Most genome‐wide association studies (GWASs) identify genetic variants for breast cancer occurrence. In contrast, few are for recurrence and mortality. We conducted a GWAS on breast cancer survival ...after diagnosis in estrogen receptor‐positive patients, including 953 Taiwanese patients with 159 events. Through Cox proportional hazard models estimation, we identified 24 risk SNPs with p < 1 × 10−5. Based on imputation and integrated analysis, one SNP, rs1024176 (located in 1q24.2, p = 2.43 × 10−5) was found to be a functional variant associated with breast cancer survival and XCL1 gene expression. A series of experimental approaches, including cell‐based analyses and CRISPR/Cas9 genome‐editing system, were then used and identified the transcription factor MYBL2 was able to discriminately bind to the A allele of rs1024176, the protective variant for breast cancer survival, which promoted XCL1 expression, but not to the G allele of rs1024176. The chemokine XCL1 attracts type 1 dendritic cells (DC1s) to the tumor microenvironment. In breast cancer tissues, we applied a two‐step Mendelian randomization analysis, using expression quantitative trait loci as instrumental variables, to confirm higher XCL1 expression was correlated with higher DC1 signatures and favorable disease progression, through the causal effect of rs1024176‐A allele. Our study supports the genetic effect on preventing breast cancer survival through XCL1‐induced DC1 recruitment in tumor microenvironment.
What's new?
Although many prognostic predictors have been identified, the factors that determine patient differences in breast cancer progression and survival are not fully understood. This study addresses the important role of cancer immune control in promoting human breast cancer survival. Using genetic, cell‐based, and multi‐omic analyses, the authors find that one of the most significant SNP, rs1024176 at 1q24.2 could be a functional variant regulating XCL1 gene expression and thus recruiting type 1 dendritic cells to the breast tumor microenvironment. These findings reveal a pathway to prevent breast cancer progression through XCL1‐induced type 1 dendritic cells recruitment in the tumor microenvironment.
The Taiwan Biobank (TWB) aims to build a nationwide research database that integrates genomic/epigenomic profiles, lifestyle patterns, dietary habits, environmental exposure history and long-term ...health outcomes of 300,000 residents of Taiwan. We describe here an investigation of the population structure of Han Chinese on this Pacific island using genotype data of 591,048 SNPs in an initial freeze of 10,801 unrelated TWB participants. In addition to the North-South cline reported in other Han Chinese populations, we find the Taiwanese Han Chinese clustered into three cline groups: 5% were of northern Han Chinese ancestry, 79.9% were of southern Han Chinese ancestry, and 14.5% belonged to a third (T) group. We also find that this T group is genetically distinct from neighbouring Southeast Asians and Austronesian tribes but similar to other southern Han Chinese. Interestingly, high degree of LD between HLA haplotype A*33:03-B*58:01, an MHC allele being of pathological relevance, and SNPs across the MHC region was observed in subjects with T origin, but not in other Han Chinese. This suggested the T group individuals may have experienced evolutionary events independent from the other southern Han Chinese. Based on the newly-discovered population structure, we detect different loci susceptible to type II diabetes in individuals with southern and northern Han Chinese ancestries. Finally, as one of the largest dataset currently available for the Chinese population, genome-wide statistics for the 10,810 subjects are made publicly accessible through Taiwan View (https://taiwanview.twbiobank.org.tw/index; date last accessed October 14, 2016) to encourage future genetic research and collaborations with the island Taiwan.
Abstract
Context
The association between circulating triglyceride (TG) and glycated hemoglobin A1c (HbA1c), a biomarker for type 2 diabetes, has been widely addressed, but the causal direction of the ...relationship is still ambiguous.
Objective
To confirm the causal relationship between TG and HbA1c by using bidirectional and 2-step Mendelian randomization (MR) approaches.
Methods
We carried out a bidirectional MR approach using the summarized results from the public database to examine any potential causal effects between serum TG and HbA1c in 16 000 individuals of the Taiwan Biobank cohort. We used the MR estimate and the MR inverse variance–weighted method to reveal that relationship between TG and HbA1c. To further determine whether the DNA methylation at specific sequences mediate the causal pathway between TG and HbA1c, using the 2-step MR approach.
