PHACTR1 and APOC1 genetic variants are associated with multi-vessel coronary artery disease.

BACKGROUND: Severe coronary artery disease (CAD) represents an advanced arterial narrowing, often associated with critical complications like myocardial infarction and angina. This study aimed to comprehensively investigate determinants of severe and multi-vessel CAD manifestations. METHODS: One thousand nine hundred patients with severe and multivessel CAD (stenosis > 70%) were recruited along with 1,056 controls without stenosis. Associations using a genotyping panel comprising 159 Single Nucleotide Polymorphisms (SNPs) previously implicated in CAD pathogenesis were examined and these associations were replicated using the UK Biobank cohort (N = 29,970). RESULTS: The investigation identified 14 genetic associations with severe CAD, of which 7 were also associated with multivessel disease. Notably, PHACTR1 SNP (rs9349379*G) showed a higher association with severe and multivessel CAD in individuals aged ≤ 65, indicating a higher risk of early disease onset. Conversely, the APOC1/APOE SNP (rs445925*T) is associated with reduced susceptibility to severe CAD and multivessel disease in individuals aged over 65, indicating a persistent negative association. CONCLUSIONS: Following replication of the associations in the large UK Biobank dataset, it was found that patients carrying the rs9349379*G variant in the PHACTR1 gene are at risk of developing severe or multivessel disease. Conversely, the rs445925*T variant in APOC1/APOE is associated with reduced susceptibility to severe CAD and multivessel disease, highlighting the significance of this genetic variant in these specific CAD presentations. This study contributes to a better understanding of CAD heterogeneity, paving the way for tailored management strategies based on genetic profiles.

Omnibus proteome-wide association study identifies 43 risk genes for Alzheimer disease dementia.

Transcriptome-wide association study (TWAS) tools have been applied to conduct proteome-wide association studies (PWASs) by integrating proteomics data with genome-wide association study (GWAS) summary data. The genetic effects of PWAS-identified significant genes are potentially mediated through genetically regulated protein abundance, thus informing the underlying disease mechanisms better than GWAS loci. However, existing TWAS/PWAS tools are limited by considering only one statistical model. We propose an omnibus PWAS pipeline to account for multiple statistical models and demonstrate improved performance by simulation and application studies of Alzheimer disease (AD) dementia. We employ the Aggregated Cauchy Association Test to derive omnibus PWAS (PWAS-O) p values from PWAS p values obtained by three existing tools assuming complementary statistical models-TIGAR, PrediXcan, and FUSION. Our simulation studies demonstrated improved power, with well-calibrated type I error, for PWAS-O over all three individual tools. We applied PWAS-O to studying AD dementia with reference proteomic data profiled from dorsolateral prefrontal cortex of postmortem brains from individuals of European ancestry. We identified 43 risk genes, including 5 not identified by previous studies, which are interconnected through a protein-protein interaction network that includes the well-known AD risk genes TOMM40, APOC1, and APOC2. We also validated causal genetic effects mediated through the proteome for 27 (63%) PWAS-O risk genes, providing insights into the underlying biological mechanisms of AD dementia and highlighting promising targets for therapeutic development. PWAS-O can be easily applied to studying other complex diseases.

M2 macrophage exosome-derived Apoc1 promotes ferroptosis resistance in osteosarcoma by inhibiting ACSF2 deubiquitination.

