Identity-by-descent mapping using empirical estimates of identity-by-descent allele sharing may be useful for studies of complex traits in founder populations, where hidden relationships may augment t Show more
Identity-by-descent mapping using empirical estimates of identity-by-descent allele sharing may be useful for studies of complex traits in founder populations, where hidden relationships may augment the inherent genetic information that can be used for localization. Through identity-by-descent mapping, using ≈400 000 single-nucleotide polymorphisms (SNPs), of serum lipid profiles, we identified a major linkage signal for triglycerides in 1007 Pima Indians (LOD=9.23; Show less
Carbohydrate response element binding protein (ChREBP) is a transcription factor that responds to glucose and activates genes involved in the glycolytic and lipogenic pathways. Recent studies have lin Show more
Carbohydrate response element binding protein (ChREBP) is a transcription factor that responds to glucose and activates genes involved in the glycolytic and lipogenic pathways. Recent studies have linked adipose ChREBP to insulin sensitivity in mice. However, while ChREBP is most highly expressed in the liver, the effect of hepatic ChREBP on insulin sensitivity remains unknown. To clarify the importance of hepatic ChREBP on glucose homeostasis, we have generated a knockout mouse model that lacks this protein specifically in the liver (Liver-ChREBP KO). Using Liver-ChREBP KO mice, we investigated whether hepatic ChREBP deletion influences insulin sensitivity, glucose homeostasis and the development of hepatic steatosis utilizing various dietary stressors. Furthermore, we determined gene expression changes in response to fasted and fed states in liver, white, and brown adipose tissues. Liver-ChREBP KO mice had impaired insulin sensitivity as indicated by reduced glucose infusion to maintain euglycemia during hyperinsulinemic-euglycemic clamps on both chow (25% lower) and high-fat diet (33% lower) (p < 0.05). This corresponded with attenuated suppression of hepatic glucose production. Although Liver-ChREBP KO mice were protected against carbohydrate-induced hepatic steatosis, they displayed worsened glucose tolerance. Liver-ChREBP KO mice did not show the expected gene expression changes in liver in response to fasted and fed states. Interestingly, hepatic ChREBP deletion also resulted in gene expression changes in white and brown adipose tissues, suggesting inter-tissue communication. This included an almost complete abolition of BAT ChREBPβ induction in the fed state (0.15-fold) (p = 0.015) along with reduced lipogenic genes. In contrast, WAT showed inappropriate increases in lipogenic genes in the fasted state along with increased PEPCK1 in both fasted (3.4-fold) and fed (5.1-fold) states (p < 0.0001). Overall, hepatic ChREBP is protective in regards to hepatic insulin sensitivity and whole body glucose homeostasis. Hepatic ChREBP action can influence other peripheral tissues and is likely essential in coordinating the body's response to different feeding states. Show less
Intratumoral hypoxia promotes the distant metastasis of cancer subclones. The clinical expression level of hypoxia-inducible factor-1α (HIF-1α) reflects the prognosis of a variety of cancers, especial Show more
Intratumoral hypoxia promotes the distant metastasis of cancer subclones. The clinical expression level of hypoxia-inducible factor-1α (HIF-1α) reflects the prognosis of a variety of cancers, especially breast cancer. Histone deacetylase (HDAC) inhibitors can target HIF-1α protein due to von Hippel-Lindau (VHL) protein-dependent degradation. Dietary organosulfur compounds, such as those in garlic, have been reported as HDAC inhibitors. The effects of diallyl sulfide (DAS), diallyl disulfide (DADS), and diallyl trisulfide (DATS) on the ratio of firefly/Renilla luciferase activity in hypoxic MDA-MB-231 cells were determined. The mRNA expressions of HIF-1α target genes ANGPTL4, LOXL4, and LOX in hypoxic MDA-MB-231 cells were significantly down-regulated by DATS. DATS attenuated the metastatic potential of MDA-MB-231 cells in hypoxia-induced embryonic zebrafish, xenograft, and orthotopic tumors. Endothelial cell-cancer cell adhesion, wound healing, transwell, and tube formation assays showed that DATS dose-dependently inhibited the migration and angiogenesis of MDA-MB-231 cells in vitro. The expressions of L1CAM, VEGF-A, and EMT-related proteins (Slug, Snail, MMP-2) were inhibited by DATS. DATS dose-dependently inhibited HIF-1α transcriptional activity and hypoxia-induced hematogenous metastasis of MDA-MB-231 cells. It reduced the protein expression of HIF-1α, which did not involve inhibition of HIF-1α mRNA expression or ubiquitin proteasome degradation. Efficient inhibition of HIF-1α expression was required for DATS to resist breast cancer. Show less
Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of low-density lipoprotein (LDL) cholesterol levels. The inhibitio Show more
Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of low-density lipoprotein (LDL) cholesterol levels. The inhibition of cholesteryl ester transfer protein (CETP) by anacetrapib reduces LDL cholesterol levels and increases high-density lipoprotein (HDL) cholesterol levels. However, trials of other CETP inhibitors have shown neutral or adverse effects on cardiovascular outcomes. We conducted a randomized, double-blind, placebo-controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg per deciliter (1.58 mmol per liter), a mean non-HDL cholesterol level of 92 mg per deciliter (2.38 mmol per liter), and a mean HDL cholesterol level of 40 mg per deciliter (1.03 mmol per liter). The patients were assigned to receive either 100 mg of anacetrapib once daily (15,225 patients) or matching placebo (15,224 patients). The primary outcome was the first major coronary event, a composite of coronary death, myocardial infarction, or coronary revascularization. During the median follow-up period of 4.1 years, the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group (1640 of 15,225 patients [10.8%] vs. 1803 of 15,224 patients [11.8%]; rate ratio, 0.91; 95% confidence interval, 0.85 to 0.97; P=0.004). The relative difference in risk was similar across multiple prespecified subgroups. At the trial midpoint, the mean level of HDL cholesterol was higher by 43 mg per deciliter (1.12 mmol per liter) in the anacetrapib group than in the placebo group (a relative difference of 104%), and the mean level of non-HDL cholesterol was lower by 17 mg per deciliter (0.44 mmol per liter), a relative difference of -18%. There were no significant between-group differences in the risk of death, cancer, or other serious adverse events. Among patients with atherosclerotic vascular disease who were receiving intensive statin therapy, the use of anacetrapib resulted in a lower incidence of major coronary events than the use of placebo. (Funded by Merck and others; Current Controlled Trials number, ISRCTN48678192 ; ClinicalTrials.gov number, NCT01252953 ; and EudraCT number, 2010-023467-18 .). Show less
MUFAs are unsaturated FAs with one double bond and are derived from endogenous synthesis and dietary intake. Accumulating evidence has suggested that plasma and erythrocyte MUFA levels are associated Show more
MUFAs are unsaturated FAs with one double bond and are derived from endogenous synthesis and dietary intake. Accumulating evidence has suggested that plasma and erythrocyte MUFA levels are associated with cardiometabolic disorders, including CVD, T2D, and metabolic syndrome (MS). Previous genome-wide association studies (GWASs) have identified seven loci for plasma and erythrocyte palmitoleic and oleic acid levels in populations of European origin. To identify additional MUFA-associated loci and the potential functional variant at each locus, we performed ethnic-specific GWAS meta-analyses and trans-ethnic meta-analyses in more than 15,000 participants of Chinese and European ancestry. We identified novel genome-wide significant associations for vaccenic acid at Show less
A large meta-analysis recently identified six new loci associated with risk of PD, but subsequent studies have given discrepant results. Here we conducted a case-control study in a Han Chinese populat Show more
A large meta-analysis recently identified six new loci associated with risk of PD, but subsequent studies have given discrepant results. Here we conducted a case-control study in a Han Chinese population in an attempt to clarify risk associations in Chinese. Among the four single-nucleotide polymorphisms (SNPs) that we examined - VPS13C-rs2414739, MIR4697-rs329648, GCH1-rs11158026, and SIPA1L2- rs10797576 we detected a significant association between rs329648 and risk of developing PD in a recessive model. This association remained significant after adjusting for gender and age (OR 1.87, 95%CI 1.295-2.694, p=8.21×10 Show less
Non-small cell lung cancer (NSCLC) has led to the highest cancer-related mortality for decades. To enhance the efficiency of early diagnosis and therapy, more efforts are urgently needed to reveal the Show more
