Genome-wide association study identifies genetic risk loci for adiposity in a Taiwanese population.

Overweight and obese are risk factors for various diseases. In Taiwan, the combined prevalence of overweight and obesity has increased dramatically. Here, we conducted a genome-wide association study (GWAS) on four adiposity traits, including body-mass index (BMI), body fat percentage (BF%), waist circumference (WC), and waist-hip ratio (WHR), using the data for more than 21,000 subjects in Taiwan Biobank. Associations were evaluated between 6,546,460 single-nucleotide polymorphisms (SNPs) and adiposity traits, yielding 13 genome-wide significant (GWS) adiposity-associated trait-loci pairs. A known gene, FTO, as well as two BF%-associated loci (GNPDA2-GABRG1 [4p12] and RNU6-2-PIAS1 [15q23]) were identified as pleiotropic effects. Moreover, RALGAPA1 was found as a specific genetic predisposing factor to high BMI in a Taiwanese population. Compared to other populations, a slightly lower heritability of the four adiposity traits was found in our cohort. Surprisingly, we uncovered the importance of neural pathways that might influence BF%, WC and WHR in the Taiwanese (East Asian) population. Additionally, a moderate genetic correlation between the WHR and BMI (γg = 0.52; p = 2.37×10-9) was detected, suggesting different genetic determinants exist for abdominal adiposity and overall adiposity. In conclusion, the obesity-related genetic loci identified here provide new insights into the genetic underpinnings of adiposity in the Taiwanese population.

The genome-wide association study of serum IgE levels demonstrated a shared genetic background in allergic diseases.

Immunoglobulin E (IgE) synthessis is highly related to a variety of atopic diseases, and several genome-wide association studies (GWASs) have demonstrated the association between genes and IgE level. In this study, we conducted the largest genome-wide association study of IgE involving a Taiwanese Han population. Eight independent variants exhibited genome-wide significance. Among them, an intronic SNP of CD28, rs1181388, and an intergenic SNP, rs1002957030, on 11q23.2 were identified as novel signals for IgE. Seven of the loci were replicated successfully in a meta-analysis using data on Japanese population. Among all the human leukocyte antigen (HLA) regions, HLA-DQA1*03:02 - HLA-DQB1*03:03 was the most significant haplotype (OR = 1.25, SE = 0.02, FDR = 1.6 × 10-14), corresponding to HLA-DQA1 Asp160 and HLA-DQB1 Leu87 amino acid residues. The genetic correlation showed significance between IgE and allergic diseases including asthma, atopic dermatitis, and pollinosis. IgE PRS was significantly correlated with total IgE levels. Furthermore, the top decile IgE polygenic risk score (PRS) group had the highest risk of asthma for the Taiwan Biobank and Biobank Japan cohorts. IgE PRS may be used to aid in predicting the occurrence of allergic reactions before symptoms occur and biomarkers are detectable. Our study provided a more comprehensive understanding of the impact of genomic variants, including complex HLA alleles, on serum IgE levels.

Human rs75776403 polymorphism links differential phenotypic and clinical outcomes to a CLEC18A p.T151M-driven multiomics.

BACKGROUND: Human traits, diseases susceptibility, and clinical outcomes vary hugely among individuals. Despite a fundamental understanding of genetic (or environmental) contributions, the detailed mechanisms of how genetic variation impacts molecular or cellular behaviours of a gene, and subsequently leads to such variability remain poorly understood. METHODS: Here, in addition to phenome-wide correlations, we leveraged multiomics to exploit mechanistic links, from genetic polymorphism to protein structural or functional changes and a cross-omics perturbation landscape of a germline variant. RESULTS: We identified a missense cis-acting expression quantitative trait locus in CLEC18A (rs75776403) in which the altered residue (T151→M151) disrupts the lipid-binding ability of the protein domain. The altered allele carriage led to a metabolic and proliferative shift, as well as immune deactivation, therefore determines human anthropometrics (body height), kidney, and hematological traits. CONCLUSIONS: Collectively, we uncovered genetic pleiotropy in human complex traits and diseases via CLEC18A rs75776403-regulated pathways.