Osteosarcoma (OS) is the most common primary malignant tumor of bone. The aim of this study was to investigate the regulatory mechanisms of M2 macrophage exosomes (M2-Exos) in ferroptosis in OS. A mouse model was established to investigate the in vivo role of M2-Exos. We investigated their effects on ferroptosis in OS using erastin, a ferroptosis activator, and deferoxamine mesylate, an iron chelator. In vitro, we investigated whether the Apoc1/Acyl-CoA Synthetase Family Member 2 (ACSF2) axis mediates these effects, using shApoc1 and shACSF2. The mechanisms whereby Apoc1 regulates ACSF2 were examined using cyclohexanone, a protein synthesis inhibitor, and MG132, a proteasomal inhibitor. M2-Exos reversed the inhibitory effects of erastin on OS cells, thus enhancing their viability, migration, invasion, proliferation, and reducing ferroptosis. Apoc1 was highly expressed in M2-Exos, and interfering with this expression reversed the effects of M2-Exos on OS cells. ACSF2 mediated the effects of M2-Exos-derived Apoc1. Apoc1 interacted with ACSF2, which, in turn, interacted with USP40. Apoc1 overexpression increased ACSF2 ubiquitination, promoting its degradation, whereas USP40 overexpression inhibited ACSF2 ubiquitination and promoted its expression. Apoc1 overexpression inhibited ACSF2 binding to USP40. M2-Exos-derived Apoc1 promoted ferroptosis resistance by inhibiting USP40 binding to ACSF2 and promoting ACSF2 ubiquitination and degradation, thus enhancing OS development.

On the effect heterogeneity of established disease susceptibility loci for Alzheimer's disease across different genetic ancestries.

INTRODUCTION: Genome-wide association studies have identified numerous disease susceptibility loci (DSLs) for Alzheimer's disease (AD). However, only a limited number of studies have investigated the dependence of the genetic effect size of established DSLs on genetic ancestry. METHODS: We utilized the whole genome sequencing data from the Alzheimer's Disease Sequencing Project (ADSP) including 35,569 participants. A total of 25,459 subjects in four distinct populations (African ancestry, non-Hispanic White, admixed Hispanic, and Asian) were analyzed. RESULTS: We found that nine DSLs showed significant heterogeneity across populations. Single nucleotide polymorphism (SNP) rs2075650 in translocase of outer mitochondrial membrane 40 (TOMM40) showed the largest heterogeneity (Cochran's Q = 0.00, I2 = 90.08), followed by other SNPs in apolipoprotein C1 (APOC1) and apolipoprotein E (APOE). Two additional loci, signal-induced proliferation-associated 1 like 2 (SIPA1L2) and solute carrier 24 member 4 (SLC24A4), showed significant heterogeneity across populations. DISCUSSION: We observed substantial heterogeneity for the APOE-harboring 19q13.32 region with TOMM40/APOE/APOC1 genes. The largest risk effect was seen among African Americans, while Asians showed a surprisingly small risk effect.

Apolipoprotein C1 promotes tumor progression in gastric cancer.

Background: Gastric cancer (GC) is a malignancy with the worst prognosis that seriously threatens human health, especially in East Asia. Apolipoprotein C1 (apoc1) belongs to the apolipoprotein family. In addition, apoc1 has been associated with various tumors. However, its role in GC remains unclear. Methods: Firstly, we quantified its expression in GC and adjacent tumor tissues, using The Cancer Genome Atlas (TCGA). Next, we assessed cell invasion and migration abilities. Finally, we revealed the role of apoc1 in the tumor microenvironment (TME), immune cell infiltration and drug sensitivity. Results: Firstly, in TCGA database, it has been shown that elevated expression of apoc1 was identified in various cancers, including GC, then we found that high expression of apoc1 was significantly correlated with poor prognosis in GC. Histologically, apoc1 expression is proportional to grade, cancer stage, and T stage. The experimental results showed that apoc1 promoted cell invasion and migration. Then GO, KEGG, and GSEA pathway analyses indicated that apoc1 may be involved in the WNT pathway and immune regulation. Furthermore, we found out the tumor-infiltrating immune cells related to apoc1 in the tumor microenvironment (TME) using TIMER. Finally, we investigated the correlation between apoc1 expression and drug sensitivity, PD-1 and CTLA-4 therapy. Conclusions: These results suggest that apoc1 participates in the evolution of GC, and may represent a potential target for detection and immunotherapy in GC.

APOC1 predicts a worse prognosis for esophageal squamous cell carcinoma and is associated with tumor immune infiltration during tumorigenesis.