Non-small cell lung cancer (NSCLC) has led to the highest cancer-related mortality for decades. To enhance the efficiency of early diagnosis and therapy, more efforts are urgently needed to reveal the origins of NSCLC. In this study, we explored the effect of miR-542-5p in NSCLC with clinical samples and in vivo models and further explored the prospective function of miR-542-5p though bioinformatics methods. A total of 125 NSCLC tissue samples were collected, and the expression of miR-542-5p was detected by qRT-PCR. The relationship between miR-542-5p level and clinicopathological features was analyzed. The effect of miR-542-5p on survival time was also explored with K-M survival curves and Cox's regression. The effect of miR-542-5p on the tumorigenesis of NSCLC was verified with a chick chorioallantoic membrane (CAM) model. The potential target genes were predicted by bioinformatics tools, and relevant pathways were analyzed by GO and KEGG. Several hub genes were validated by Proteinatlas. The expression of miR-542-5p was down-regulated in NSCLC tissues, and consistent results were also found in the subgroups of adenocarcinoma and squamous cell carcinoma. Down-regulation of miR-542-5p was found to be connected with advanced TNM stage, vascular invasion, lymphatic metastasis and EGFR. Survival analyses showed that patients with lower miR-542-5p levels had markedly poorer prognosis. Both tumor growth and angiogenesis were significantly suppressed by miR-542-5p mimic in the CAM model. The potential 457 target genes of miR-542-5p were enriched in several key cancer-related pathways, such as morphine addiction and the cAMP signaling pathway from KEGG. Interestingly, six genes (GABBR1, PDE4B, PDE4C, ADCY6, ADCY1 and GIPR) from the cAMP signaling pathway were confirmed to be overexpressed in NSCLCs tissues. This evidence suggests that miR-542-5p is a potential tumor-suppressed miRNA in NSCLC, which has the potential to act as a diagnostic and therapeutic target of NSCLC. Show less
Multiple osteochondromas (MO) is one of the most common benign bone tumors in humans with an autosomal dominant hereditary mode. MO is a genetic heterogeneity disease with variable number and size of Show more
Multiple osteochondromas (MO) is one of the most common benign bone tumors in humans with an autosomal dominant hereditary mode. MO is a genetic heterogeneity disease with variable number and size of osteochondromas, as well as changeable number and location of diseased bones. Mutations in Exostosin-1/Exostosin-2 (EXT1/EXT2) genes are the main molecular basis of MO. EXT1 and EXT2 genes encode exostosin 1 and exostosin 2, respectively, both of which are transmembrane glycosyltransferases that elongate the chains of heparin sulfate (HS) at HS proteoglycans (HSPGs). HSPGs are considered to be involved in regulating the proliferation and differentiation of chondrocytes. Owing to large size of EXT1/EXT2 genes and lack of mutation hotspots, molecular diagnosis of MO is challenging. Here, we applied targeted next-generation sequencing (t-NGS) in mutation screening of EXT1/EXT2 genes for 10 MO patients. The results were compared and validated with Sanger sequencing. Overall, nine mutations identified by t-NGS were confirmed with Sanger sequencing, excluding two variants of false positive, suggesting the reliability of mutation screening by t-NGS. The nine mutations identified by t-NGS include two missense mutations (EXT1: c.1088G>A and c.2120C>T), one splicing mutation (EXT2: c.744-1G>T), and six nonsense mutations (EXT1: c.351C>G, c.1121G>A, and c.1843₁₈₄₆dup; EXT2: c.67C>T, c.561delG, and c.575T>A). In summary, our paper provides the primary data of the application of t-NGS in MO molecular diagnosis, including six newly identified mutations (EXT1: c.1843₁₈₄₆dup, c.1088G>A, c.351C>G, and c.2120C>T and EXT2: c.744-1G>T and c.575T>A), which further enrich the mutation database of MO from the Chinese population. Show less
Understanding the physiological mechanisms by which common variants predispose to type 2 diabetes requires large studies with detailed measures of insulin secretion and sensitivity. Here we performed Show more
Understanding the physiological mechanisms by which common variants predispose to type 2 diabetes requires large studies with detailed measures of insulin secretion and sensitivity. Here we performed the largest genome-wide association study of first-phase insulin secretion, as measured by intravenous glucose tolerance tests, using up to 5,567 individuals without diabetes from 10 studies. We aimed to refine the mechanisms of 178 known associations between common variants and glycemic traits and identify new loci. Thirty type 2 diabetes or fasting glucose-raising alleles were associated with a measure of first-phase insulin secretion at Show less
Epidemiological studies suggest that levels of n-3 and n-6 long-chain polyunsaturated fatty acids are associated with risk of cardio-metabolic outcomes across different ethnic groups. Recent genome-wi Show more
