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.

Characterization of T-Cell receptor repertoire in immunoglobulin a nephropathy.

Immunoglobulin A nephropathy (IgAN) is an autoimmune disease characterized by abnormal IgA deposition in glomerulus. Current diagnosis of IgAN still depends on renal biopsy, an invasive method that might increase the risk of clinical outcomes. Therefore, we aimed to explore the characteristics of T cell repertoire in IgAN from peripheral blood samples for identifying innovative diagnostic biomarkers. Herein, we included 8 IgAN patients, 25 non-IgAN patients, and 10 healthy controls in the study. A high-throughput immune repertoire sequencing was conducted to investigate the T-cell receptor beta-chain (TCRß) repertoire of peripheral blood. Characteristics of TCRß repertoire were assessed for these three distinct groups. A reduced TCRß repertoire diversity was observed in IgAN patients compared to non-IgAN and healthy individuals. A skewed distribution toward shorter TCRß complementarity determining region (CDR3) length was found in non-IgAN relative to IgAN patients. In addition, the differences in usages of five TRBV genes (TRBV5-4, TRBV6-4, TRBV12-1, TRBV16, and TRBV21-1) were identified between IgAN, non-IgAN, and healthy subjects. Of note, the TRBV6-4 gene, which is associated with mucosal-associated invariant T (MAIT) cells, exhibited higher usage in IgAN patients, suggesting potential importance of MAIT cells in IgAN. In short, our findings supported TCR repertoire characteristics as potential biomarkers for IgAN diagnosis.

Genetic Association Studies of MICB and PLCE1 with Severity of Dengue in Indonesian and Taiwanese Populations.

Dengue is an arboviral disease that has spread globally and become a major public health concern. A small proportion of patients may progress from symptomatic dengue fever (DF) to dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS). Findings from a previous genome-wide association study (GWAS) demonstrated that variations in the major histocompatibility complex (MHC) class I chain-related B (MICB) and the phospholipase C epsilon 1 (PLCE1) genes were related to DSS in a Vietnamese population. This study investigated associations of variations in MICB (rs3132468) and PLCE1 (rs3740360, rs3765524) with dengue severity and thrombocytopenia in both the Indonesian and Taiwanese populations. We sampled 160 patients from the Indonesian population and 273 patients from the Taiwanese population. None of the patients had DSS in the Taiwanese population. Based on age demographics, we found that dengue is more prevalent among younger individuals in the Indonesian population, whereas it has a greater impact on adults in the Taiwanese population. Our results showed the association between MICB rs3132468 and DSS. In addition, an association was identified between PLCE1 rs3740360 and DHF in secondary dengue in Indonesian patients. However, there is no association of MICB or PLCE1 variants with thrombocytopenia. This study highlights the value of genetic testing, which might be included in the clinical pathway for specific patients who can be protected from severe dengue.

Genetic alterations in peritoneal metastatic tumors predicted the outcomes for hyperthermic intraperitoneal chemotherapy.

Introduction: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are considered for patients with peritoneal metastasis (PM). However, patients selection that relies on conventional prognostic factors is not yet optimal. In this study, we performed whole exome sequencing (WES) to establish tumor molecular characteristics and expect to identify prognosis profiles for PM management. Methods: In this study, blood and tumor samples were collected from patients with PM before HIPEC. Tumor molecular signatures were determined using WES. Patient cohort was divided into responders and non-responders according to 12-month progression-free survival (PFS). Genomic characteristics between the two cohorts were compared to study potential targets. Results: In total, 15 patients with PM were enrolled in this study. Driver genes and enriched pathways were identified from WES results. AGAP5 mutation was found in all responders. This mutation was significantly associated with better OS (p = 0.00652). Conclusions: We identified prognostic markers that might be useful to facilitate decision-making before CRS/HIPEC.

Current Trends in Neoantigen-Based Cancer Vaccines.