Background: Esophageal carcinoma (ESCA), a common malignant tumor of the digestive tract with insidious onset, is a serious threat to human health. Despite multiple treatment modalities for patients with ESCA, the overall prognosis remains poor. Apolipoprotein C1 (APOC1) is involved in tumorigenesis as an inflammation-related molecule, and its role in esophageal cancer is still unknown. Methods: We downloaded documents and clinical data using The Cancer Genome Atlas (TCGA)and Gene Expression Omnibus (GEO) databases. We also conducted bioinformatics studies on the diagnostic value, prognostic value, and correlation between APOC1 and immune infiltrating cells in ESCA through STRING (https://cn.string-db.org/), the TISIDB (http://cis.hku.hk/TISIDB/) website, and various other analysis tools. Results: In patients with ESCA, APOC1 was significantly more highly expressed in tumor tissues than in normal tissues (p < 0.001). APOC1 could diagnose ESCA more accurately and determine the TNM stage and disease classification with high accuracy (area under the curve, AUC≥0.807). The results of the Kaplan-Meier curve analysis showed that APOC1 has prognostic value for esophageal squamous carcinoma (ESCC) (p = 0.043). Univariate analysis showed that high APOC1 expression in ESCC was significantly associated with worse overall survival (OS) (p = 0.043), and multivariate analysis shows that high APOC1 expression was an independent risk factor for the OS of patients with ESCC (p = 0.030). In addition, the GO (gene ontology)/KEGG (Kyoto encyclopedia of genes and genomes) analysis showed a concentration of gene enrichment in the regulation of T-cell activation, cornification, cytolysis, external side of the plasma membrane, MHC protein complex, MHC class II protein complex, serine-type peptidase activity, serine-type endopeptidase activity, Staphylococcus aureus infection, antigen processing and presentation, and graft-versus-host disease (all p < 0.001). GSEA (gene set enrichment analysis) showed that enrichment pathways such as immunoregulatory-interactions between a lymphoid and non-lymphoid cell (NES = 1.493, p. adj = 0.023, FDR = 0.017) and FCERI-mediated NF-KB activation (NES = 1.437, p. adj = 0.023, FDR = 0.017) were significantly enriched in APOC1-related phenotypes. In addition, APOC1 was significantly associated with tumor immune infiltrating cells and immune chemokines. Conclusion: APOC1 can be used as a prognostic biomarker for esophageal cancer. Furthermore, as a novel prognostic marker for patients with ESCC, it may have potential value for further investigation regarding the diagnosis and treatment of this group of patients.

ApoC1 promotes glioma metastasis by enhancing epithelial-mesenchymal transition and activating the STAT3 pathway.

OBJECTIVE: One of the apolipoprotein's members, apolipoprotein C1 (ApoC1), is critical in the metabolism of both very-low-density lipoprotein (VLDL) and high-density lipoprotein (HDL) cholesterols. Multiple studies have recently revealed that ApoC1 may be a viable therapeutic target in solid malignancies. However, the motor protein ApoC1's specific role and mechanism in glioblastoma remain unknown. METHODS: In this study, the Cancer Genome Atlas (TCGA) database was used to look at the level of ApoC1 in glioma tissues and normal tissues, as well as how it related to the prognosis of glioma. Glioma cell lines (U87 and U251) were subjected to a wide range of experiments to determine the involvement of ApoC1 in cell proliferation, migration, and invasion. RESULTS: Cell proliferation, migration, and invasion decreased in glioma cell lines when ApoC1 was silenced. Furthermore, ApoC1 increased glioma cell metastasis through the epithelial-mesenchymal transition (EMT), while ApoC1 deletion reduced this impact. Additionally, APOC1 influenced the evolution of glioma by affecting the STAT3 pathway. In addition, APOC1 knockdown reduced the activation of the phosphorylated-total signal transducer and activator of transcription (STAT3) in the glioma cells. ApoC1-induced glioma cell metastatic ability was prevented by niclosamide (a STAT3 inhibitor). CONCLUSIONS: These results uncover that ApoC1 may serve as a biomarker or therapeutic target for future fundamental study or clinical treatment of glioma.