Results
We identified that a single-unit increase in TG measured via log transformation of mg/dL data was associated with a significant increase of 10 units of HbA1c (95% CI = 1.05−18.95, P = 0.029). In contrast, the genetic determinants of HbA1c do not contribute to the amount of circulating TG (beta = 1.75, 95% CI = –11.50 to 14.90). Sensitivity analyses, included the weighted-median approach and MR-Egger regression, were performed to confirm no pleiotropic effect among these instrumental variables. Furthermore, we identified the genetic variant, rs1823200, is associated with both methylation of the CpG site adjacent to CADPS gene and HbA1c level.
Conclusion
Our study suggests that higher circulating TG can have an affect on genomic methylation status, ultimately causing elevated level of circulating HbA1c.
Although many genome-wide association studies (GWASs) of hyperuricemia or gout have been reported, the related genetic factors and the mechanisms from hyperuricemia to gouty attack remain unclear. ...This study aimed to identify genetic factors and pathogenesis of gout from hyperuricemia by genome-wide association study (GWAS). 747 gout patients, 747 hyperuricemia and 2071 age-matched controls were recruited and analyzed with Affymetrix 650 K chip to find the related genetic variants. The functions of the related genes were investigated in an endothelial cell (EC) with urate crystal stimulation. The GWAS results showed 36 SNPs to be strongly associated with gout compared to controls (all p-values < 10
). Whereas the rs2231142 in ABCG2 gene had significant associations between gout and controls, between gout and hyperuricemia, and between hyperuricemia and controls (all p-values < 10
), and the ORs were 4.34, 3.37 and 2.15 (all p-values < 0.001) after adjustment of potential confounders, respectively. The cell model showed significantly higher IL-8 release from EC combined with ABCG2 knockdown. We concluded that ABCG2 gene contributed to hyperuricemia but also gout, and that it was involved in the inflammation dysregulation via augmented IL-8 release in EC.
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.
Diabetes, dyslipidemia and hypertension are important metabolic diseases that impose a great burden on many populations worldwide. However, certain population strata have reduced prevalence for all ...three diseases, but the underlying mechanisms are poorly understood. We sought to identify the phenotypic, genomic and metabolomic characteristics of the low-prevalence population to gain insights into possible innate non-susceptibility against metabolic diseases. We performed k-means cluster analysis of 16,792 subjects using anthropometric and clinical biochemistry data collected by the Taiwan Biobank. Nuclear magnetic resonance spectra-based metabolome analysis was carried out for 217 subjects with normal body mass index, good exercise habits and healthy lifestyles. We found that the gene APOA5 was significantly associated with reduced prevalence of disease, and lesser associations included the genes HIF1A, LIMA1, LPL, MLXIPL, and TRPC4. Blood plasma of subjects belonging to the low disease prevalence cluster exhibited lowered levels of the GlycA inflammation marker, very low-density lipoprotein and low-density lipoprotein cholesterol, triglycerides, valine and leucine compared to controls. Literature mining revealed that these genes and metabolites are biochemically linked, with the linkage between lipoprotein metabolism and inflammation being particularly prominent. The combination of phenomic, genomic and metabolomic analysis may also be applied towards the study of metabolic disease prevalence in other populations.
Tumor recurrence and metastasis result in an unfavorable prognosis for cancer patients. Recent studies have suggested that specific microRNAs (miRNAs) may play important roles in the development of ...cancer cells. However, prognostic markers and the outcome prediction of the miRNA signature in breast cancer patients have not been comprehensively assessed. The aim of this study was to identify miRNA biomarkers relating to clinicopathological features and outcome of breast cancer. A miRNA microarray analysis was performed on breast tumors of different lymph node metastasis status and with different progression signatures, indicated by overexpression of
cyclin D1
and
β
-
catenin
genes, to identify miRNAs showing a significant difference in expression. The functional interaction between the candidate miRNA, miR-30a, and the target gene,
Vim
, which codes for vimentin, a protein involved in epithelial–mesenchymal transition, was examined using the luciferase reporter assay, western blotting, and migration and invasion assays. The association between the decreased miR-30a levels and breast cancer progression was examined in a survival analysis. miR-30a negatively regulated vimentin expression by binding to the 3′-untranslated region of
Vim
. Overexpression of miR-30a suppressed the migration and invasiveness phenotypes of breast cancer cell lines. Moreover, reduced tumor expression of miR-30a in breast cancer patients was associated with an unfavorable outcome, including late tumor stage, lymph node metastasis, and worse progression (mortality and recurrence) (
p
< 0.05). In conclusion, these findings suggest a role for miR-30a in inhibiting breast tumor invasiveness and metastasis. The finding that miR-30a downmodulates vimentin expression might provide a therapeutic target for the treatment of breast cancer.