Cancer immunotherapies are treatments that use drugs or cells to activate patients' own immune systems against cancer cells. Among them, cancer vaccines have recently been rapidly developed. Based on tumor-specific antigens referred to as neoantigens, these vaccines can be in various forms such as messenger (m)RNA and synthetic peptides to activate cytotoxic T cells and act with or without dendritic cells. Growing evidence suggests that neoantigen-based cancer vaccines possess a very promising future, yet the processes of immune recognition and activation to relay identification of a neoantigen through the histocompatibility complex (MHC) and T-cell receptor (TCR) remain unclear. Here, we describe features of neoantigens and the biological process of validating neoantigens, along with a discussion of recent progress in the scientific development and clinical applications of neoantigen-based cancer vaccines.

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.

Application of Whole Exome Sequencing and Functional Annotations to Identify Genetic Variants Associated with Marfan Syndrome.

Marfan syndrome (MFS) is a rare disease that affects connective tissue, which causes abnormalities in several organ systems including the heart, eyes, bones, and joints. The autosomal dominant disorder was found to be strongly associated with FBN1, TGFBR1, and TGFBR2 mutations. Although multiple genetic mutations have been reported, data from Asian populations are still limited. As a result, we utilized the whole exome sequencing (WES) technique to identify potential pathogenic variants of MFS in a Taiwan cohort. In addition, a variety of annotation databases were applied to identify the biological functions as well as the potential mechanisms of candidate genes. In this study, we confirmed the pathogenicity of FBN1 to MFS. Our results indicated that TTN and POMT1 may be likely related to MFS phenotypes. Furthermore, we found nine unique variants highly shared in a MFS family cohort, of which eight are novel variants worthy of further investigation.

Identification of Druggable Genes for Asthma by Integrated Genomic Network Analysis.

Asthma is a common and heterogeneous disease characterized by chronic airway inflammation. Currently, the two main types of asthma medicines are inhaled corticosteroids and long-acting ß2-adrenoceptor agonists (LABAs). In addition, biological drugs provide another therapeutic option, especially for patients with severe asthma. However, these drugs were less effective in preventing severe asthma exacerbation, and other drug options are still limited. Herein, we extracted asthma-associated single nucleotide polymorphisms (SNPs) from the genome-wide association studies (GWAS) and phenome-wide association studies (PheWAS) catalog and prioritized candidate genes through five functional annotations. Genes enriched in more than two categories were defined as "biological asthma risk genes." Then, DrugBank was used to match target genes with FDA-approved medications and identify candidate drugs for asthma. We discovered 139 biological asthma risk genes and identified 64 drugs targeting 22 of these genes. Seven of them were approved for asthma, including reslizumab, mepolizumab, theophylline, dyphylline, aminophylline, oxtriphylline, and enprofylline. We also found 17 drugs with clinical or preclinical evidence in treating asthma. In addition, eleven of the 40 candidate drugs were further identified as promising asthma therapy. Noteworthy, IL6R is considered a target for asthma drug repurposing based on its high target scores. Through in silico drug repurposing approach, we identified sarilumab and satralizumab as the most promising drug for asthma treatment.

Whole-Exome Sequencing Identifies Genetic Variants for Severe Adolescent Idiopathic Scoliosis in a Taiwanese Population.

Adolescent idiopathic scoliosis (AIS) is a three-dimensional spinal curvature deformity that appears in the adolescent period. In this study, we performed whole-exome sequencing on 11 unrelated Taiwanese patients with a Cobb's angle greater than 40 degrees. Our results identified more than 200 potential pathogenic rare variants, however, most of which were carried only by one individual. By in silico pathogenicity annotation studies, we found that TTN, CLCN1, and SOX8 were the most important genes, as multiple pathogenic variants were within these genes. Furthermore, biological functional annotation indicated critical roles of these AIS candidate genes in the skeletal muscle. Importantly, a pathogenic variant on SOX8 was shared by over 35% of the patients. These results highlighted TTN, CLCN1, and SOX8 as the most likely susceptibility genes for severe AIS.