Systematic pan-cancer analysis identifies APOC1 as an immunological biomarker which regulates macrophage polarization and promotes tumor metastasis.

Apolipoprotein C1 (APOC1) has been found to play an essential part in proliferation and metastasis of numerous cancers, but related mechanism has not been elucidated, especially its function and role in tumor immunity. Through systematic pan-cancer analysis, we identified that APOC1 was closely associated with the infiltration of various immune cells in multiple cancers. Besides, APOC1 was significantly co-expressed with the immune checkpoints, major histocompatibility complex (MHC) molecules, chemokines and other immune-related genes. Furthermore, single-cell sequencing analysis suggested that the vast majority of APOC1 was expressed in macrophages or tumor-associated macrophages (TAMs). Additionally, the expression of APOC1 was significantly related to the prognosis of different cancers. Since APOC1 was most significantly abnormally expressed in renal cell cancer (RCC), subsequent experiments were carried out in RCC to explore the role of APOC1 in tumor immunity. The expression of APOC1 was significantly elevated in the tumor and serum of RCC patients. Besides, APOC1 was mainly expressed in the macrophage and it was closely related to the immune cell infiltration of RCC. Co-culture with RCC cells could induce the generation of TAMs with M2 phenotype which be blocked by silencing APOC1. The expression of APOC1 was elevated in the M2 or TAMs and APOC1 promoted M2 polarization of macrophages through interacting with CD163 and CD206. Furthermore, macrophages overexpressing APOC1 promoted the metastasis of RCC cells via secreting CCL5. Together, these data indicate that APOC1 is an immunological biomarker which regulates macrophage polarization and promotes tumor metastasis.

Genetic Variants and Haplotypes of TOMM40, APOE, and APOC1 are Related to the Age of Onset of Late-onset Alzheimer Disease in a Colombian Population.

BACKGROUND: The Apolipoprotein E (APOE) gene is the main risk factor for late-onset Alzheimer disease (LOAD). Genetic variants and haplotypes in regions near the APOE locus may be associated with LOAD in the Colombian population. OBJECTIVE: We evaluated frequencies and risk of genetic variants and haplotypes in APOE, TOMM40, and APOC1 promoters, also in putative regulatory enhancer elements (TOMM40 IVS2-4 and TOMM40 IVS6), and in cis-regulatory elements (ME1 and BCR). MATERIALS AND METHODS: Our case-control association study was carried out in 50 patients with LOAD and 50 controls. We determined frequencies and odd ratios for genetic variants and haplotypes. RESULTS: We found a significant association between LOAD and genetic variants at the TOMM40 promoter, at TOMM40 IVS2-4 and TOMM40 IVS6 regulatory enhancer elements, and at the APOC1 promoter. Particularly, variants of Poly-T and APOC1 promoter could anticipate the age of onset of LOAD in our population. We identified three risk haplotypes in TOMM40 (ACGGAG, ACGGGG, and ATAGGC) related to LOAD's age of onset. We also found other risk or protection haplotypes at the TOMM40 and APOE promoters, at TOMM40 IVS2-4, TOMM40 IVS6 regulatory enhancer elements, and at ME1. CONCLUSION: Genetic variants and haplotypes near the APOE locus are related to LOAD risk and accelerated onset of LOAD in the Colombian population.

Pharmacogenetic loci for rosuvastatin are associated with intima-media thickness change and coronary artery disease risk.

