs1899663 variant was not found in any patients and healthy controls., Conclusion: In the study, the T allele of rs920778 was prominent among the sporadic breast cancer in the studied cohort while only a wild allele (T) of rs1899663 was more prominent in the patients and healthy controls.

Association between STAT4 gene polymorphism and susceptibility to pulmonary tuberculosis in the Moldavian population.

Signal transducer and activator of transcription 4 (STAT4) plays a crucial role in the host immune response against Mycobacterium tuberculosis. This study investigates the association between STAT4 gene polymorphisms and pulmonary tuberculosis (TB) risk in the Moldavian population. A total of 272 TB patients and 251 community-matched controls underwent screening for functional single-nucleotide polymorphisms (SNPs) rs897200 and rs7574865 in the STAT4 gene. The minor T allele and the TT/CT genotype of rs897200 demonstrated a significant association with reduced pulmonary TB risk (allelic model: adjusted OR=.74, p=.025; log-additive model: adjusted OR=.72, p=.02; and dominant model: adjusted OR=.65, p=.023), indicating a protective effect. Similar associations, characterized by an even more pronounced reduction in risk, were observed among females and late-onset TB patients (>44 years). No significant associations were found for rs7574865. In addition, a combined genotype analysis incorporating 43 SNPs from our previous studies revealed potential associations, such as STAT4 rs897200 CT with IFNG rs2430561 AA (adjusted OR=.36, p=.0025) and STAT4 rs897200 CT with TNFA rs1800629 GA (adjusted OR=.33, p=.0012). This study emphasizes the significant association of STAT4 rs897200 with pulmonary TB risk in the Moldavian population, underscoring its role in the disease development.

Genetic evidence for involvement of β2-adrenergic receptor in brown adipose tissue thermogenesis in humans.

Sympathetic activation of brown adipose tissue (BAT) thermogenesis can ameliorate obesity and related metabolic abnormalities. However, crucial subtypes of the β-adrenergic receptor (AR), as well as effects of its genetic variants on functions of BAT, remains unclear in humans. We conducted association analyses of genes encoding β-ARs and BAT activity in human adults. Single nucleotide polymorphisms (SNPs) in β1-, β2-, and β3-AR genes (ADRB1, ADRB2, and ADRB3) were tested for the association with BAT activity under mild cold exposure (19 °C, 2 h) in 399 healthy Japanese adults. BAT activity was measured using fluorodeoxyglucose-positron emission tomography and computed tomography (FDG-PET/CT). To validate the results, we assessed the effects of SNPs in the two independent populations comprising 277 healthy East Asian adults using near-infrared time-resolved spectroscopy (NIRTRS) or infrared thermography (IRT). Effects of SNPs on physiological responses to intensive cold exposure were tested in 42 healthy Japanese adult males using an artificial climate chamber. We found a significant association between a functional SNP (rs1042718) in ADRB2 and BAT activity assessed with FDG-PET/CT (p < 0.001). This SNP also showed an association with cold-induced thermogenesis in the population subset. Furthermore, the association was replicated in the two other independent populations; BAT activity was evaluated by NIRTRS or IRT (p < 0.05). This SNP did not show associations with oxygen consumption and cold-induced thermogenesis under intensive cold exposure, suggesting the irrelevance of shivering thermogenesis. The SNPs of ADRB1 and ADRB3 were not associated with these BAT-related traits. The present study supports the importance of β2-AR in the sympathetic regulation of BAT thermogenesis in humans. The present collection of DNA samples is the largest to which information on the donor's BAT activity has been assigned and can serve as a reference for further in-depth understanding of human BAT function.

Additional prognostic value of polymorphisms within the 3'-untranslated region of programmed cell death pathway genes in early-stage breast cancer.