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.

Genetic Association of the Functional WDR4 Gene in Male Fertility.

Infertility is one of the important problems in the modern world. Male infertility is characterized by several clinical manifestations, including low sperm production (oligozoospermia), reduced sperm motility (asthenozoospermia), and abnormal sperm morphology (teratozoospermia). WDR4, known as Wuho, controls fertility in Drosophila. However, it is unclear whether WDR4 is associated with clinical manifestations of male fertility in human. Here, we attempted to determine the physiological functions of WDR4 gene. Two cohorts were applied to address this question. The first cohort was the general population from Taiwan Biobank. Genomic profiles from 68,948 individuals and 87 common physiological traits were applied for phenome-wide association studies (PheWAS). The second cohort comprised patients with male infertility from Wan Fang Hospital, Taipei Medical University. In total, 81 male participants were recruited for the genetic association study. Clinical records including gender, age, total testosterone, follicle-stimulating hormone (FSH), luteinizing hormone (LH), total sperm number, sperm motility, and sperm morphology were collected. In the first cohort, results from PheWAS exhibited no associations between WDR4 genetic variants and 87 common physiological traits. In the second cohort, a total of four tagging single-nucleotide polymorphisms (tSNPs) from WDR4 gene (rs2298666, rs465663, rs2248490, and rs3746939) were selected for genotyping. We found that SNP rs465663 solely associated with asthenozoospermia. Functional annotations through the GTEx portal revealed the correlation between TT or TC genotype and low expression of WDR4. Furthermore, we used mouse embryonic fibroblasts cells from mwdr4 heterozygous (+/‒) mice for functional validation by western blotting. Indeed, low expression of WDR4 contributed to ROS-induced DNA fragmentation. In conclusion, our results suggest a critical role of WDR4 gene variant as well as protein expression in asthenozoospermia.

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.

Functional correlations between CXCL10/IP10 gene polymorphisms and risk of Kawasaki disease.

BACKGROUND: Kawasaki disease (KD) is an acute systemic vasculitis syndrome with unknown pathogen. The immune system has been suggested to involve in the pathogenesis in KD. IP10 is a chemoattractant for initiating T-cell activation. The aim of this study was to investigate the association between genetic polymorphisms of IP10 and KD. METHODS: A total of 354 KD patients and 1,709 control subjects (709 subjects in cohort 1 and 1,000 subjects in cohort 2) were enrolled in this study. Four tagging single nucleotide polymorphisms (rs3921, rs4256246, rs4508917, and rs4386624) were chosen for genotyping. RESULTS: Our results indicated that CC genotype of rs3921 and GG genotype of rs4386624 had higher frequency in KD patients compared to control. In addition, higher plasma IP10 level was observed in CC genotype of rs3921 than CG genotype and GG genotype. C/G haplotype carriers of rs3921/rs4386624 had 5.48-fold risk for KD compared to G/C haplotype carriers. Two-locus analysis further showed the combinatorial effects of rs3921 and rs4386624 in KD susceptibility. CONCLUSIONS: This study indicated the close correlation between IP10 and the risk of Kawasaki disease.

Evaluation for the Genetic Association between Store-Operated Calcium Influx Pathway (STIM1 and ORAI1) and Human Hepatocellular Carcinoma in Patients with Chronic Hepatitis B Infection.