Aim: Polymorphisms at LPA, LDLR, APOE, APOC1, MYLIP and ABCG2 are attractive targets for assessment of their impact on lipid-lowering therapy with rosuvastatin. The present study investigated whether polymorphisms at these genes are associated with the risk of coronary artery disease (CAD) development, and reduction of atherogenic lipids and carotid intima-media thickness (CIMT) in CAD patients, taking rosuvastatin. Materials & methods: 190 CAD patients and 1697 subjects were enrolled in pharmacogenetic and genetic association study, respectively. SNP genotyping was done using the MassARRAY-4 system. Results:MYLIP rs6924995, rs3757354, APOC1 rs445925, LDLR rs6511720, APOE rs7412, ABCG2 rs2199936, rs1481012 variants were significantly associated with CAD susceptibility (p = 0.016, 0.0003, <0.0001, <0.0001, 0.013, 0.016, 0.0035, respectively), as well as with CIMT regression (except ABCG2 variants; p = 0.05, 0.039, 0.039, 0.016, 0.0065), and changes in plasma lipids during rosuvastatin therapy. Conclusion: The studied polymorphisms possess pleiotropic effects on plasma lipids and CIMT, CAD susceptibility, and determine lipid-lowering response to rosuvastatin.

Associations of genetic variants of lysophosphatidylcholine metabolic enzymes with levels of serum lipids.

OBJECTIVE: Metabolic disturbance of lysophosphatidylcholine (LPC) is related with dyslipidemia. Therefore, eight single-nucleotide polymorphisms (SNPs) were selected from LPC metabolic enzymes to study their associations with obesity and serum levels of lipids. METHODS: A total of 3305 children were recruited from four independent studies. Eight SNPs of LPC metabolic enzymes were selected and genotyped with the matrix-assisted laser desorption ionization time of flight mass spectrometry (MALDI-TOF MS). The multivariable linear regression model was applied to detect the associations of eight SNPs with obesity-related phenotypes and levels of lipids in each study. Meta-analyses were used to combine the results of four studies. RESULTS: Only SNP rs4420638 of APOC-1 gene was associated with serum lipids even after Bonferroni correction. The rs4420638 was positively associated with TC (ß = 0.15, P = 8.59 × 10-9) and low-density-lipoprotein-cholesterol (LDL-C, ß = 0.16, P = 9.98 × 10-14) individually. CONCLUSION: The study firstly revealed the association between APOC-1/rs4420638 and levels of serum lipids in Chinese children, providing evidence for susceptible gene variants of dyslipidemia.

Definitive roles of TOMM40-APOE-APOC1 variants in the Alzheimer's risk.

Despite advances, the roles of genetic variants from the APOE-harboring 19q13.32 region in Alzheimer's disease (AD) remain controversial. We leverage a comprehensive approach to gain insights into a more homogeneous genetic architecture of AD in this region. We use a sample of 2,673 AD-affected and 16,246 unaffected subjects from 4 studies and validate our main findings in the landmark Alzheimer's Disease Genetics Consortium cohort (3,662 AD-cases and 1,541 controls). We report the remarkably high excesses of the AD risk for carriers of the ε4 allele who also carry minor alleles of rs2075650 (TOMM40) and rs12721046 (APOC1) polymorphisms compared to carriers of their major alleles. The exceptionally high 4.37-fold (p=1.34 × 10-3) excess was particularly identified for the minor allele homozygotes. The beneficial and adverse variants were significantly depleted and enriched, respectively, in the AD-affected families. This study provides compelling evidence for the definitive roles of the APOE-TOMM40-APOC1 variants in the AD risk.

Cholesterol-related gene variants are associated with diabetes in coronary artery disease patients.