The programmedcell death (PCD) pathway plays an important role in restricting cancer cell survival and proliferation. However, limited studies have investigated the association between genetic variants in the 3'-untranslated region of the PCD pathway genes and breast cancer outcomes. In this study, we genotyped 28 potentially functional single nucleotide polymorphisms (SNPs)in 23 PCD pathwaygenesin 1,177patients withearly-stagebreast cancer(EBC)from a Han Chinese population.The median follow-up period was 174 months. Among all the candidateSNPs, fourindependent SNPs (rs4900321 and rs7150025 in ATG2B, rs6753785 in BCL2L11, and rs2213181 in c-Kit) were associated with invasive disease-free survival (iDFS), distant disease-free survival (DDFS), breast cancer-specific survival (BCSS)and overall survival (OS), respectively. Further combined genotypes of these four SNPs revealed that the survival decreasedas the number of unfavorable genotypes increased(Ptrend= 1.0 × 10-6, 8.5 × 10-8, 3.6 × 10-4, and 1.3 × 10-4for iDFS, DDFS, BCSS, and OS, respectively). Receiver operating characteristiccurve analysis demonstrated that incorporating unfavorable genotypes and clinicopathological variables improved the ability to predict EBC survival (P= 0.006, 0.004, 0.029, and 0.019 for iDFS, DDFS, BCSS, and OS, respectively).Additionally, rs6753785 and rs2213181 were associated with BCL2L11and c-KitmRNA expression, respectively. Our results suggest that these four SNPs may act as novel biomarkers for EBC survival, possibly by modulating the expression of the corresponding genes.

Genetic Susceptibility, Mendelian randomization and Nomogram Model Construction of Gestational Diabetes Mellitus

Abstract Context Gestational diabetes mellitus (GDM) is a pregnancy complicated disease that poses a risk to maternal and infant health. However, the etiology of the disease has been not yet elucidated. Objective To detect the genetic susceptibility and construct a nomogram model with significantly associated polymorphisms and key clinical indicators for early prediction of gestational diabetes mellitus (GDM). Methods 11 functional single nucleotide polymorphisms (SNPs) screened by genome-wide association study (GWAS) were genotyped in 554 GDM cases and 641 healthy controls. Functional analysis of GDM positively associated SNPs, Multivariate mendelian randomization (MVMR) and a GDM early predictive nomogram model construction were performed. Result rs1965211, rs3760675 and rs7814359 were significantly associated with genetic susceptibility to GDM after adjusting age and pre-pregnancy BMI (pre-BMI). It seems that GDM associated SNPs have effects on regulating target gene transcription factor binding, post transcriptional splicing, and translation product structure. Besides, rs3760675 can be expression quantitative trait locis (eQTLs) and increase the XAB2 mRNA expression level (P = 0.047). The MVMR analysis showed that the increase of clinical variables of BMI, HbA1c and FPG had significant causal effects on GDM (BMI-ORMVMR = 1.52, HbA1c-ORMVMR = 1.32, FPG-ORMVMR = 1.78), P &amp;lt;0.05. A nomogram model constructed with pre-BMI, FPG, HbA1c, and genotypes of rs1965211, rs3760675 and rs7814359 showed an area under the ROC curve of 0.824. Conclusion Functional polymorphisms can change women's susceptibility to GDM and the predictive nomogram model based on genetic and environmental factors can effectively distinguish individuals with different GDM risks in early stages of pregnancy.

Genome-wide analysis to uncover how Pocillopora acuta survives the challenging intertidal environment

Characterisation of genomic variation among corals can help uncover variants underlying trait differences and contribute towards genotype prioritisation in coastal restoration projects. For example, there is growing interest in identifying resilient genotypes for transplantation, and to better understand the genetic processes that allow some individuals to survive in specific conditions better than others. The coral species Pocillopora acuta is known to survive in a wide range of habitats, from reefs artificial coastal defences, suggesting its potential use as a starter species for ecological engineering efforts involving coral transplantation onto intertidal seawalls. However, the intertidal section of coastal armour is a challenging environment for corals, with conditions during periods of emersion being particularly stressful. Here, we scanned the entire genome of P. acuta corals to identify the regions harbouring single nucleotide polymorphisms (SNPs) and copy number variations (CNVs) that separate intertidal colonies (n = 18) from those found in subtidal areas (n = 21). Findings revealed 74,391 high quality SNPs distributed across 386 regions of the P. acuta genome. While the majority of the detected SNPs were in non-coding regions, 12% were identified in exons (i.e. coding regions). Functional SNPs that were significantly associated with intertidal colonies were found in overrepresented genomic regions linked to cellular homeostasis, metabolism, and signalling processes, which may represent local environmental adaptation in the intertidal. Interestingly, regions that exhibited CNVs were also associated with metabolic and signalling processes, suggesting P. acuta corals living in the intertidal have a high capacity to perform biological functions critical for survival in extreme environments.

