Functional Single Nucleotide Polymorphisms Research Articles

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.

The HSP90AA1 gene is involved in heat stress responses and its functional genetic polymorphisms 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 SNPs associated with thermotolerance in Holstein cattle. For the in vitro validation experiment of acute HS, cells from the Madin-Darby bovine kidney 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 validated in vitro. 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 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 and respiration score 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 microRNA (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 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.

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.

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.

Target genes regulated by CLEC16A intronic region associated with common variable immunodeficiency

BackgroundCLEC16A intron 19 has been identified as a candidate locus for common variable immunodeficiency (CVID). ObjectiveThe objective of this study is to elucidate the molecular mechanism by which variants at the CLEC16A intronic locus may contribute to the pathogenesis of CVID. MethodsWe performed fine-mapping of the CLEC16A locus in a CVID cohort, then deleted the candidate functional SNP in T-cell lines by the CRISPR-Cas9 technique and conducted RNA-seq to identify target gene(s). The interactions between the CLEC16A locus and its target genes were identified using Circularized Chromosome Conformation Capture. The transcription factor complexes mediating the chromatin interactions were determined by proteomic approach. The molecular pathways regulated by the CLEC16A locus were examined by RNA-seq and reverse phase protein array. ResultsOur study showed that the CLEC16A locus is an enhancer regulating expression of multiple target genes including a distant gene ATF7IP2 through chromatin interactions. Distinct transcription factor complexes mediate the chromatin interactions in an allele-specific manner. Disruption of the CLEC16A locus affects the AKT signaling pathway, as well as the molecular response of CD4+T cells to immune stimulation. ConclusionThrough multi-omics and targeted experimental approaches, we elucidated the underlying target genes and signaling pathways involved in the genetic association of CLEC16A with CVID, and highlighted plausible molecular targets for developing novel therapeutics.

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.

Multi-modal deep learning from imaging genomic data for schizophrenia classification.

Schizophrenia (SZ) is a psychiatric condition that adversely affects an individual's cognitive, emotional, and behavioral aspects. The etiology of SZ, although extensively studied, remains unclear, as multiple factors come together to contribute toward its development. There is a consistent body of evidence documenting the presence of structural and functional deviations in the brains of individuals with SZ. Moreover, the hereditary aspect of SZ is supported by the significant involvement of genomics markers. Therefore, the need to investigate SZ from a multi-modal perspective and develop approaches for improved detection arises. Our proposed method employed a deep learning framework combining features from structural magnetic resonance imaging (sMRI), functional magnetic resonance imaging (fMRI), and genetic markers such as single nucleotide polymorphism (SNP). For sMRI, we used a pre-trained DenseNet to extract the morphological features. To identify the most relevant functional connections in fMRI and SNPs linked to SZ, we applied a 1-dimensional convolutional neural network (CNN) followed by layerwise relevance propagation (LRP). Finally, we concatenated these obtained features across modalities and fed them to the extreme gradient boosting (XGBoost) tree-based classifier to classify SZ from healthy control (HC). Experimental evaluation on clinical dataset demonstrated that, compared to the outcomes obtained from each modality individually, our proposed multi-modal approach performed classification of SZ individuals from HC with an improved accuracy of 79.01%. We proposed a deep learning based framework that selects multi-modal (sMRI, fMRI and genetic) features efficiently and fuse them to obtain improved classification scores. Additionally, by using Explainable AI (XAI), we were able to pinpoint and validate significant functional network connections and SNPs that contributed the most toward SZ classification, providing necessary interpretation behind our findings.

Common Genetic Variants in SIRT1 Gene Promoter and Type 2 Diabetes Mellitus in Saudi Arabia.

Type 2 diabetes mellitus (T2DM) is common in Saudi Arabia and represents a major health concern. Silent information regulator of transcription-1 (SIRT1) positively influences insulin sensitivity and might contribute to the pathogenesis of T2DM. This study aimed to investigate the frequency of two common functional single nucleotide polymorphisms (SNPs) in the promoter region of SIRT1; rs12778366 (T>C) and rs3758391 (T>C) in Saudi Arabian population and examine any association with T2DM. A total of 445 volunteers were divided into 224 healthy controls and 221 patients previously diagnosed with T2DM. Genomic DNA was extracted from all samples and genotyped for SIRT1 rs12778366 and rs3758391 SNPs by TaqMan RT-PCR allelic discrimination assay. Logistic regression analysis was used to establish any relationship between these polymorphisms and T2DM. In the total study population, rs12778366 genotype frequencies were TT (89.2%), TC (10.3%), and CC (0.45%) and for the rs3758391 they were TT (16.4%), TC (44.5%), and CC (39.1%). The distribution of these genotypes, in both polymorphisms, were similar among T2DM and controls. Logistic regression analysis confirmed the lack of association between the presence of CC or CT variants and T2DM for rs12778366 and rs3758391 SNP (OR = 0.98 [CI]: 0.55 - 1.75; p = 0.999 and OR= 0.75; [CI]: 0.45 - 1.24; p = 0.313), respectively. This study revealed the frequency of SIRT1 rs12778366 and rs3758391 SNPs in our population and reported no association between these polymorphisms and the risk for T2DM. This finding might add to the growing body of literature exploring the genetics of T2DM.

