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.

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.

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.

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.

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.

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.

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.

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.

Germline Genetic Association between Stromal Interaction Molecule 1 (STIM1) and Clinical Outcomes in Breast Cancer Patients.

Among all cancers in women, breast cancer has the highest incidence. The mortality of breast cancer is highly associated with metastasis. Migration and malignant transformation of cancer cells have been reported to be modulated by store-operated calcium (SOC) channels, which control calcium signaling and cell proliferation pathways. Stromal interaction molecule 1 (STIM1) is a calcium sensor in the endoplasmic reticulum, triggering the activation of store-operated calcium signaling. However, the clinical relevance of STIM1 in breast cancer is still unclear. Here, we recruited 348 breast cancer patients and conducted a genetic association study to address this question. Four tagging germline single nucleotide variants (SNVs) in STIM1 were selected and RNA sequencing data of 525 breast cancer samples from The Cancer Genome Atlas (TCGA) database were evaluated. The results show that rs2304891 and rs3750996 were correlated with clinical stage of breast cancer. Expression quantitative trait loci (eQTL) analysis indicated that risk G allele of STIM1 contributed to the higher expression of STIM1. In addition, we found an increased risk of rs2304891 G allele and rs3750996 A allele in estrogen receptor (ER) positive and progesterone receptor (PR) positive patients. In conclusion, our results suggest that germline SNV, rs2304891 and rs3750996 as well as STIM1 expression are important biomarkers for the prediction of clinical outcomes in breast cancer patients.

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.

Prognostic Effect of Comorbid Disease and Immune Gene Expression on Mortality in Kidney Cancer-A Population Based Study.

The effect of comorbidities and the immune profiles of the kidney cancer microenvironment play a major role in patients' prognosis and survival. Using the National Health Insurance Research Database (Taiwan), we identified patients aged >20 years with a first diagnosis of kidney cancer between 2005 and 2014. Differences in demographic characteristics and comorbidities were examined using the Pearson chi-squared test or the t test. The Cox regression model was used to construct the nomogram. RNA-seq data were applied from The Cancer Genome Atlas database, and correlations between immune metagenes and clinical characteristics were determined using a linear regression model. In this nationwide cohort study, including 5090 patients with kidney cancer, predictors in our prediction models included age, sex, chronic kidney disease, dialysis requirements, renal stones, cerebrovascular disease, and metastasis tumor. In the tumor tissue profiles, significant positive correlations between immune metagenes and clinical stage or overall survival were observed among Natural Killer (NK) cells (CD56-), CD4+ T-helper 2 (Th2) cells, and activated Dendritic Cell (aDC). A negative correlation was observed between expression level of Dendritic Cell (DC) and overall survival. Patients with kidney cancer exhibit high prevalence of comorbid disease, especially in older patients. Comorbid disease types exert unique effects, and a particular comorbidity can affect cancer mortality. Moreover, the expression of immune metagenes can be utilized as potentialbiomarkers especially for further study of molecular mechanisms as well as microenvironments in kidney cancer.

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.

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.

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.

Characterization of T-Cell Receptor Repertoire in Patients with Rheumatoid Arthritis Receiving Biologic Therapies.

Rheumatoid arthritis (RA) is a systematic autoimmune disease, predominantly causing chronic polyarticular inflammation and joint injury of patients. For the treatment of RA, biologic disease-modifying antirheumatic drugs (bDMARDs) have been used to reduce inflammation and to interfere with disease progression through targeting and mediating the immune system. Although the therapeutic effects of bDMARDs in RA patients have been widely reported, whether these drugs also play important roles in T-cell repertoire status is still unclear. We therefore designed the study to identify the role of T-cell repertoire profiles in RA patients with different types of bDMARD treatments. A high-throughput sequencing approach was applied to profile the T-cell receptor beta chain (TCRB) repertoire of circulating T lymphocytes in eight patients given adalimumab (anti-TNF-α) with/without the following use of either rituximab (anti-CD20) or tocilizumab (anti-IL6R). We subsequently analyzed discrepancies in the clonal diversity and CDR3 length distribution as well as usages of the V and J genes of TCRB repertoire and interrogated the association between repertoire diversity and disease activities followed by the treatment of bDMARDs in these RA patients. All groups of patients showed well-controlled DAS28 scores (<2.6) after different treatment regimens of drugs and displayed no significant statistical differences in repertoire diversity, distribution of CDR3 lengths, and usage of V and J genes of TCRB. Nonetheless, a trend between overall TCRB repertoire diversity and disease activity scores in all bDMARD-treated RA patients was observed. Additionally, age was found to be associated with repertoire diversity in RA patients treated with bDMARDs. Through the profiling of the TCR repertoire in RA patients receiving different biologic medications, our study indicated an inverse tendency between TCR repertoire diversity and disease activity after biologic treatment in RA patients.