Transcriptome network analyses in human coronavirus infections suggest a rational use of immunomodulatory drugs for COVID-19 therapy.

The recent outbreak of coronavirus disease 2019 (COVID-19) by SARS-CoV-2 has led to uptodate 24.3 M cases and 0.8 M deaths. It is thus in urgent need to rationalize potential therapeutic targets against the progression of diseases. An effective, feasible way is to use the pre-existing ΔORF6 mutant of SARS-CoV as a surrogate for SARS-CoV-2, since both lack the moiety responsible for interferon antagonistic effects. By analyzing temporal profiles of upregulated genes in ΔORF6-infected Calu-3 cells, we prioritized 55 genes and 238 ligands to reposition currently available medications for COVID-19 therapy. Eight of them are already in clinical trials, including dexamethasone, ritonavir, baricitinib, tofacitinib, naproxen, budesonide, ciclesonide and formoterol. We also pinpointed 16 drug groups from the Anatomical Therapeutic Chemical classification system, with the potential to mitigate symptoms of SARS-CoV-2 infection and thus to be repositioned for COVID-19 therapy.

Integration of genetic variants and gene network for drug repurposing in colorectal cancer.

Even though many genetic risk loci for human diseases have been identified and comprehensively cataloged, strategies to guide clinical research by integrating the extensive results of genetic studies and biological resources are still limited. Moreover, integrative analyses that provide novel insights into disease biology are expected to be especially useful for drug discovery. Herein, we used text mining of genetic studies on colorectal cancer (CRC) and assigned biological annotations to identified risk genes in order to discover novel drug targets and potential drugs for repurposing. Risk genes for CRC were obtained from PubMed text mining, and for each gene, six functional and bioinformatic annotations were analyzed. The annotations include missense mutations, cis-expression quantitative trait loci (cis-eQTL), molecular pathway analyses, protein-protein interactions (PPIs), a genetic overlap with knockout mouse phenotypes, and primary immunodeficiency (PID). We then prioritized the biological risk candidate genes according to a scoring system of the six functional annotations. Each functional annotation was assigned one point, and those genes with a score ≥2 were designated "biological CRC risk genes". Using this method, we revealed 82 biological CRC risk genes, which were mapped to 128 genes in an expanded PPI network. Further utilizing DrugBank and the Therapeutic Target Database, we found 21 genes in our list that are targeted by 166 candidate drugs. Based on data from ClinicalTrials.gov and literature review, we found four known target genes with six drugs for clinical treatment in CRC, and three target genes with nine drugs supported by previous preclinical results in CRC. Additionally, 12 genes are targeted by 32 drugs approved for other indications, which can possibly be repurposed for CRC treatment. Finally, analysis from Connectivity Map (CMap) showed that 18 drugs have a high potential for CRC.

Genomic interrogation of familial short stature contributes to the discovery of the pathophysiological mechanisms and pharmaceutical drug repositioning.

BACKGROUND: Genetic factors, dysregulation in the endocrine system, cytokine and paracrine factors are implicated in the pathogenesis of familial short stature (FSS). Nowadays, the treatment choice for FSS is limited, with only recombinant human growth hormone (rhGH) being available. METHODS: Herein, starting from the identification of 122 genetic loci related to FSS, we adopted a genetic-driven drug discovery bioinformatics pipeline based on functional annotation to prioritize crucial biological FSS-related genes. These genes were suggested to be potential targets for therapeutics. RESULTS: We discovered five druggable subnetworks, which contained seven FSS-related genes and 17 druggable targerts. CONCLUSIONS: This study provides a valuable drug repositioning accompanied by corresponding targetable gene clusters for FSS therapy.

The functional roles of IGF-1 variants in the susceptibility and clinical outcomes of mild traumatic brain injury.