Epidemiological studies suggest that levels of n-3 and n-6 long-chain polyunsaturated fatty acids are associated with risk of cardio-metabolic outcomes across different ethnic groups. Recent genome-wide association studies in populations of European ancestry have identified several loci associated with plasma and/or erythrocyte polyunsaturated fatty acids. To identify additional novel loci, we carried out a genome-wide association study in two population-based cohorts consisting of 3521 Chinese participants, followed by a trans-ethnic meta-analysis with meta-analysis results from 8962 participants of European ancestry. Four novel loci (MYB, AGPAT4, DGAT2 and PPT2) reached genome-wide significance in the trans-ethnic meta-analysis (log10(Bayes Factor) ≥ 6). Of them, associations of MYB and AGPAT4 with docosatetraenoic acid (log10(Bayes Factor) = 11.5 and 8.69, respectively) also reached genome-wide significance in the Chinese-specific genome-wide association analyses (P = 4.15 × 10(-14) and 4.30 × 10(-12), respectively), while associations of DGAT2 with gamma-linolenic acid (log10(Bayes Factor) = 6.16) and of PPT2 with docosapentaenoic acid (log10(Bayes Factor) = 6.24) were nominally significant in both Chinese- and European-specific genome-wide association analyses (P ≤ 0.003). We also confirmed previously reported loci including FADS1, NTAN1, NRBF2, ELOVL2 and GCKR. Different effect sizes in FADS1 and independent association signals in ELOVL2 were observed. These results provide novel insight into the genetic background of polyunsaturated fatty acids and their differences between Chinese and European populations. Show less
Exostosin glycosyltransferase (EXT) 1 and EXT2 have been identified as causative genes in osteochondroma; however, it is not known whether these genes are also involved in condylar osteochondromas. Th Show more
Exostosin glycosyltransferase (EXT) 1 and EXT2 have been identified as causative genes in osteochondroma; however, it is not known whether these genes are also involved in condylar osteochondromas. The aim of this study was to identify EXT1 and EXT2 mutations in patients with non-hereditary osteochondromas of the mandibular condyle. DNA was obtained from resected tissues (cartilage cap) of 12 patients with solitary condylar osteochondromas. The exons, 3',5'-untranslated regions and intron-exon boundaries of EXT1 and EXT2 were amplified by polymerase chain reaction and the products were sequenced directly. Through direct sequencing, four genetic variations of EXT1 in 4 cases and three variations of EXT2 in 5 cases were identified. The intronic alteration of the EXT2 gene, occurring in 2 cases, was novel, whereas the other alterations had been previously reported. Nonsense somatic mutations were detected in tumor DNA. Our study extended the mutational spectrum in EXT1 and EXT2 and may facilitate a better understanding of the pathophysiology of condylar osteochondromas. Show less
Recent studies have shown that activation of liver X receptors (LXRs) attenuates the development of atherosclerosis, not only by regulating lipid metabolism but also by suppressing inflammatory signal Show more
Recent studies have shown that activation of liver X receptors (LXRs) attenuates the development of atherosclerosis, not only by regulating lipid metabolism but also by suppressing inflammatory signaling. Sphingosine 1-phosphate receptor 2 (S1PR2), an important inflammatory gene product, plays a role in the development of various inflammatory diseases. It was proposed that S1PR2 might be regulated by LXR-α. In the present study, the effect of LXR-α on tumor necrosis factor-α (TNF-α)-induced S1PR2 expression in human umbilical vein endothelial cells (HUVECs) was investigated and the underlying mechanism was explored. The results demonstrated that TNF-α led to an increase in S1PR2 expression and triggered a downregulation of LXR-α expression in HUVECs as well. Downregulation of LXR-α with specific small interfering RNA (siRNA) remarkably enhanced the primary as well as TNF-α-induced expression of S1PR2 in HUVECs. Activation of LXR-α by agonist GW3965 inhibited both primary and TNF-α-induced S1PR2 expression. GW3965 also attenuated S1PR2-induced endothelial barrier dysfunction. The data further showed that TNF-α induced a significant decrease in miR-130a-3p expression. Overexpression of miR-130a-3p with mimic product reduced S1PR2 protein expression, and inhibition of miR-130a-3p by specific inhibitor resulted in an increase in S1PR2 protein expression. Furthermore, activation of LXRs with agonist enhanced the expression of miR-130a-3p, and knockdown of LXR-α by siRNA suppressed miR-130a-3p expression. These results suggest that LXR-α might downregulate S1PR2 expression via miR-130a-3p in quiescent HUVECs. Stimulation of TNF-α attenuates the activity of LXR-α and results in enhanced S1PR2 expression. Show less
Fetal akinesia deformation sequence (FADS) refers to a broad spectrum of disorder with the absent fetal movement as the unifying feature. The etiology of FADS is heterogeneous, and the majority remain Show more
Circulating blood cell counts and indices are important indicators of hematopoietic function and a number of clinical parameters, such as blood oxygen-carrying capacity, inflammation, and hemostasis. Show more