TIM3 and CTLA4 immune checkpoint polymorphisms are associated with acute myeloid leukemia in Saudi Arabia

ABSTRACT Background Immune checkpoints are receptors on the surface of T cells that function crucially in suppressing the immune response, and they are implicated in autoimmunity and cancer diseases. Aim The present study aimed to investigate the relationship between functional single nucleotide polymorphisms (SNPs) of two immune checkpoint molecules, CTLA-4 and TIM-3, and acute myeloid leukemia (AML) in a Saudi population. Methods Two SNPs in CTLA-4 (rs231775, A > G) and TIM-3 (rs10515746, A > C) were genotyped in 229 subjects, including 98 patients and 131 healthy controls, from the Saudi population using TaqMan assay methods. Differential expression of these two genes was performed using in silico analysis. Results An association was found between polymorphisms in TIM-3 (OR: 6.01; 95% CI: 3.99–9.05, P < 0.0001) and the risk of AML. Inversely, the rs231775 SNP in the CTLA-4 gene was found to protect against AML in allelic, dominant, and additive models (P < 0.05). A significantly higher expression of TIM-3 in the blood of individuals with AML was observed. Conclusion This is the first study focusing on single nucleotide polymorphisms (SNPs) for CTLA-4 and TIM-3 in acute myeloid leukemia patients in a Saudi community and could be a potential new prognostic factor for this disease.

Interferon Regulatory Factor 5 Gene Polymorphisms and mRNA Expression Levels Are Associated with Neuromyelitis Optica Spectrum Disorder.

Interferon regulatory factor 5 (IRF5) is a critical transcription factor in the toll-like receptor signaling pathway. It is associated with autoimmune disorders, such as rheumatoid arthritis, systemic lupus erythematosus, and inflammatory bowel disease. However, the relationship between the functional single nucleotide polymorphisms (SNPs) of IRF5 and its mRNA expression level in patients with neuromyelitis optica spectrum disorder remains unclear. The present study aimed to investigate the relationship between polymorphisms and mRNA expression levels of the IRF5 gene with the incidence of neuromyelitis optica spectrum disorder (NMOSD) in northern Chinese Han people. Two loci of the IRF5 gene (rs2004640 and rs2280714) of 164 patients with NMOSD and 269 healthy subjects were genotyped using the multiple SNaPshot technique. The frequencies of alleles, genotypes, and haplotypes were compared. Stratified analysis was performed according to age, sex, AQP4 status, onset age, and Expanded Disability Status Scale (EDSS) score. The IRF5 mRNA levels in peripheral blood mononuclear cells (PBMCs) of 64 NMOSD patients (32 patients in the acute stage and 32 patients in the remission stage) and 35 healthy subjects were detected by real-time PCR. The association of SNP polymorphisms with the mRNA expression level was determined by nonparametric tests. Allele and genotype frequency distributions of rs2004640 showed significant differences between both groups. Compared to healthy controls, the frequency of rs2004640 T allele markedly increased in patients (OR = 1.51, 95% CI = 1.09-2.08, P = 0.005). Minor allele T and GT genotype of rs2004640 that significantly increases the risk of NMOSD were discovered using genetic inheritance models (codominant, dominant, and overdominant) and haplotype analyses. Subsequent haplotype analyses revealed that the major haplotype "T-A" containing the risk alleles (the SNP sequence of the alleles was rs2004640 and rs2280714) had adverse effects on NMOSD. Based on the stratification analysis according to the EDSS score, the GT genotype frequency in the EDSS ≥ 4 group (38.2%) was markedly lower than that in the EDSS < 4 group (61.8%) (OR = 0.32, 95% CI = 0.15-0.68, P = 0.0054), with a significant difference. The IRF5 mRNA expression level was increased in NMOSD patients compared to that in normal subjects. IRF5 gene polymorphisms may be tightly associated with the genesis and progression of NMOSD in northern Chinese Han people. IRF5 mRNA expression was increased in patients with NMOSD and significantly increased in patients with acute phase. Perhaps IRF5 expression levels can be used as a predictor of disease activity in the future.