BACKGROUND: Insulin-like growth factor 1 (IGF-1) is an important pleiotropic hormone that exerts neuroprotective and neuroreparative effects after a brain injury. However, the roles of IGF-1 variants in mild traumatic brain injury (mTBI) are not yet fully understood. This study attempted to elucidate the effects of IGF-1 variants on the risk and neuropsychiatric outcomes of mTBI. METHODS: Based on 176 recruited mTBI patients and 1517 control subjects from the Taiwan Biobank project, we first compared the genotypic distributions of IGF-1 variants between the two groups. Then, we analyzed associations of IGF-1 variants with neuropsychiatric symptoms after mTBI, including anxiety, depression, dizziness, and sleep disturbances. Functional annotation of IGF-1 variants was also performed through bioinformatics databases. RESULTS: The minor allele of rs7136446 was over-represented in mTBI patients compared to community-based control subjects. Patients carrying minor alleles of rs7136446 and rs972936 showed more dizziness and multiple neuropsychiatric symptoms after brain injury. CONCLUSIONS: IGF-1 variants were associated with the risk and neuropsychiatric symptoms of mTBI. The findings highlight the important role of IGF-1 in the susceptibility and clinical outcomes of mTBI.

The association between BDNF Val66Met polymorphism and emotional symptoms after mild traumatic brain injury.

BACKGROUND: Brain-derived neurotrophic factor (BDNF) is one of the most abundant neurotrophins in the adult brain, and it plays important roles in modulating synaptic plasticity and synaptogenesis. This study attempted to elucidate the role of the BDNF variant rs6265 in emotional symptoms following mild traumatic brain injury (mTBI). METHODS: To investigate the association between BDNF Val66Met polymorphism (rs6265) and emotional symptoms in mTBI patients, we recruited 192 mTBI patients and evaluated their Beck Anxiety Inventory (BAI) and Beck Depression Inventory (BDI) scores in the first and sixth week after mTBI. RESULTS: The patients carrying the T allele of rs6265 had significantly higher BAI scores in the first week following mTBI. In addition, the patients carrying the T allele also showed higher scores of BDI in the first week. In the gender-specific subgroup analysis, the male patients carrying the T allele of rs6265 had higher scores of both BAI and BDI in the first and sixth week. Meanwhile, female patients carrying the T allele also had significantly higher scores of BDI in the first week following mTBI. CONCLUSIONS: This study provides evidence for the association between the BDNF variant rs6265 and emotional symptoms following mTBI.

Identification of genes and pathways related to lymphovascular invasion in breast cancer patients: A bioinformatics analysis of gene expression profiles.

Surgery is the most effective treatment for breast cancer patients. However, some patients developed recurrence and distant metastasis after surgery. Adjuvant therapy is considered for high-risk patients depending on several prognostic markers, and lymphovascular invasion has become one of such prognostic markers that help physicians to identify the risk for distant metastasis and recurrence. However, the mechanism of lymphovascular invasion in breast cancer remains unknown. This study aims to unveil the genes and pathways that may involve in lymphovascular invasion in breast cancer. In total, 108 breast cancer samples were collected during surgery and microarray analysis was performed. Significance analysis of the microarrays and limma package for R were used to examine differentially expressed genes between lymphovascular invasion-positive and lymphovascular invasion-negative cases. Network and pathway analyses were mapped using the Ingenuity Pathway Analysis and the Database for Annotation, Visualization and Integrated Discovery. In total, 86 differentially expressed genes, including 37 downregulated genes and 49 upregulated genes were identified in lymphovascular invasion-positive patients. Among these genes, TNFSF11, IL6ST, and EPAS1 play important roles in cytokine-receptor interaction, which is the most enriched pathway related to lymphovascular invasion. Moreover, the results also suggested that an imbalance between extracellular matrix components and tumor micro-environment could induce lymphovascular invasion. Our study evaluated the underlying mechanisms of lymphovascular invasion, which may further help to assess the risk of breast cancer progression and identify potential targets of adjuvant treatment.

V-J combinations of T-cell receptor predict responses to erythropoietin in end-stage renal disease patients.