Functional Effects of let-7g Expression in Colon Cancer Metastasis.

MicroRNA regulation is crucial for gene expression and cell functions. It has been linked to tumorigenesis, development and metastasis in colorectal cancer (CRC). Recently, the let-7 family has been identified as a tumor suppressor in different types of cancers. However, the function of the let-7 family in CRC metastasis has not been fully investigated. Here, we focused on analyzing the role of let-7g in CRC. The Cancer Genome Atlas (TCGA) genomic datasets of CRC and detailed data from a Taiwanese CRC cohort were applied to study the expression pattern of let-7g. In addition, in vitro as well as in vivo studies have been performed to uncover the effects of let-7g on CRC. We found that the expression of let-7g was significantly lower in CRC specimens. Our results further supported the inhibitory effects of let-7g on CRC cell migration, invasion and extracellular calcium influx through store-operated calcium channels. We report a critical role for let-7g in the pathogenesis of CRC and suggest let-7g as a potential therapeutic target for CRC treatment.

Meta-Analysis of Genome-Wide Association Studies Identifies Three Loci Associated With Stiffness Index of the Calcaneus.

The stiffness index (SI) from quantitative ultrasound measurements is a good indicator of BMD and may be used to predict the risk of osteoporotic fracture. We conducted a genomewide association study (GWAS) for SI using 7742 individuals from the Taiwan Biobank, followed by a replication study in a Korean population (n = 2955). Approximately 6.1 million SNPs were subjected to association analysis, and SI-associated variants were identified. We further conducted a meta-analysis of Taiwan Biobank significant SNPs with a Korean population-based cohort. Candidate genes were prioritized according to epigenetic annotations, gene ontology, protein-protein interaction, GWAS catalog, and expression quantitative trait loci analyses. Our results revealed seven significant single-nucleotide polymorphisms (SNPs) within three loci: 7q31.31, 17p13.3, and 11q14.2. Conditional analysis showed that three SNPs, rs2536195 (CPED1/WNT16), rs1231207 (SMG6), and rs4944661 (LOC10050636/TMEM135), were the most important signals within these regions. The associations for the three SNPs were confirmed in a UK Biobank estimated BMD GWAS; these three cytobands were replicated successfully after a meta-analysis with a Korean population cohort as well. However, two SNPs were not replicated. After prioritization, we identified two novel genes, RAB15 and FNTB, as strong candidates for association with SI. Our study identified three SI-associated SNPs and two novel SI-related genes. Overall, these results provide further insight into the genetic architecture of osteoporosis. Further studies in larger East Asian populations are needed. © 2019 American Society for Bone and Mineral Research.

Integrative genomic analysis for the functional roles of ITPKC in bone mineral density.

Osteoporosis is defined by low bone mineral density (BMD), which is mainly due to the imbalances in osteoclast and osteoblast activity. Previous studies indicated that early activation of osteoclasts relies on calcium entry through store-operated calcium (SOC) entry, and several genes, including STIM1, ORAI1, and ITPKC, are known as key regulators of SOC entry. However, the relationships between STIM1, ORAI1, ITPKC, and human BMD are still unclear. In order to investigate the plausible associations between these genes and BMD, we conducted a meta-analysis of genes expression and BMD using the publicly available GEO database. We further recruited 1044 subjects and tested associations between polymorphisms in these genes and BMD. Clinical information (including age, sex, and BMI) was collected and used for the analysis. Our results indicated that ITPKC gene expression was significantly associated with BMD. Furthermore, we found that one ITPKC SNP (rs2607420) was significantly associated with lumbar spine BMD. Through bioinformatics analysis, rs2607420 was found to be very likely to participate in the regulation of ITPKC expression. Our findings suggest that ITPKC is a susceptibility gene for BMD, and rs2607420 may play an important role in the regulation of this gene.

Losses of cytokines and chemokines are common genetic features of human cancers: the somatic copy number alterations are correlated with patient prognoses and therapeutic resistance.

Intricate relationships among cytokines (including chemokines) shape the tumor microenvironment (TME) and reflect cell-cell interactions between malignant cells and other cells from the TME. Although our previous study indicated the transcriptional landscape of cytokines in 19 cancer types, the global pattern somatic copy number (SCN) alterations and the clinical relevance of cytokines have not been systematically investigated. Here, we reported a significant negative selection on cytokine genes. We also linked the SCN losses of cytokine genes to the abundance of immune infiltrates which affects cancer progression and patient prognoses. We also demonstrated and validated the correlations between SCN alterations of cytokine-containing loci and drug sensitivity. The results indicated the genomic loss of cytokines in malignant cells as a crucial theme for interrogating cancer progression, malignant cell-TME interactions, and therapeutics.