Functional polymorphisms of NOS3 and GUCY1A3 affect both nitric oxide formation and association with hypertensive disorders of pregnancy.

Impaired nitric oxide (NO) formation may be associated with endothelial dysfunction and increased cardiovascular disease risk in preeclampsia (PE). Functional single-nucleotide polymorphisms (SNPs) of nitric oxide synthase 3 (NOS3) (rs3918226) and guanylate cyclase 1, soluble, alpha 3 (GUCY1A3) (rs7692387) increase susceptibility to the adverse consequences due to inadequate generation of NO by the endothelium. However, no previous study has examined whether these SNPs affect NO formation in healthy pregnancy and in gestational hypertension (GH) and PE. Here, we compared the alleles and genotypes of NOS3 (rs3918226) and GUCY1A3 (rs7692387) SNPs in normotensive pregnant women (NP, n = 153), in GH (n = 96) and PE (n = 163), and examined whether these SNPs affect plasma nitrite concentrations (a marker of NO formation) in these groups. We further examined whether the interaction among SNP genotypes is associated with GH and PE. Genotypes were determined using TaqMan allele discrimination assays, and plasma nitrite concentrations were determined by an ozone-based chemiluminescence assay. Multifactor dimensionality reduction was used to examine the interactions among SNP genotypes. Regarding NOS3 rs3918226, the CT genotype (p = 0.046) and T allele (p = 0.020) were more frequent in NP than in GH, and GH patients carrying the CT+TT genotypes showed lower nitrite concentrations than NP carrying the CT+TT genotypes (p < 0.05). Regarding GUCY1A3 rs7692387, the GA genotype (p = 0.013) and A allele (p = 0.016) were more frequent in PE than in NP, and NP women carrying the GG genotype showed higher nitrite concentrations than GH or PE patients carrying the GG genotype (p < 0.05). However, we found no significant interactions among genotypes for these functional SNPs to be associated with GH or PE. Our novel findings suggest that NOS3 rs3918226 and GUCY1A3 rs7692387 may affect NO formation and association with hypertensive disorders of pregnancy.

A mutation in LPAR2 activates the miR-939-5p-LPAR2-PI3K/AKT axis to regulate the proliferation and apoptosis of granulosa cells in sheep

Lysophosphatidic acid receptor-2 (LPAR2) is a G protein-coupled receptor, which is involved in various physiological processes such as cell development, proliferation, and apoptosis, and is thought to play an important role in follicular development and reproduction. There is evidence that miRNA recognition elements (MRE) in the gene 3′UTR often contain single nucleotide polymorphisms (SNPs) that can alter the binding affinity of the target miRNA, leading to dysregulation of gene expression. In this study, we detected a SNP in LPAR2 3 ′UTR (rs410670692, c.*701C > T) in 384 small-tailed Han sheep using Sequenom MassARRAY®SNP genotyping. Association analysis showed that the SNP was significantly associated with litter size. Then, the effect of LPAR2 rs410670692 mutation on gene expression in sheep hosts was studied by molecular biotechnology. The results showed that the expression of LPAR2 in the TT genotype was significantly higher than that in the CC genotype, which confirmed the existence of rs410670692, a functional SNP, in LPAR2 3′UTR. We then used bioinformatics methods and double luciferase reporter gene assay to predict and confirm LPAR2 SNP rs410670692 as the direct targeting regulatory element of miR-939-5p. Cell transfection experiments further found that SNP rs410670692 down-regulated the mRNA and protein levels of LPAR2 by influencing the binding of miR-939-5p. To understand the function and mechanism of miR-939-5p in sheep granulosa cells (GCs), we conducted cell proliferation and apoptosis experiments which showed inhibited GCs proliferation along with promoted GCs apoptosis upon overexpression of miR-939-5p. Moreover, overexpression of miR-939-5p promotes apoptosis of granulosa cells by blocking the LPAR2-dependent PI3K/Akt signaling pathway. In conclusion, these results indicate that the SNP rs410670692 of LPAR2 is related to the litter size of small-tailed cold sheep, and miR-939-5p can act as a regulatory element binding to the C mutation of rs410670692 to regulate the expression of LPAR2, affect the development of GCs, and thus indirectly affect the litter size of sheep. These studies provide evidence for the involvement of LPAR2 polymorphism in sheep reproduction and are expected to provide new insights into the molecular genetic mechanisms of litter size traits in sheep.