Coronary artery disease (CAD) which is a complex cardiovascular disease is the leading cause of death worldwide. The changing prevalence of the disease in different ethnic groups pointing out the genetic background of CAD. In this study, we aimed to evaluate the contribution of selected cholesterol metabolism-related gene polymorphisms to CAD presence. A total of 493 individuals who underwent coronary angiography were divided into 2 groups: normal coronary arteries (≤ 30% stenosis) and critical disease (≥ 50% stenosis). Individuals were genotyped for APOC1 (rs11568822), APOD (rs1568565), LIPA (rs13500), SORL1 (rs2282649), and LDLR (rs5930) polymorphisms using hydrolysis probes in Real-Time PCR. Blood samples were drawn before coronary angiography and biochemical analyses were done. The results were statistically evaluated. When the study group was stratified according to CAD, the minor allele of APOD polymorphism was found related to decreased risk for T2DM in the non-CAD group. In logistic regression analysis adjusted for several confounders, LDLR rs5930 polymorphism was found associated with T2DM presence in the male CAD group [OR = 0.502, 95%CI (0.259-0.974), p = 0.042]. Besides, APOD and LIPA polymorphisms were shown to affect serum lipid levels in non-CAD T2DM patients (p < 0.05). The minor allele of APOC1 was found associated with triglyceride levels in males independent of CAD status. Besides, LDLR minor allele carrier females had elevated HbA1c and glucose levels independent from CAD status in the whole group. The cholesterol metabolism-related gene polymorphisms were found associated with T2DM and biochemical parameters stratified to sex, CAD, and T2DM status.

Analysis of whole genome sequenced cases and controls shows that the association of variants in TOMM40, BCAM, NECTIN2 and APOC1 with late onset Alzheimer's disease is driven by linkage disequilibrium with APOE ε2/ε3/ε4 alleles.

Variants in APOE are associated with risk of late onset Alzheimer's disease (LOAD) but the magnitude of the effect has been reported to vary across ancestries. Also, other variants in the region have been reported to show association though it has been unclear whether this was secondary to their linkage disequilibrium with the APOE variants rs429358 and rs7412. Previous analyses of exome-sequenced samples have identified other genes in which rare variants impact risk of disease. In this study 2000 whole genome sequenced cases and controls with different ancestries were subjected to gene-based weighted burden analysis to identify risk genes. Additionally, individual variants in the APOE region were tested for association with LOAD. When using the APOE variants as covariates no individual genes showed statistically significant evidence for association after Bonferroni correction for multiple testing, which may well be a consequence of the modest sample size. Likewise, for those variants initially showing evidence of association with LOAD incorporating the APOE variants as covariates dramatically reduced the strength of association. These results demonstrate that the differential association of APOE across ancestries does not appear to be driven by another variant in the region. It seems likely that no other genes in the region have a direct effect on LOAD risk.

Overexpression of Apolipoprotein C1 (APOC1) in Clear Cell Renal Cell Carcinoma and Its Prognostic Significance.

BACKGROUND The aims of this study included 3 aspects: 1) assessing the expression of Apolipoprotein C1 (APOC1) in clear cell renal cell carcinoma (ccRCC) and normal groups; 2) evaluating the prognostic significance of APOC1 expression in the overall survival (OS) of ccRCC patients; and 3) exploring APOC1-related signaling pathways. MATERIAL AND METHODS The APOC1 expression value and clinical data of ccRCC patients were obtained from the cBioPortal database. We then evaluated the association of APOC1 expression with clinical characteristics of ccRCC patients. We also assessed the correlation between APOC1 expression and clinical outcome using Kaplan-Meier method. Our work then verified the independent prognostic factors of ccRCC by Cox regression analysis. Finally, the potential role of genes co-expressed with APOC1 was revealed via functional enrichment analysis. RESULTS Bioinformatic data revealed that APOC1 was expressed at higher levels in ccRCC tissue than in the normal group (all P<0.05). The high expression of APOC1 was associated with unfavorable prognosis of female patients (P<0.01), but not of male patients. APOC1 high expression also shortened the survival time of ccRCC patients age ≥60 years old (P<0.05). Cox regression analysis further indicated that APOC1 expression was an independent prognostic factor for OS of ccRCC patients. Additionally, we found that APOC1 expression was significantly associated with sex, grade, clinical stage, and T stage. Finally, enrichment analysis suggested that APOC1-associated pathways were involved in tumor growth and metastasis. CONCLUSIONS The current study indicated that APOC1 was highly expressed in ccRCC and was significantly associated with key clinical features. APOC1 appears to be an independent prognostic factor in patients with ccRCC. Importantly, APOC1 might be a potential therapeutic target for ccRCC via regulating pathways involved in cell growth and metastasis.