Circulating blood cell counts and indices are important indicators of hematopoietic function and a number of clinical parameters, such as blood oxygen-carrying capacity, inflammation, and hemostasis. By performing whole-exome sequence association analyses of hematologic quantitative traits in 15,459 community-dwelling individuals, followed by in silico replication in up to 52,024 independent samples, we identified two previously undescribed coding variants associated with lower platelet count: a common missense variant in CPS1 (rs1047891, MAF = 0.33, discovery + replication p = 6.38 × 10(-10)) and a rare synonymous variant in GFI1B (rs150813342, MAF = 0.009, discovery + replication p = 1.79 × 10(-27)). By performing CRISPR/Cas9 genome editing in hematopoietic cell lines and follow-up targeted knockdown experiments in primary human hematopoietic stem and progenitor cells, we demonstrate an alternative splicing mechanism by which the GFI1B rs150813342 variant suppresses formation of a GFI1B isoform that preferentially promotes megakaryocyte differentiation and platelet production. These results demonstrate how unbiased studies of natural variation in blood cell traits can provide insight into the regulation of human hematopoiesis. Show less
Targeting leukemia-initiating cells (LICs) is the key to eradicating leukemia and preventing its relapse. Recent studies have indicated that metabolic regulation may play a critical role in the mainte Show more
Targeting leukemia-initiating cells (LICs) is the key to eradicating leukemia and preventing its relapse. Recent studies have indicated that metabolic regulation may play a critical role in the maintenance of stemness in LICs, although the detailed mechanisms are poorly understood. Herein, we provide intriguing evidence showing that a glucose-responsive transcription factor, carbohydrate responsive element binding protein (ChREBP), served as a tumor suppressor rather than an oncogene, as previously described, to inhibit the development of acute myeloid leukemia by promoting the differentiation of LICs. Using an MLL-AF9-induced murine leukemia model, we demonstrated that the deletion of ChREBP resulted in the blockage of the differentiation of LICs and significantly reduced survival in ChREBP-null leukemic mice. However, ChREBP was not required for the normal repopulation abilities of hematopoietic stem cells. ChREBP promoted leukemia cell differentiation through the direct inhibition of RUNX1 or the transactivation of TXNIP to downregulate the RUNX1 level and ROS generation. Moreover, knockdown of ChREBP in human leukemia THP1 cells led to markedly enhanced proliferation and decreased differentiation upon PMA treatment. Collectively, we unraveled an unexpected role of ChREBP in leukemogenesis, which may provide valuable clues for developing novel metabolic strategies for leukemia treatment. Show less
Although major depressive disorder (MDD) has low heritability, a genome-wide association study in humans has recently implicated type 3 adenylyl cyclase (AC3; ADCY3) in MDD. Moreover, the expression l Show more
Although major depressive disorder (MDD) has low heritability, a genome-wide association study in humans has recently implicated type 3 adenylyl cyclase (AC3; ADCY3) in MDD. Moreover, the expression level of AC3 in blood has been considered as a MDD biomarker in humans. Nevertheless, there is a lack of supporting evidence from animal studies. We employed multiple approaches to experimentally evaluate if AC3 is a contributing factor for major depression using mouse models lacking the Adcy3 gene. We found that conventional AC3 knockout (KO) mice exhibited phenotypes associated with MDD in behavioral assays. Electroencephalography/electromyography recordings indicated that AC3 KO mice have altered sleep patterns characterized by increased percentage of rapid eye movement sleep. AC3 KO mice also exhibit neuronal atrophy. Furthermore, synaptic activity at cornu ammonis 3-cornu ammonis 1 synapses was significantly lower in AC3 KO mice, and they also exhibited attenuated long-term potentiation as well as deficits in spatial navigation. To confirm that these defects are not secondary responses to anosmia or developmental defects, we generated a conditional AC3 floxed mouse strain. This enabled us to inactivate AC3 function selectively in the forebrain and to inducibly ablate it in adult mice. Both AC3 forebrain-specific and AC3 inducible knockout mice exhibited prodepression phenotypes without anosmia. This study demonstrates that loss of AC3 in mice leads to decreased neuronal activity, altered sleep pattern, and depression-like behaviors, providing strong evidence supporting AC3 as a contributing factor for MDD. Show less
Recent molecular and pathological studies suggest that endometriosis may serve as a precursor of ovarian cancer (endometriosis-associated ovarian cancer, EAOC), especially of the endometrioid and clea Show more