Abstract A010: AIB1 genotypes impact prognosis in endocrine-treated breast cancer patients – data from a population-based cohort

Abstract Background and purpose: The response to exogenous hormones differs between individuals. Part of the interindividual drug response can be attributed to genetic variation in the host. Previously it has been shown that the estrogen receptor (ER) coactivator amplified in breast cancer-1 (AIB1) genotype plays a role in response to oral contraceptives. Certain AIB1 genotypes have also been associated with breast cancer risk. Since others have shown that tumor AIB1 protein levels may predict response to different types of endocrine treatments, we aimed to investigate the prognostic impact of three functional single nucleotide polymorphisms (SNPs) in the AIB1 gene in patients with ER+ breast cancer. Method and materials: The study comprises 503 patients with a first invasive primary ER-positive breast cancer from the BCBlood cohort. Patients were included October 2002 to October 2008 in Lund, Sweden and followed until June 2019. DNA was extracted from blood. Clinicopathological factors, treatments and breast cancer events were obtained from preoperative questionnaires, patient charts and registry data. The AIB1 SNPs (rs6094752, rs2230782, rs2076546) were analyzed at the Region Skåne Competence Center of Skåne University Hospital in Malmö, Sweden. The software and equipment in the MassARRAY® platform (Sequenom, inc.) with the reagents included in the iPLEX™ genotyping kit were used to perform analyses according to the manufacturer’s instructions. Haplotypes were constructed based on crosstabulation and diplotypes were assembled from haplotypes. Univariable survival analyses were conducted with Kaplan-Meier and Log-rank tests and multivariable Cox regression was used to obtain adjusted hazard ratios (HR) with 95% confidence intervals. Results: In terms of adjuvant endocrine treatment, 127 used no endocrine treatment, 170 received Tamoxifen (TAM), 63 received an aromatase inhibitor (AI), and 143 received sequential treatment with TAM&amp;gt;AI or AI&amp;gt;TAM. During follow-up, 123 patients had breast cancer events. Four haplotypes were found: CGA (77.0%), CCA (12.2%), CGG (7.4%), TGA (3.3%). The common diplotype CGA_CGA (59.9%) was not associated with breast cancer events in TAM-treated patients (Log-rank P=0.54). Conversely, in non TAM-treated patients (± AIs), CGA_CGA was associated with less than half the risk for breast cancer events (HR 0.48 (95% CI 0.26-0.87), adjusted for age, BMI, tumor characteristics and adjuvant treatments. In all patients, there was a significant interaction (Pinteraction=0.023) between TAM and CGA_CGA with a 2-fold risk for breast cancer events in TAM-treated CGA_CGA carriers compared with other patients. Conclusion: The results suggest that AIB1 genotypes have differential prognostic impact depending on type of endocrine treatment in breast cancer patients. The study lends further support that host factors yield important information that can be used to refine selection of adjuvant treatment. If confirmed in a randomized trial of endocrine treatments, AIB1 genotype may be used to better tailor endocrine therapy to each patient. Citation Format: Louise Ebbesen, Alexandra Wiberg, Christopher Godina, Helga Tryggvadottir, Karolin Isaksson, Helena Jernstrom. AIB1 genotypes impact prognosis in endocrine-treated breast cancer patients – data from a population-based cohort [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr A010.

The HSP90AA1 Gene Is Involved in Heat Stress Responses and Its Functional Genetic Polymorphism Are Associated with Heat Tolerance in Holstein Cows