Human apolipoprotein C1 transgenesis reduces atherogenesis in hypercholesterolemic rabbits.

BACKGROUND AND AIMS: Apolipoprotein (apo) C1 is a 6.6 kDa protein associated with HDL and VLDL. ApoC1 alters triglyceride clearance, and it also favors cholesterol accumulation in HDL, especially by inhibiting CETP in human plasma. Apart from studies in mice, which lack CETP, the impact of apoC1 on atherosclerosis in animal models expressing CETP, like in humans, is not known. This study aimed at determining the net effect of human apoC1 on atherosclerosis in rabbits, a species with naturally high CETP activity but with endogenous apoC1 without CETP inhibitory potential. METHODS: Rabbits expressing a human apoC1 transgene (HuApoC1Tg) were generated and displayed significant amounts of human apoC1 in plasma. RESULTS: After cholesterol feeding, atherosclerosis lesions were significantly less extensive (-22%, p < 0.05) and HDL displayed a reduced ability to serve as CETP substrates (-25%, p < 0.05) in HuApoC1Tg rabbits than in WT littermates. It was associated with rises in plasma HDL cholesterol level and PON-1 activity, and a decrease in the plasma level of the lipid oxidation markers 12(S)-HODE and 8(S)HETE. In chow-fed animals, the level of HDL-cholesterol was also significantly higher in HuApoC1Tg than in WT animals (0.83 ± 0.11 versus 0.73 ± 0.11 mmol/L, respectively, p < 0.05), and it was associated with significantly lower CETP activity (cholesteryl ester transfer rate, -10%, p < 0.05; specific CETP activity, -14%, p < 0.05). CONCLUSIONS: Constitutive expression of fully functional human apoC1 in transgenic rabbit attenuates atherosclerosis. It was found to relate, at least in part, to the inhibition of plasma CETP activity and to alterations in plasma HDL.

The APOE gene cluster responds to air pollution factors in mice with coordinated expression of genes that differs by age in humans.

Little is known of gene-environment interactions for Alzheimer's disease (AD) risk factors. Apolipoprotein E (APOE) and neighbors on chromosome 19q13.3 have variants associated with risks of AD, but with unknown mechanism. This study describes novel links among the APOE network, air pollution, and age-related diseases. Mice exposed to air pollution nano-sized particulate matter (nPM) had coordinate responses of Apoe-Apoc1-Tomm40 in the cerebral cortex. In humans, the AD vulnerable hippocampus and amygdala had stronger age decline in APOE cluster expression than the AD-resistant cerebellum and hypothalamus. Using consensus weighted gene co-expression network, we showed that APOE has a conserved co-expressed network in rodent and primate brains. SOX1, which has AD-associated single nucleotide polymorphisms, was among the co-expressed genes in the human hippocampus. Humans and mice shared 87% of potential binding sites for transcription factors in APOE cluster promoter, suggesting similar inducibility and a novel link among environment, APOE cluster, and risk of AD.

Bayesian Genome-wide TWAS Method to Leverage both cis- and trans-eQTL Information through Summary Statistics.

Transcriptome-wide association studies (TWASs) have been widely used to integrate gene expression and genetic data for studying complex traits. Due to the computational burden, existing TWAS methods do not assess distant trans-expression quantitative trait loci (eQTL) that are known to explain important expression variation for most genes. We propose a Bayesian genome-wide TWAS (BGW-TWAS) method that leverages both cis- and trans-eQTL information for a TWAS. Our BGW-TWAS method is based on Bayesian variable selection regression, which not only accounts for cis- and trans-eQTL of the target gene but also enables efficient computation by using summary statistics from standard eQTL analyses. Our simulation studies illustrated that BGW-TWASs achieved higher power compared to existing TWAS methods that do not assess trans-eQTL information. We further applied BWG-TWAS to individual-level GWAS data (N = ∼3.3K), which identified significant associations between the genetically regulated gene expression (GReX) of ZC3H12B and Alzheimer dementia (AD) (p value = 5.42 × 10-13), neurofibrillary tangle density (p value = 1.89 × 10-6), and global measure of AD pathology (p value = 9.59 × 10-7). These associations for ZC3H12B were completely driven by trans-eQTL. Additionally, the GReX of KCTD12 was found to be significantly associated with ß-amyloid (p value = 3.44 × 10-8) which was driven by both cis- and trans-eQTL. Four of the top driven trans-eQTL of ZC3H12B are located within APOC1, a known major risk gene of AD and blood lipids. Additionally, by applying BGW-TWAS with summary-level GWAS data of AD (N = ∼54K), we identified 13 significant genes including known GWAS risk genes HLA-DRB1 and APOC1, as well as ZC3H12B.