BACKGROUND: Anemia is common among end-stage renal disease (ESRD) patients who undergone hemodialysis. The total reduction of red blood cell (RBC) count is associated with poor prognosis in these patients. Although erythropoietin (EPO) has been used as an effective treatment for ESRD patients with anemia, a large number of patients still present poor responses to EPO treatment. METHODS: We measured T-cell receptor sequencing profiles, including length of complementarity-deteremining region 3 (CDR3), intra- and inter-group (EPO resistant vs. responsive) clonotype diversity, V(D)J usage profiles and V-J combinations from ESRD patients and to investigate the correlation between these features and EPO treatment efficacy. RESULTS: Our results revealed statistical significance in the top 3 ~ 15 most abundant joint distributions of Vß/Jß among the two groups, suggesting the importance of V or J gene utilization in the EPO response of ESRD patients. CONCLUSIONS: In summary, we provided evidence addressing the potential correlation between the immune repertoire and EPO response in ESRD patients. TRIAL REGISTRATION: TMU-JIRB 201309026. Registered 16 October 2013.

rs657075 (CSF2) Is Associated with the Disease Phenotype (BAS-G) of Ankylosing Spondylitis.

Ankylosing spondylitis (AS) is a systemic autoimmune disease mainly affecting the lumbar spine and sacroiliac joints, and exhibits peripheral inflammatory arthropathy. More than 25 loci have been identified as associated with AS. Because both AS and rheumatoid arthritis (RA) are autoimmune diseases that may share some common genetic factors, we therefore examined if the newly identified RA genetic polymorphisms were associated with AS in a Taiwanese population. In this study, we enrolled 475 AS patients and 11,301 healthy subjects from a Taiwanese biobank as controls. Although none of single-nucleotide polymorphisms (SNPs) were associated with the susceptibility to AS, the AS disease index Bath AS Global (BAS-G) clinical phenotype was observed as significantly correlated to the AA genotype of rs657075 (CSF2). The significance remains after gender/age/disease duration adjustment and after group categorization by human leukocyte antigen-B 27 (HLA-B27) genotype. We further investigated the possible functions of rs657075 through bioinformatics approaches. Results revealed that polymorphism of rs657075 is able to influence the expression of acyl-CoA synthetase long-chain family member 6 (ACSL6). In conclusion, our study indicated that rs657075 (CSF2) is strongly associated with the AS disease index Bath AS Global (BAS-G) clinical phenotype.

Bioinformatic analyses revealed underlying biological functions correlated with oxaliplatin responsiveness.

Colorectal cancer is one of the most common cancers worldwide. Surgery is usually the primary treatment for colon cancers that have not spread to distant sites. However, chemotherapy may be considered after surgery to eliminate remaining cancer cells or in case the cancer has a high risk of recurrence. Oxaliplatin is often used in combination regimens such as FOLFOX, CapeOX, and FOLFOXIRI because of the cost-effectiveness of adjuvant treatment for patients and also the good tolerability profile. However, some patients show resistance to oxaliplatin which causes poor treatment outcomes. Most colon cancer studies focused on treatments and patient survival. Some studies focused on genetic associations of specific genes. However, pathway and network analyses of oxaliplatin resistance in colon cancer cells using gene expression patterns are still lacking. We performed a microarray analysis and found that endothelin-1 (EDN1), dishevelled segment polarity protein (DV1), toll-like receptor 5(TLR5), mitogen-activated protein kinase 3 (MAP2K3), phosphatidylinositol-4,5-bisphosphate 3-kinase, and catalytic subunit beta (PIK3CB) were closely related to responsiveness to oxaliplatin treatment. Furthermore, we found that the signal transduction, melanogenesis, and toll-like receptor signaling pathways might be involved in oxaliplatin-resistant colon cancer. These genes and pathways might be potential targets for improving oxaliplatin treatment in colon cancer patients.

Gene expression profiling combined with functional analysis identify integrin beta1 (ITGB1) as a potential prognosis biomarker in triple negative breast cancer.

Triple negative breast cancer (TNBC) accounts for approximately 15-20% of all types of breast cancer, and treatment is still limited. This type of breast cancer shows a high risk of recurrence, visceral metastasis, a worse prognosis, and shorter distant metastasis-free survival. Several studies have been reported that genetics factors are associated with breast cancer disease progression and patients' survival. In this study, we combined Taiwanese microarray data from the GEO database and The Cancer Genome Atlas (TCGA) database to study the role of Integrin Beta1 (ITGB1) in TNBC. Two triple negative breast cancer cell lines (MDA-MB-231; MDA-MB-468) were used to validate the functions of ITGB1. We found that a higher ITGB1 gene expression level was associated to lower survival. Silencing of ITGB1 inhibited TNBC cell migration, invasion and store-operated calcium influx. Our study provided a potential candidate biomarker for breast cancer cells migration, invasion and TNBC patients' survival.