Hepatocellular carcinoma (HCC) often develops from chronic hepatitis B (CHB) through replication of hepatitis B virus (HBV) infection. Calcium (Ca2+) signaling plays an essential role in HBV replication. Store-operated calcium (SOC) channels are a major pathway of Ca2+ entry into non-excitable cells such as immune cells and cancer cells. The basic components of SOC signaling include the STIM1 and ORAI1 genes. However, the roles of STIM1 and ORAI1 in HBV-mediated HCC are still unclear. Thus, long-term follow-up of HBV cohort was carried out in this study. This study recruited 3631 patients with chronic hepatitis (345 patients with HCC, 3286 patients without HCC) in a Taiwanese population. Genetic variants of the STIM1 and ORAI1 genes were detected using an Axiom CHB1 genome-wide array. Clinical associations of 40 polymorphisms were analyzed. Three of the STIM1 single-nucleotide polymorphisms (SNPs) (rs6578418, rs7116520, and rs11030472) and one SNP of ORAI1 (rs6486795) showed a trend of being associated with HCC disease (p < 0.05). However, after correction for multiple testing, none of the SNPs reached a significant level (q > 0.05); in contrast, neither STIM1 nor ORAI1 showed a significant association with HCC progression in CHB patients. Functional studies by both total internal reflection fluorescence images and transwell migration assay indicated the critical roles of SOC-mediated signaling in HCC migration. In conclusion, we reported a weak correlation between STIM1/ORAI1 polymorphisms and the risk of HCC progression in CHB patients.

Association of UBE3C Variants with Reduced Kidney Function in Patients with Diabetic Kidney Disease.

Diabetic kidney disease (DKD) is the leading cause of morbidity and mortality in patients with diabetes mellitus (DM) and the most common variant of end-stage renal disease (ESRD) globally. The economic burden of ESRD treatment with dialysis is substantial. The incidence and prevalence of ESRD in Taiwan remain the highest worldwide. Therefore, identifying genetic factors affecting kidney function would have valuable clinical implications. We performed microarray experiments and identified that ubiquitin protein ligase E3C (UBE3C) is differentially expressed in two DKD patient groups with extreme (low and high) urine protein-to-creatinine ratios. A follow-up genotyping study was performed in a larger group to investigate any specific variants of UBE3C associated with DKD. A total of 263 patients were included in the study, comprising 172 patients with DKD and 91 control subjects (patients with DM without chronic kidney disease (CKD)). Two UBE3C variants (rs3802129(AA) and rs7807(CC)) were determined to be associated with reduced kidney function. The haplotype analysis revealed that rs3802129/rs3815217 (block 1) with A/G haplotype and rs8101/rs7807 (block 2) with T/C haplotype were associated with higher risks of CKD phenotypes. These findings suggest a clinical role of UBE3C variants in DKD risk.

Gender Differences in Genetic Associations of RAB38 with Urinary Protein-to-Creatinine Ratio (UPCR) Levels in Diabetic Nephropathy Patients.

Renal dysfunction is common in patients with diabetes mellitus (DM). Previous findings from a meta-analysis of GWAS indicated that the variation of RAB38/CTSC is highly associated with the urinary albumin-to-creatinine ratio (UACR) in European populations. In addition, RAB38 knockout rats showed an increase in urinary albumins. Although the prevalence of chronic kidney disease is high in Taiwan, the role of genetic variants in diabetic renal function is still unclear. In the current study, 275 diabetic nephropathy (DN) patients were recruited to perform a genetic association study. Our results indicated that rs1027027, rs302647, and rs302646 in RAB38 were significantly associated with urinary protein-to-creatinine ratio (UPCR) levels in DN patients. Importantly, after analysis stratified by gender, a significant genetic influence on UPCR levels was observed in the male population. The findings confirmed the roles of gender and variants of RAB38 in the risk of UPCR in Diabetic Nephropathy patients.

Pharmacogenomics Study for Raloxifene in Postmenopausal Female with Osteoporosis.

Osteoporosis is characterized by decreased bone mineral density and increased risk of fracture. Raloxifene is one of the treatments of osteoporosis. However, the responses were variable among patients. Previous studies revealed that the genetic variants are involved in the regulation of treatment outcomes. To date, studies that evaluate the influence of genes across all genome on the raloxifene treatment response are still limited. In this study, a total of 41 postmenopausal osteoporosis patients under regular raloxifene treatment were included. Gene-based analysis using MAGMA was applied to investigate the genetic association with the bone mineral density response to raloxifene at the lumbar spine or femoral neck site. Results from gene-based analysis indicated several genes (GHRHR, ABHD8, and TMPRSS6) related to the responses of raloxifene. Besides, the pathways of iron ion homeostasis, osteoblast differentiation, and platelet morphogenesis were enriched which implies that these pathways might be relatively susceptible to raloxifene treatment outcome. Our study provided a novel insight into the response to raloxifene.