Recent molecular and pathological studies suggest that endometriosis may serve as a precursor of ovarian cancer (endometriosis-associated ovarian cancer, EAOC), especially of the endometrioid and clear cell subtypes. Accordingly, this study had two cardinal aims: first, to obtain mutation profiles of EAOC from Taiwanese patients; and second, to determine whether somatic mutations present in EAOC can be detected in preneoplastic lesions. Formalin-fixed paraffin-embedded (FFPE) tissues were obtained from ten endometriosis patients with malignant transformation. Macrodissection was performed to separate four different types of cells from FFPE sections in six patients. The four types of samples included normal endometrium, ectopic endometriotic lesion, atypical endometriosis, and carcinoma. Ultra-deep (>1000×) targeted sequencing was performed on 409 cancer-related genes to identify pathogenic mutations associated with EAOC. The most frequently mutated genes were PIK3CA (6/10) and ARID1A (5/10). Other recurrently mutated genes included ETS1, MLH1, PRKDC (3/10 each), and AMER1, ARID2, BCL11A, CREBBP, ERBB2, EXT1, FANCD2, MSH6, NF1, NOTCH1, NUMA1, PDE4DIP, PPP2R1A, RNF213, and SYNE1 (2/10 each). Importantly, in five of the six patients, identical somatic mutations were detected in atypical endometriosis and tumor lesions. In two patients, genetic alterations were also detected in ectopic endometriotic lesions, indicating the presence of genetic alterations in preneoplastic lesion. Genetic analysis in preneoplastic lesions may help to identify high-risk patients at early stage of malignant transformation and also shed new light on fundamental aspects of the molecular pathogenesis of EAOC. Molecular characterization of endometriosis-associated ovarian cancer genes by targeted NGS. Candidate genes predictive of malignant transformation were identified. Chromatin remodeling, PI3K-AKT-mTOR, Notch signaling, and Wnt/β-catenin pathway may promote cell malignant transformation. Show less
Dyslipidemia is common in polycystic ovary syndrome (PCOS). This study was aimed to investigate whether fatty acid desaturase genes (FADS), a dyslipidemia-related gene cluster, are associated with PCO Show more
Dyslipidemia is common in polycystic ovary syndrome (PCOS). This study was aimed to investigate whether fatty acid desaturase genes (FADS), a dyslipidemia-related gene cluster, are associated with PCOS. We scanned variations of FADS genes using our previous data of genome-wide association study (GWAS) for PCOS and selected rs174570 for further study. The case-control study was conducted in an independent cohort of 1918 PCOS cases and 1889 age-matched controls and family-based study was conducted in a set of 243 core family trios with PCOS probands. Minor allele frequency (allele T) of rs174570 was significantly lower in PCOS cases than that in age-matched controls (P = 2.17E-03, OR = 0.85), even after adjustment of BMI and age. PCOS subjects carrying CC genotype had higher testosterone level and similar lipid/glucose level compared with those carrying TT or TC genotype. In trios, transmission disequilibrium test (TDT) analysis revealed risk allele C of rs174570 was significantly over-transmitted (P = 2.00E-04). Decreased expression of FADS2 was detected in PCOS cases and expression quantitative trait loci (eQTL) analysis revealed the risk allele C dosage was correlated with the decline of FADS2 expression (P = 0.002). Our results demonstrate that FADS1-FADS2 are susceptibility genes for PCOS. Show less
Long non-coding RNAs (lncRNAs) have been shown to be critical biomarkers or therapeutic targets for human diseases. However, only a small number of lncRNAs were screened and characterized. Here, we id Show more
Long non-coding RNAs (lncRNAs) have been shown to be critical biomarkers or therapeutic targets for human diseases. However, only a small number of lncRNAs were screened and characterized. Here, we identified 15 lncRNAs, which are associated with fatty liver disease. Among them, APOA4-AS is shown to be a concordant regulator of Apolipoprotein A-IV (APOA4) expression. APOA4-AS has a similar expression pattern with APOA4 gene. The expressions of APOA4-AS and APOA4 are both abnormally elevated in the liver of ob/ob mice and patients with fatty liver disease. Knockdown of APOA4-AS reduces APOA4 expression both in vitro and in vivo and leads to decreased levels of plasma triglyceride and total cholesterol in ob/ob mice. Mechanistically, APOA4-AS directly interacts with mRNA stabilizing protein HuR and stabilizes APOA4 mRNA. Deletion of HuR dramatically reduces both APOA4-AS and APOA4 transcripts. This study uncovers an anti-sense lncRNA (APOA4-AS), which is co-expressed with APOA4, and concordantly and specifically regulates APOA4 expression both in vitro and in vivo with the involvement of HuR. Show less
Recently, a large-scale meta-analysis of genome-wide association study (GWAS) data identified several new risk loci that can modulate the risk of Parkinson's disease (PD). These associations have yet Show more