A Single Nucleotide Polymorphism (rs4236480) in TRPV5 Calcium Channel Gene Is Associated with Stone Multiplicity in Calcium Nephrolithiasis Patients.

Nephrolithiasis is characterized by calcification of stones in the kidneys from an unknown cause. Animal models demonstrated the functional roles of the transient receptor potential vanilloid member 5 (TRPV5) gene in calcium renal reabsorption and hypercalciuria. Therefore, TRPV5 was suggested to be involved in calcium homeostasis. However, whether genetic polymorphisms of TRPV5 are associated with kidney stone multiplicity or recurrence is unclear. In this study, 365 Taiwanese kidney-stone patients were recruited. Both biochemical data and DNA samples were collected. Genotyping was performed by a TaqMan allelic discrimination assay. We found that a TRPV5 polymorphism (rs4236480) was observed to be associated with stone multiplicity of calcium nephrolithiasis, as the risk of stone multiplicity was higher in patients with the TT+CT genotype than in patients with the CC genotype (p = 0.0271). In summary, despite the complexity of nephrolithiasis and the potential association of numerous calcium homeostatic absorption/reabsorption factors, TRPV5 plays an important role in the pathogenesis of calcium nephrolithiasis.

FCGR2A Promoter Methylation and Risks for Intravenous Immunoglobulin Treatment Responses in Kawasaki Disease.

Kawasaki disease (KD) is characterized by pediatric systemic vasculitis of an unknown cause. The low affinity immunoglobulin gamma Fc region receptor II-a (FCGR2A) gene was reported to be involved in the susceptibility of KD. DNA methylation is one of the epigenetic mechanisms that control gene expression; thus, we hypothesized that methylation status of CpG islands in FCGR2A promoter associates with the susceptibility and therapeutic outcomes of Kawasaki disease. In this study, 36 KD patients and 24 healthy subjects from out-patient clinic were recruited. Eleven potential methylation sites within the targeted promoter region of FCGR2A were selected for investigation. We marked the eleven methylation sites from A to K. Our results indicated that methylation at the CpG sites G, H, and J associated with the risk of KD. CpG sites B, C, E, F, H, J, and K were found to associate with the outcomes of IVIG treatment. In addition, CpG sites G, J, and K were predicted as transcription factors binding sites for NF-kB, Myc-Max, and SP2, respectively. Our study reported a significant association among the promoter methylation of FCGR2A, susceptibility of KD, and the therapeutic outcomes of IVIG treatment. The methylation levels of CpG sites of FCGR2A gene promoter should be an important marker for optimizing IVIG therapy.

Phenomic landscape and pharmacogenomic implications for HLA region in a Taiwan Han Chinese population.