ApoC1 promotes the metastasis of clear cell renal cell carcinoma via activation of STAT3.

Clear cell renal cell carcinoma (ccRCC) is the most common renal cancer and frequently diagnosed at an advanced stage. It is prone to develop unpredictable metastases even with proper treatment. Antiangiogenic therapy is the most effective medical treatment for metastatic ccRCC. Thus, exploration of novel approaches to inhibit angiogenesis and metastasis may potentially lead to a better therapeutic option for ccRCC. Among all the types of cancer, renal cancer samples exhibited the maximum upregulation of ApoC1 as referred to in the Oncomine database. The expression of ApoC1 was increased accompanied by ccRCC progression. A high level of ApoC1 was closely related to poor survival time in ccRCC patients. Furthermore, ApoC1 was over-expressed in the highly invasive ccRCC cells as compared to that in the low-invasive ccRCC cells. Besides, ApoC1 promoted metastasis of ccRCC cells via EMT pathway, whereas depletion of ApoC1 alleviated these effects. ApoC1 as a novel pro-metastatic factor facilitates the activation of STAT3 and enhances the metastasis of ccRCC cells. Meanwhile, ApoC1 in the exosomes were transferred from the ccRCC cells to the vascular endothelial cells and promoted metastasis of the ccRCC cells via activating STAT3. Finally, the metastatic potential of the ccRCC cells driven by ApoC1 was suppressed by DPP-4 inhibition. Our study not only identifies a novel ApoC1-STAT3 pathway in ccRCC metastasis but also provides direction for the exploration of novel strategies to predict and treat metastatic ccRCC in the future.

[Analysis of rs4420638A/G and -317H1/H2 polymorphisms of APOC1 gene among Chinese patients with pre-eclampsia].

OBJECTIVE: To assess the association of apolipoprotein (apo) C1 (APOC1) gene rs4420638A/G and -317H1/H2 polymorphisms with the risk of pre-eclampsia (PE) and the influence of their genotypes on the clinical and metabolic indexes among Chinese women. METHODS: In total 289 PE patients and 824 women with uncomplicated pregnancies were included. The rs4420638A/G genotype was determined by a Taqman real-time PCR allelic discrimination assay. The -317H1/H2 genotype was measured through PCR and restriction fragment length polymorphism analysis. Serum lipid and apo levels were measured by an enzymatic kit and a PEG-enhanced immunoturbidimetric assay. RESULTS: Allelic and genotypic frequencies of the APOC1 gene rs4420638A/G and -317H1/H2 were not significantly different between the two groups (all P> 0.05). However, patients carrying the G allele of the rs4420638A/G locus had higher serum levels of triglyceride, non-HDL-C and apoB, and a higher apoB/apoA1 ratio compared with those with an AA genotype (all P< 0.05). Patients carrying the H2 allele of the -317H1/H2 polymorphism had smaller delivery gestational weeks compared with those with the H1H1 genotype (P< 0.05). CONCLUSION: Polymorphisms of the APOC1 gene rs4420638 and -317H1/H2 sites may be associated with abnormal lipoprotein metabolism among Chinese patients with PE, though no association was found between variants of the APOC1 gene and the risk of PE among them.