Recently, a large-scale meta-analysis of genome-wide association study (GWAS) data identified several new risk loci that can modulate the risk of Parkinson's disease (PD). These associations have yet to be examined in PD patients in Chinese or Asian population. Because ethnic-specific effect is an important concern for GWAS analysis, we genotyped single-nucleotide polymorphisms in the new genetic loci, GCH1 (rs11158026), SIPA1L2 (rs10797576), VPS13C (rs2414739), and MIR4697 (rs329648), to investigate their associations with risk of PD in Taiwan. Another single-nucleotide polymorphism GCH1 rs7155501, previously identified by GWAS listed at the top 20 genes in PDGene database was also included. A total of 1151 study subjects comprising 598 patients with PD and 553 unrelated healthy controls were recruited. The frequency of minor allele (C allele) of GCH1 rs11158026 was found to be significantly higher in PD cases than in controls (p = 0.003). The CC genotype of rs11158026 increased PD risk compared to TT genotype (odds ratio [OR] = 1.29, 95% confidence interval [CI] = 1.09, 1.53, p = 0.004). Under additive model, the GCH1 rs11158026 increased the risk of developing PD (OR = 1.30, 95% CI = 1.10, 1.54, p = 0.002). In recessive model, the genotype TT of MIR4697 rs329648 marginally decreased the PD risk (OR = 0.62, 95% CI = 0.43, 0.90, p = 0.01). The PD patients demonstrated similar genotypic and allelic frequencies in GCH1 rs7155501, SIPA1L2 rs10797576, and VPS13C rs2414739 with the controls. These findings suggest that the GCH1 and MIR4697 but not SIPA1L2 and VPS13C are genetic loci influencing risk of PD in Taiwan. Show less
White blood cells play diverse roles in innate and adaptive immunity. Genetic association analyses of phenotypic variation in circulating white blood cell (WBC) counts from large samples of otherwise Show more
White blood cells play diverse roles in innate and adaptive immunity. Genetic association analyses of phenotypic variation in circulating white blood cell (WBC) counts from large samples of otherwise healthy individuals can provide insights into genes and biologic pathways involved in production, differentiation, or clearance of particular WBC lineages (myeloid, lymphoid) and also potentially inform the genetic basis of autoimmune, allergic, and blood diseases. We performed an exome array-based meta-analysis of total WBC and subtype counts (neutrophils, monocytes, lymphocytes, basophils, and eosinophils) in a multi-ancestry discovery and replication sample of ∼157,622 individuals from 25 studies. We identified 16 common variants (8 of which were coding variants) associated with one or more WBC traits, the majority of which are pleiotropically associated with autoimmune diseases. Based on functional annotation, these loci included genes encoding surface markers of myeloid, lymphoid, or hematopoietic stem cell differentiation (CD69, CD33, CD87), transcription factors regulating lineage specification during hematopoiesis (ASXL1, IRF8, IKZF1, JMJD1C, ETS2-PSMG1), and molecules involved in neutrophil clearance/apoptosis (C10orf54, LTA), adhesion (TNXB), or centrosome and microtubule structure/function (KIF9, TUBD1). Together with recent reports of somatic ASXL1 mutations among individuals with idiopathic cytopenias or clonal hematopoiesis of undetermined significance, the identification of a common regulatory 3' UTR variant of ASXL1 suggests that both germline and somatic ASXL1 mutations contribute to lower blood counts in otherwise asymptomatic individuals. These association results shed light on genetic mechanisms that regulate circulating WBC counts and suggest a prominent shared genetic architecture with inflammatory and autoimmune diseases. Show less
Women with epithelial ovarian cancer (EOC) are usually treated with platinum/taxane therapy after cytoreductive surgery but there is considerable inter-individual variation in response. To identify ge Show more
Women with epithelial ovarian cancer (EOC) are usually treated with platinum/taxane therapy after cytoreductive surgery but there is considerable inter-individual variation in response. To identify germline single-nucleotide polymorphisms (SNPs) that contribute to variations in individual responses to chemotherapy, we carried out a multi-phase genome-wide association study (GWAS) in 1,244 women diagnosed with serous EOC who were treated with the same first-line chemotherapy, carboplatin and paclitaxel. We identified two SNPs (rs7874043 and rs72700653) in TTC39B (best P=7x10-5, HR=1.90, for rs7874043) associated with progression-free survival (PFS). Functional analyses show that both SNPs lie in a putative regulatory element (PRE) that physically interacts with the promoters of PSIP1, CCDC171 and an alternative promoter of TTC39B. The C allele of rs7874043 is associated with poor PFS and showed increased binding of the Sp1 transcription factor, which is critical for chromatin interactions with PSIP1. Silencing of PSIP1 significantly impaired DNA damage-induced Rad51 nuclear foci and reduced cell viability in ovarian cancer lines. PSIP1 (PC4 and SFRS1 Interacting Protein 1) is known to protect cells from stress-induced apoptosis, and high expression is associated with poor PFS in EOC patients. We therefore suggest that the minor allele of rs7874043 confers poor PFS by increasing PSIP1 expression. Show less