BACKGROUND: The human leukocyte antigen (HLA) genes, exhibiting significant genetic diversity, are associated with susceptibility to various clinical diseases and diverse in drug responses. High costs of HLA sequencing and the population-specific architecture of this genetic region necessitate the establishment of a population-specific HLA imputation reference panel. Moreover, there is a lack of understanding about the genetic and phenotypic landscape of HLA variations within the Taiwanese population. METHODS: We created models for a Taiwanese-specific HLA imputation reference panel. These models were trained with the array genotype data and HLA sequencing data from 845 Taiwanese subjects. HLA imputation was applied for 59,448 Taiwanese subjects to characterize the HLA allele and haplotype frequencies. Additionally, a phenome-wide association study (PheWAS) was conducted to identify the phenotypes associated with HLA variations. The association of the biallelic HLA variants with the binary and quantitative traits were evaluated with additive logistic and linear regression models, respectively. Furthermore, an omnibus test with likelihood-ratio test was applied for each HLA amino acid position in the multiallelic HLA amino acid polymorphisms to compare the difference between a fitted model and a null model following a χ2 distribution of n-1 degree of freedom at a position with n residues. Finally, we estimated the prevalence of adverse drug reactions (ADR)-related HLA alleles in the Taiwanese population. RESULTS: In this study, the reference panel models displayed remarkable accuracy, with averages of 99.3%, 98.9%, and 99.1% for 2-, 4-, 6-digit alleles of the eight classical HLA genes, respectively. For PheWAS, a total of 18,136 significant associations with HLA variants across 26 phenotypes are identified (p < 5×10-8), highlighting the pleiotropy feature of the HLA region. Among the independent signals, 15 are novel, including the association of HLA-B pos 138 variation with ankylosing spondylitis (AS), and rs9266290 and rs9266292 with allergy. Through an analysis spanning the entire HLA region, we identified clusters of phenotype correlations. Finally, the carriers of pharmacogenomic related HLA alleles, including HLA-C*01:02 (35.86%), HLA-B*58:01 (20.9%), and HLA-B*15:02 (8.38%), were characterized in the Taiwanese general population. CONCLUSIONS: We successfully delivered the HLA imputation for 59,448 Taiwanese subjects and characterized the genetic and phenotypic landscapes of the HLA variations. In addition, we quantified the estimated prevalence of the ADR-related HLA alleles in the Taiwanese population. The developed HLA imputation reference panel could be used for estimation of population HLA allele frequencies, which can facilitate further studies in the role of HLA variants in a wider range of phenotypes in the population.

Genome-Wide Association Study for eGFR in a Taiwanese Population.

BACKGROUND AND OBJECTIVES: Chronic kidney disease (CKD) is a global public health issue associated with large economic burdens. CKD contributes to higher risks of cardiovascular complications, kidney failure, and mortality. The incidence and prevalence rates of kidney failure in Taiwan have remained the highest in the world. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Assessing genetic factors that influence kidney function in specific populations has substantial clinical relevance. We investigated associations of genetic variants with eGFR. The quality control filtering and genotype imputation resulted in 10,008 Taiwan Biobank participants and 6,553,511 variants for final analyses. We examined these loci with in silico replication in individuals of European and African ancestry. RESULTS: Our results revealed one significant locus (4q21.1) and three suggestive significant loci (17q23.2, 22q13.2, and 3q29) for eGFR in the Taiwanese population. In total, four conditional-independent single nucleotide polymorphisms were identified as the most important variants within these regions, including rs55948430 (Coiled-Coil Domain Containing 158), rs1010269 (BCAS3), rs56108505 (MKL1), and rs34796810 (upstream of DLG1). By performing a meta-analysis, we found that the 4q21.1 and 17q23.2 loci were successfully replicated in the European population, whereas only the 17q23.2 locus was replicated in African ancestry. Therefore, these two loci are suggested to be transethnic loci, and the other two eGFR-associated loci (22q13.2 and 3q29) are likely population specific. CONCLUSIONS: We identified four susceptibility loci on 4q21.1, 17q23.2, 22q13.2, and 3q29 that associated with kidney-related traits in a Taiwanese population. The 22q13.2 (MKL1) and 3q29 (DLG1) were prioritized as critical candidates. Functional analyses delineated novel pathways related to kidney physiology in Taiwanese and East Asian ancestries.

Single-cell melanoma transcriptomes depicting functional versatility and clinical implications of STIM1 in the tumor microenvironment.