With the promotion of Industry 4.0, which emphasizes interconnected and intelligent devices, several factories have introduced numerous terminal Internet of Things (IoT) devices to collect relevant ...data or monitor the health status of equipment. The collected data are transmitted back to the backend server through network transmission by the terminal IoT devices. However, as devices communicate with each other over a network, the entire transmission environment faces significant security issues. When an attacker connects to a factory network, they can easily steal the transmitted data and tamper with them or send false data to the backend server, causing abnormal data in the entire environment. This study focuses on investigating how to ensure that data transmission in a factory environment originates from legitimate devices and that related confidential data are encrypted and packaged. This paper proposes an authentication mechanism between terminal IoT devices and backend servers based on elliptic curve cryptography and trusted tokens with packet encryption using the TLS protocol. Before communication between terminal IoT devices and backend servers can occur, the authentication mechanism proposed in this paper must first be implemented to confirm the identity of the devices and, thus, the problem of attackers imitating terminal IoT devices transmitting false data is resolved. The packets communicated between devices are also encrypted, preventing attackers from knowing their content even if they steal the packets. The authentication mechanism proposed in this paper ensures the source and correctness of the data. In terms of security analysis, the proposed mechanism in this paper effectively withstands replay attacks, eavesdropping attacks, man-in-the-middle attacks, and simulated attacks. Additionally, the mechanism supports mutual authentication and forward secrecy. In the experimental results, the proposed mechanism demonstrates approximately 73% improvement in efficiency through the lightweight characteristics of elliptic curve cryptography. Moreover, in the analysis of time complexity, the proposed mechanism exhibits significant effectiveness.
The vigorous development of the Industrial Internet of Things brings the advanced connection function of the new generation of industrial automation and control systems. The Supervisory Control and ...Data Acquisition (SCADA) network is converted into an open and highly interconnected network, where the equipment connections between industrial electronic devices are integrated with a SCADA system through a Modbus protocol. As SCADA and Modbus are easily used for control and monitoring, the interconnection and operational efficiency between systems are highly improved; however, such connectivity inevitably exposes the system to the open network environment. There are many network security threats and vulnerabilities in a SCADA network system. Especially in the era of the Industrial Internet of Things, any security vulnerability of an industrial system may cause serious property losses. Therefore, this paper proposes an encryption and verification mechanism based on the trusted token authentication service and Transport Layer Security (TLS) protocol to prevent attackers from physical attacks. Experimentally, this paper deployed and verified the system in an actual field of energy management system. According to the experimental results, the security defense architecture proposed in this paper can effectively improve security and is compatible with the actual field system.
Nephrolithiasis is a common disease affecting almost all populations, with an increasing prevalence over the past decades. Previous studies revealed several functional polymorphisms associated with ...the pathogenesis of nephrolithiasis. However, data on Asian populations are limited. In this study, three candidate polymorphisms were selected from previous studies to investigate the correlations with nephrolithiasis in a Taiwanese population. In total, 454 nephrolithiasis patients were recruited from Kaohsiung Medical University Hospital, with SNP frequency for 1513 subjects of general population from the Taiwan Biobank (TWB) as a genotypic reference. Results revealed that subjects with minor TT genotype at rs1256328 (alkaline phosphatase, liver/bone/kidney (ALPL)) have higher susceptibility to nephrolithiasis (odds ratio (OR) = 2.03, p = 0.0013). In addition, subjects carrying the minor AA genotype at rs12654812 (regulator of G protein signaling 14 (RGS14)) have higher susceptibility to nephrolithiasis (OR = 1.91, p = 0.0017). Among nephrolithiasis patients, subjects with GG at rs7627468 (calcium-sensing receptor (CASR)) have lower pH level in urine (p = 0.0088). Importantly, rs7627468 is associated with the expressions of IQCB1 and EAF2. rs12654812 could influence the expression of RGS14 itself, MXD3, and FGFR4. In summary, this study successfully validated the genetic roles of rs1256328 and rs12654812 in human nephrolithiasis.
PDF