Genetic Polymorphism in Alcohol Metabolism and Drinking Behavior are Associated with Gastric Cancer Risk in Men.

Objective In recent years, there has been a growing focus on health risks associated with alcohol consumption. The present study investigated whether or not the genetic variant of aldehyde dehydrogenase 2 (ALDH2) influences the risk of gastric cancer among individuals identified as hazardous drinkers using the Alcohol Use Disorders Identification Test (AUDIT), which provides a comprehensive assessment of hazardous drinking behavior. Patients We enrolled men with hazardous drinking behavior (AUDIT score ≥ 8) who had undergone gastric cancer screening (either endoscopy or a barium X-ray examination of the upper gastrointestinal tract) between April 2013 and March 2020 within 1 year from entry and who had subsequently undergone at least one more gastric cancer screening up to March 2021. Functional single-nucleotide polymorphisms of ALDH2 (rs671) were measured using a direct TaqMan PCR method with unprocessed saliva. Results A total of 246 men were enrolled, comprising 193 individuals with active ALDH2 (ALDH2*1/*1) and 53 with less-active ALDH2 (ALDH2*1/*2). The cumulative incidence of gastric cancer in the less-active group was higher than in the active ALDH2 group (p=0.01, hazard ratio: 4.6, 95% confidence interval: 1.2-16.7). Alcohol consumption was lower in the less-active ALDH2 group than in the active ALDH2 group, although no marked difference was observed in the AUDIT score. Conclusion In individuals with hazardous drinking behavior, a heightened risk of gastric cancer was observed among those with less-active ALDH2 variants, even when their alcohol consumption was comparatively lower than in those with active ALDH2 variants.

A Functional Single-Nucleotide Polymorphism Upstream of the Collagen Type III Gene Is Associated with Catastrophic Fracture Risk in Thoroughbred Horses.

Fractures caused by bone overloading are a leading cause of euthanasia in Thoroughbred racehorses. The risk of fatal fracture has been shown to be influenced by both environmental and genetic factors but, to date, no specific genetic mechanisms underpinning fractures have been identified. In this study, we utilised a genome-wide polygenic risk score to establish an in vitro cell system to study bone gene regulation in horses at high and low genetic risk of fracture. Candidate gene expression analysis revealed differential expression of COL3A1 and STAT1 genes in osteoblasts derived from high- and low-risk horses. Whole-genome sequencing of two fracture cases and two control horses revealed a single-nucleotide polymorphism (SNP) upstream of COL3A1 that was confirmed in a larger cohort to be significantly associated with fractures. Bioinformatics tools predicted that this SNP may impact the binding of the transcription factor SOX11. Gene modulation demonstrated SOX11 is upstream of COL3A1, and the region binds to nuclear proteins. Furthermore, luciferase assays demonstrated that the region containing the SNP has promoter activity. However, the specific effect of the SNP depends on the broader genetic background of the cells and suggests other factors may also be involved in regulating COL3A1 expression. In conclusion, we have identified a novel SNP that is significantly associated with fracture risk and provide new insights into the regulation of the COL3A1 gene.

Potentially functional genetic variants in ferroptosis-related CREB3 and GALNT14 genes predict survival of hepatitis B virus-related hepatocellular carcinoma.

Ferroptosis is a known crucial player in the development of cancers. However, the effect of single nucleotide polymorphisms (SNPs) in ferroptosis-related genes on survival in hepatitis B virus (HBV)-related hepatocellular carcinoma (HBV-HCC) patients remains unknown. We used two-stage multivariable Cox proportional hazards regression analyses to estimate the associations between 48,774 SNPs in 480 ferroptosis-related genes and overall survival (OS) of 866 HBV-HCC patients. We identified that two potentially functional SNPs (CREB3 rs10814274 C > T and GALNT14 rs17010547 T > C) were significantly independently associated with the OS of HBV-HCC patients (CT + TT verse CC, hazards ratio (HR) = 0.77, 95% confidence interval (CI) = 0.67-0.89, p < 0.001 for rs10814274 and TC + CC verse TT, HR = 0.66, 95% CI = 0.53-0.82, p < 0.001 for rs17010547, respectively). Additional joint assessment of protective genotypes of these two SNPs showed that patients with 1-2 protective genotypes had a significantly better OS compared with those carrying 0 protective genotypes (HR = 0.56, 95% CI = 0.45-0.70, p < 0.001). Moreover, the expression quantitative trait loci (eQTL) analysis revealed that the survival-associated SNP rs10814274 T allele was significantly correlated with reduced CREB3 transcript levels in both normal liver tissues and whole blood cells, while the GALNT14 rs17010547 C allele had a significant correlation with increased GALNT14 transcript levels in whole blood cells. These results suggest that genetic variants of CREB3 and GALNT14 may affect the survival of HBV-HCC patients, likely via transcriptional regulation of respective genes. However, further studies are required to confirm these findings.