Rationale: Previous studies have implicated the functions of stromal interaction molecule 1 (STIM1) in immunity and malignancy, however, the specificity and effects of STIM1 expression in malignant and non-malignant cells in the tumor microenvironment are unclear. Methods: In the current study, we posed two central questions: (1) does STIM1 expression elicit different cellular programs in cell types within the melanoma tumor microenvironment (2) whether the expression of STIM1 and STIM1-coexpressed genes (SCGs) serve as prognostic indicators of patient's outcomes? To answer these questions, we dissected cell-specific STIM1-associated cellular programs in diverse cell types within the melanoma tumor microenvironment by measuring cell-type specificity of STIM1 expression and SCGs. Results: A distinct set of SCGs was highly affected in malignant melanoma cells, but not in the other cell types, suggesting the existence of malignant-cell-specific cellular programs reflected by STIM1 expression. In contrast to malignant cells, STIM1 expression appeared to trigger universal and non-specific biological functions in non-malignant cell types, as exemplified by the transcriptomes of macrophages and CD4+ T regulatory cells. Results from bioinformatic analyses indicated that SCGs in malignant cells may alter cell-cell interactions through cytokine/chemokine signaling and/or orchestrate immune infiltration into the tumor. Moreover, a prognostic association between SCGs in CD4+ T regulatory cells and patient's outcomes was identified. However, we didn't find any correlation between SCGs and responsiveness of immunotherapy. Conclusions: Overall, our results provide an integrated biological framework for understanding the functional and clinical consequences of cell-specific STIM1 expression in melanoma.

The role of genetic polymorphisms in STIM1 and ORAI1 for erythropoietin resistance in patients with renal failure.

ABSTRACT: Anemia is a common complication in patients with renal failure. While erythropoietin is commonly used to treat anemia, some patients exhibit a poor response to erythropoietin. Since store-operated calcium channel (SOC) signaling is one of the erythropoietin activated pathways, we aimed to investigate the association between the genetic polymorphisms of SOC signaling pathway and erythropoietin resistance in patients with renal failure.Four tagging single nucleotide polymorphisms in STIM1 and five in ORAI1 were selected in this study. Genotyping was performed with the TaqMan Allelic Discrimination assay and the association of individual tagging single nucleotide polymorphisms with erythropoietin resistance was analyzed by multivariable adjusted random intercepts model.194 patients were enrolled in this study. The mean age of participants is 68 years, and 56% were men. The mean erythropoietin resistance index was 9.04 ±â€Š4.51 U/Kg/week/g/dL. We found that patients with the AA genotype of rs1561876 in STIM1, and the CC or CT genotypes of rs6486795 in ORAI1, were associated with increased risk of erythropoietin resistance. Functional annotation of expression quantitative trait loci revealed that the AA genotype of rs1561876 in STIM1 has a relatively lower expression of ribonucleotide reductase catalytic subunit M1 in skeletal muscle, while the CC genotype of rs6486795 in ORAI1 has a relatively higher expression of ORAI1 in the whole blood and thyroid.Overall, we demonstrate a significant association between erythropoietin resistance and genetic polymorphisms of STIM1 and ORAI1. Annotation prediction revealed the importance of SOC-mediated calcium signaling for erythropoietin resistance.

Drug Repurposing for Atopic Dermatitis by Integration of Gene Networking and Genomic Information.

Atopic Dermatitis (AD) is a chronic and relapsing skin disease. The medications for treating AD are still limited, most of them are topical corticosteroid creams or antibiotics. The current study attempted to discover potential AD treatments by integrating a gene network and genomic analytic approaches. Herein, the Single Nucleotide Polymorphism (SNPs) associated with AD were extracted from the GWAS catalog. We identified 70 AD-associated loci, and then 94 AD risk genes were found by extending to proximal SNPs based on r2 > 0.8 in Asian populations using HaploReg v4.1. Next, we prioritized the AD risk genes using in silico pipelines of bioinformatic analysis based on six functional annotations to identify biological AD risk genes. Finally, we expanded them according to the molecular interactions using the STRING database to find the drug target genes. Our analysis showed 27 biological AD risk genes, and they were mapped to 76 drug target genes. According to DrugBank and Therapeutic Target Database, 25 drug target genes overlapping with 53 drugs were identified. Importantly, dupilumab, which is approved for AD, was successfully identified in this bioinformatic analysis. Furthermore, ten drugs were found to be potentially useful for AD with clinical or preclinical evidence. In particular, we identified filgotinub and fedratinib, targeting gene JAK1, as potential drugs for AD. Furthermore, four monoclonal antibody drugs (lebrikizumab, tralokinumab, tocilizumab, and canakinumab) were successfully identified as promising for AD repurposing. In sum, the results showed the feasibility of gene networking and genomic information as a potential drug discovery resource.