As the stress-inducible isoform of the Heat Shock Protein 90 (HSP90), the HSP90AA1 gene encodes HSP90α and plays an important role in heat stress (HS) response. Therefore, this study aimed to investigate the role of the HSP90AA1 gene in cellular responses during HS and to identify functional single nucleotide polymorphisms (SNP) associated with thermotolerance in Holstein cattle. For the in vitro validation experiment of acute HS, cells from the Madin-Darby bovine kidney (MDBK) cell line were exposed to 42°C for 1 h, and various parameters were assessed, including cell apoptosis, cell autophagy, and the cellular functions of HSP90α by using its inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG). Furthermore, the polymorphisms identified in the HSP90AA1 gene and their functions related to HS were in vitro validated. Acute HS exposure induced cell apoptosis, cell autophagy, and upregulated expression of the HSP90AA1 gene. Inhibition of HSP90α by 17-AAG treatment had a significant effect on the expression of the HSP90α protein (P < 0.05) and increased cell apoptosis. However, autophagy decreased in comparison to the control treatment when cells were exposed to 42°C for 1 h. Five SNPs identified in the HSP90AA1 gene were significantly associated with rectal temperature (RT; P < 0.05) and respiration score (RS; P < 0.05) in Holstein cows, in which the rs109256957 SNP is located in the 3' untranslated region (3' UTR). Furthermore, we demonstrated that the 3' UTR of HSP90AA1 is a direct target of bta-miR-1224 by cell transfection with exogenous miRNA mimic and inhibitor. The luciferase assays revealed that the SNP rs109256957 affects the regulation of bta-miR-1224 binding activity and alters the expression of the HSP90AA1 gene. Heat stress-induced HSP90AA1 expression maintains cell survival by inhibiting cell apoptosis and increasing cell autophagy. The rs109256957 SNP located in the 3' UTR region is a functional variation and it affects the HSP90AA1 expression by altering its binding activity with bta-miR-1224, thereby associating with the physiological parameters of Holstein cows.

Functional genetic variants of the disulfidptosis-related INF2 gene predict survival of hepatitis B virus-related hepatocellular carcinoma.

Disulfidptosis is a novel form of programmed cell death involved in migration and invasion of cancer cells, but few studies investigated the roles of genetic variants in disulfidptosis-related genes in survival of patients with hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). We used Cox proportional hazards regression analyses, Kaplan-Meier curves and receiver operating characteristic curves to assess effects of genetic variants in 14 disulfidptosis-related genes on overall survival of 866 HBV-HCC patients. The Bayesian false discovery probability was used for multiple testing corrections. We also investigated biological mechanisms of the significant variants through expression quantitative trait loci analyses using the data from publicly available databases, luciferase reporter assays and differential expression analyses. As a result, we identified two independently functional single nucleotide polymorphisms (SNPs) (INF2 rs4072285 G > A and INF2 rs4444271 A > T) that predicted overall survival of HBV-HCC patients, with adjusted hazard ratios of 1.60 (95% CI = 1.22-2.11, P = 0.001) and 1.50 (95% CI = 1.80-1.90, P < 0.001), respectively, after multiple testing correction. Luciferase reporter assays indicated that both INF2 rs4072285 A and INF2 rs4444271 T alleles increased INF2 mRNA expression levels (P < 0.001) that were also higher in HCC tumor tissues than in adjacent normal tissues (P < 0.001); such elevated INF2 expression levels were associated with a poorer survival of HBV-HCC patients (P < 0.001) in the TCGA database. In summary, this study supported that INF2 rs4072285 and INF2 rs4444271 may be novel biomarkers for survival of HBV-HCC patients.

Functional AGXT2 SNP rs180749 variant and depressive symptoms: Baseline data from the Aidai Cohort Study in Japan.

No study has shown the relationship between alanine-glyoxylate aminotransferase 2 (AGXT2) single nucleotide polymorphisms (SNPs) and depressive symptoms. The present case-control study examined this relationship in Japanese adults. Cases and control participants were selected from those who participated in the baseline survey of the Aidai Cohort Study, which is an ongoing cohort study. Cases comprised 280 participants with depressive symptoms based on a Center for Epidemiologic Studies Depression Scale (CES-D) score ≥ 16. Control participants comprised 2034 participants without depressive symptoms based on the CES-D who had not been diagnosed by a physician as having depression or who had not been currently taking medication for depression. Adjustment was made for age, sex, smoking status, alcohol consumption, leisure time physical activity, education, body mass index, hypertension, dyslipidemia, and diabetes mellitus. Compared with the GG genotype of rs180749, both the GA and AA genotypes were significantly positively associated with the risk of depressive symptoms assessed by the CES-D: the adjusted odds ratios for the GA and AA genotypes were 2.83 (95% confidence interval [CI] 1.23-8.24) and 3.10 (95% CI 1.37-8.92), respectively. The TGC haplotype of rs37370, rs180749, and rs16899974 was significantly inversely related to depressive symptoms (crude OR 0.67; 95% CI 0.49-0.90), whereas the TAC haplotype was significantly positively associated with depressive symptoms (crude OR 1.24; 95% CI 1.01-1.52). This is the first study to show significant associations between AGXT2 SNP rs180749, the TGC haplotype, and the TAC haplotype and depressive symptoms.