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.

Genetic variants that influence SARS-CoV-2 receptor TMPRSS2 expression among population cohorts from multiple continents.

The World Health Organization recently announced that pandemic status has been achieved for coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Exponential increases in patient numbers have been reported around the world, along with proportional increases in the number of COVID-19-related deaths. The SARS-CoV-2 infection rate in a population is expected to be influenced by social practices, availability of vaccines or prophylactics, and the prevalence of susceptibility genes in the population. Previous work revealed that cellular uptake of SARS-CoV-2 requires Angiotensin Converting Enzyme 2 (ACE-2) and a cellular protease. The spike (S) protein on SARS-CoV-2 binds ACE-2, which functions as an entry receptor. Following receptor binding, transmembrane protease serine 2 (encoded by TMPRSS2) primes the S protein to allow cellular uptake. Therefore, individual expression of TMPRSS2 may be a crucial determinant of SARS-CoV-2 infection susceptibility. Here, we utilized multiple large genome databases, including the GTEx portal, SNP nexus, and Ensembl genome project, to identify gene expression profiles for TMPRSS2 and its important expression quantitative trait loci. Our results show that four variants (rs464397, rs469390, rs2070788 and rs383510) affect expression of TMPRSS2 in lung tissue. The allele frequency of each variant was then assessed in regional populations, including African, American, European, and three Asian cohorts (China, Japan and Taiwan). Interestingly, our data shows that TMPRSS2-upregulating variants are at higher frequencies in European and American populations than in the Asian populations, which implies that these populations might be relatively susceptible to SARS-CoV-2 infection.

Single-nucleotide polymorphism of rs7944135 (macrophage-expressed gene 1) is associated with hepatitis B surface antigen seroclearance in chronic hepatitis B infection: A cohort study.

Clearance of the hepatitis B surface antigen (HBsAg) is the ultimate aim of treatment for patients with chronic hepatitis B (CHB) infection. Genetic, factor age, and gender were reported to be involved in the clearance of HBsAg. However, the rate of HBsAg seroclearance in CHB patients is still low globally and few of the single-nucleotide polymorphism (SNP) had been identified to associated with HBsAg seroclearance in CHB patients.Recently, 3 associated SNPs (rs7944135, rs171941, and rs6462008) were reported in the clearance of HBsAg in the Korean population. However, these SNPs have not been investigated in the CHB Taiwanese population. In present study, these 3 SNPs were genotyped in 2565 Taiwanese CHB patients including 493 CHB patients with HBsAg seroclearance and 2072 without HBsAg seroclearance.We observed that SNP rs7944135 was solely associated with HBsAg seroclearance. Subjects with the AA genotype at rs7944135 of macrophage-expressed gene 1 had a higher susceptibility to HBsAg clearance, compared to those with the AG or GG genotype under the genotypic model (odds ratio [OR] = 1.76. 95% confidence interval [CI] = 1.14-2.72, P = .045). Furthermore, we found a 1.74-fold increased risk of acquiring HBsAg seroclearance associated with the AA genotype compared to AG + GG of rs7944135 under the recessive model (OR = 1.74. 95% CI = 1.13-2.66, P = .014). According to the cumulative fraction curve with the log-rank test revealed that patients with the AA genotype of rs7944135 showed higher susceptibility to occur HBsAg seroclearance (P = .039) and HBV DNA undetectable (P = .0074) compared to those with the AG or GG genotype.This study examined the associations of 3 SNPs (rs7944135, rs171941, and rs6462008) with HBsAg seroclearance, and we identified that rs7944135 is solely associated with HBsAg seroclearance in Taiwanese CHB patients.