Identification of the SIRT1 gene's most harmful non-synonymous SNPs and their effects on functional and structural features-an in silico analysis.

The sirtuin (Silent mating type information regulation 2 homolog)1(SIRT1) protein plays a vital role in many disorders such as diabetes, cancer, obesity, inflammation, and neurodegenerative and cardiovascular diseases. The objective of this in silico analysis of SIRT1's functional single nucleotide polymorphisms (SNPs) was to gain valuable insight into the harmful effects of non-synonymous SNPs (nsSNPs) on the protein. The objective of the study was to use bioinformatics methods to investigate the genetic variations and modifications that may have an impact on the SIRT1 gene's expression and function. nsSNPs of SIRT1 protein were collected from the dbSNP site, from its three (3) different protein accession IDs. These were then fed to various bioinformatic tools such as SIFT, Provean, and I- Mutant to find the most deleterious ones. Functional and structural effects were examined using the HOPE server and I-Tasser. Gene interactions were predicted by STRING software. The SIFT, Provean, and I-Mutant tools detected the most deleterious three nsSNPs (rs769519031, rs778184510, and rs199983221). Out of 252 nsSNPs, SIFT analysis showed that 94 were deleterious, Provean listed 67 dangerous, and I-Mutant found 58 nsSNPs resulting in lowered stability of proteins. HOPE modelling of rs199983221 and rs769519031 suggested reduced hydrophobicity due to Ile 4Thr and Ile223Ser resulting in decreased hydrophobic interactions. In contrast, on modelling rs778184510, the mutant protein had a higher hydrophobicity than the wild type. Our study reports that three nsSNPs (D357A, I223S, I4T) are the most damaging mutations of the SIRT1 gene. Mutations may result in altered protein structure and functions. Such altered protein may be the basis for various disorders. Our findings may be a crucial guide in establishing the pathogenesis of various disorders.

Impact of OPRM1 (Mu-opioid Receptor Gene) A112G Polymorphism on Dual Oxycodone and Cocaine Self-administration Behavior in a Mouse Model

The use of mu-opioid receptor (MOP-r) agonists such as oxycodone together with cocaine is prevalent, and deaths attributed to using these combinations have increased. Rationale: It is unknown if functional single nucleotide polymorphisms (SNPs), such as the OPRM1 (MOP-r gene) SNP A118G, can predispose individuals to more dual opioid and psychostimulant intake. The dual self-administration (SA) of MOP-r agonists and cocaine has not been thoroughly examined, especially with regard to neurobiological changes. Objectives: We examined oxycodone SA and subsequent dual oxycodone and cocaine SA in male and female A112G (A/G and G/G, heterozygote and homozygote, respectively) mice, models of human A118G carriers, versus wild-type (A/A) mice. Methods: Adult male and female A/G, G/G and A/A mice self-administered oxycodone (0.25 mg/kg/infusion, 4hr/session, FR 1.) for 10 consecutive days (sessions 1–10). Mice then self-administered cocaine (2 hr) following oxycodone SA (4 hr, as above) in each session for a further 10 consecutive days (sessions 11–20). Message RNA transcripts of 24 reward-related genes were examined in the dorsal striatum. Results: Male and female A/G and G/G mice had greater oxycodone SA than A/A mice did in the initial 10 days and in the last 10 sessions. Further, A/G and G/G mice showed greater cocaine intake than A/A mice. Dorsal striatal mRNA levels of Pdyn, Fkbp5, Oprk1, and Oprm1 were altered following oxycodone and cocaine SA. Conclusions: These studies demonstrated that this functional genetic variation in Oprm1 affected dual opioid and cocaine SA and altered specific gene expression in the striatum.

Association of verbal and non-verbal theory of mind abilities with non-coding variants of OXTR in youth with autism spectrum disorder and typically developing individuals: a case-control study

BackgroundThe ability to attribute mental states to others is called theory of mind (ToM) and is a substantial component of social cognition. This ability is abnormally developed in individuals with autism spectrum disorder (ASD). Several studies over the past decade have identified the oxytocin receptor gene (OXTR) and its variants as promising components for explaining the molecular mechanisms underlying Theory of Mind (ToM). The main aim of this study is to examine the association between rs2268498 and rs53576, two functional single nucleotide polymorphisms (SNPs), and verbal and non-verbal ToM in children and adolescents with ASD and a group of typically developing youth.MethodsThe study involved 44 children and adolescents with high-functioning ASD aged 8 to 18 years old and 44 TD individuals who were matched on age and sex. In all participants, blood samples were collected and rs2268498 and rs53576 were genotyped. Happe’s Strange Stories test and the moving shapes paradigm were used to measure verbal and non-verbal ToM in all participants.ResultsThe results of permutation tests and logistic regression suggested that in TD group, rs2268498 AA carriers showed significant higher scores in variables representing verbal ToM (ToM stories and appropriateness score) whereas, in ASD group, rs53576 AA carriers exhibited significant better performance in parameters related to non-verbal ToM (ToM general rule and intentionality score). The results of hierarchical clustering in both groups support the findings by distinguishing between language-related and language-independent aspects of ToM.ConclusionsIn the present study, we examined the association between rs2268498 and rs53576 and social functioning in individuals with ASD and TD group. We found preliminary evidence that rs2268498 and rs53576 are associated with ToM related abilities in healthy individuals as well as in autistic individuals. Accordingly, rs2268498 and rs53576 may play an important role in predicting ToM capabilities. It will be necessary to conduct further research to address the association of genetic variants with a deficit in ToM in individuals with ASD.

CD38 gene polymorphism rs1130169 contribution to the increased gene expression and risk of colorectal cancer (pilot study).

Genetic variations in immune signaling genes may have regulatory effect on phenotypic heterogeneity of immune cells and immune functions, hence promoting tumor growth. We compared the frequencies of potentially functional CD38 gene single nucleotide polymorphisms rs1130169 (T > C) in 86 healthy controls and 90 colorectal cancer (CRC) cases to assess their association with cancer risk and CD38 gene expression. The association between allele C rs1130169 and CRC risk was observed. Allele C was also significantly correlated with an increased CD38 mRNA level and CD38 positive cell percentages in peripheral blood of healthy controls that could be a possible explanation for CRC risk in C allele carriers. In peripheral blood of CRC patients CD38 mRNA and serum soluble CD38 protein levels significantly differed from those in healthy controls. Calculation of the CD38 full-length and with the third exon deletion mRNA ratio in corresponding samples showed that the mRNA isoform ratio was significantly higher in CRC cases than in controls. It suggests that alternative splicing regulates elevation of CD38 full-length mRNA level in peripheral blood of CRC patients. We also have observed higher expression levels of CD38 full-length mRNA in peripheral blood of CRC patients with lymph node metastases compared to patients without metastases. This study indicated biological significance of rs1130169 variations that can alter differences in CRC risk by regulating CD38 gene expression.

CE-GAN: Community Evolutionary Generative Adversarial Network for Alzheimer's Disease Risk Prediction.

In the studies of neurodegenerative diseases such as Alzheimer's Disease (AD), researchers often focus on the associations among multi-omics pathogeny based on imaging genetics data. However, current studies overlook the communities in brain networks, leading to inaccurate models of disease development. This paper explores the developmental patterns of AD from the perspective of community evolution. We first establish a mathematical model to describe functional degeneration in the brain as the community evolution driven by entropy information propagation. Next, we propose an interpretable Community Evolutionary Generative Adversarial Network (CE-GAN) to predict disease risk. In the generator of CE-GAN, community evolutionary convolutions are designed to capture the evolutionary patterns of AD. The experiments are conducted using functional magnetic resonance imaging (fMRI) data and single nucleotide polymorphism (SNP) data. CE-GAN achieves 91.67% accuracy and 91.83% area under curve (AUC) in AD risk prediction tasks, surpassing advanced methods on the same dataset. In addition, we validated the effectiveness of CE-GAN for pathogeny extraction. The source code of this work is available at https://github.com/fmri123456/CE-GAN.