Histone H3 trimethylation of lysine 9 (H3K9me3) and proteins of the heterochromatin protein 1 (HP1) family are hallmarks of heterochromatin, a state of compacted DNA essential for genome stability and Show more
Histone H3 trimethylation of lysine 9 (H3K9me3) and proteins of the heterochromatin protein 1 (HP1) family are hallmarks of heterochromatin, a state of compacted DNA essential for genome stability and long-term transcriptional silencing. The mechanisms by which H3K9me3 and HP1 contribute to chromatin condensation have been speculative and controversial. Here we demonstrate that human HP1β is a prototypic HP1 protein exemplifying most basal chromatin binding and effects. These are caused by dimeric and dynamic interaction with highly enriched H3K9me3 and are modulated by various electrostatic interfaces. HP1β bridges condensed chromatin, which we postulate stabilizes the compacted state. In agreement, HP1β genome-wide localization follows H3K9me3-enrichment and artificial bridging of chromatin fibres is sufficient for maintaining cellular heterochromatic conformation. Overall, our findings define a fundamental mechanism for chromatin higher order structural changes caused by HP1 proteins, which might contribute to the plastic nature of condensed chromatin. Show less
Transcription factor carbohydrate responsive element binding protein (ChREBP) promotes glycolysis and lipogenesis in metabolic tissues and cancer cells. ChREBP-α and ChREBP-β, two isoforms of ChREBP t Show more
Transcription factor carbohydrate responsive element binding protein (ChREBP) promotes glycolysis and lipogenesis in metabolic tissues and cancer cells. ChREBP-α and ChREBP-β, two isoforms of ChREBP transcribed from different promoters, are both transcriptionally induced by glucose. However, the mechanism by which glucose increases ChREBP mRNA levels remains unclear. Here we report that hepatocyte nuclear factor 4 alpha (HNF-4α) is a key transcription factor for glucose-induced ChREBP-α and ChREBP-β expression. Ectopic HNF-4α expression increased ChREBP transcription while knockdown of HNF-4α greatly reduced ChREBP mRNA levels in liver cancer cells and mouse primary hepatocytes. HNF-4α not only directly bound to an E-box-containing region in intron 12 of the ChREBP gene, but also promoted ChREBP-β transcription by directly binding to two DR1 sites and one E-box-containing site of the ChREBP-β promoter. Moreover, HNF-4α interacted with ChREBP-α and synergistically promoted ChREBP-β transcription. Functionally, HNF-4α suppression reduced glucose-dependent ChREBP induction. Increased nuclear abundance of HNF-4α and its binding to cis-elements of ChREBP gene in response to glucose contributed to glucose-responsive ChREBP transcription. Taken together, our results not only revealed the novel mechanism by which HNF-4α promoted ChREBP transcription in response to glucose, but also demonstrated that ChREBP-α and HNF-4α synergistically increased ChREBP-β transcription. Show less
5-Hydroxytryptamine (5-HT), a neurotransmitter and vasoactive factor, has been reported to promote proliferation of serum-deprived hepatocellular carcinoma (HCC) cells but the detailed intracellular m Show more
5-Hydroxytryptamine (5-HT), a neurotransmitter and vasoactive factor, has been reported to promote proliferation of serum-deprived hepatocellular carcinoma (HCC) cells but the detailed intracellular mechanism is unknown. As Wnt/β-catenin signalling is highly dysregulated in a majority of HCC, this study explored the regulation of Wnt/β-catenin signalling by 5-HT. The expression of various 5-HT receptors was studied by quantitative real-time polymerase chain reaction (qPCR) in HCC cell lines as well as in 33 pairs of HCC tumours and corresponding adjacent non-tumour tissues. Receptors 5-HT1D (21/33, 63.6%), 5-HT2B (12/33, 36.4%) and 5-HT7 (15/33, 45.4%) were overexpressed whereas receptors 5-HT2A (17/33, 51.5%) and 5-HT5 (30/33, 90.1%) were reduced in HCC tumour tissues. In vitro data suggests 5-HT increased total β-catenin, active β-catenin and decreased phosphorylated β-catenin protein levels in serum deprived HuH-7 and HepG2 cells compared to control cells under serum free medium without 5-HT. Activation of Wnt/β-catenin signalling was evidenced by increased expression of β-catenin downstream target genes, Axin2, cyclin D1, dickoppf-1 (DKK1) and glutamine synthetase (GS) by qPCR in serum-deprived HCC cell lines treated with 5-HT. Additionally, biochemical analysis revealed 5-HT disrupted Axin1/β-catenin interaction, a critical step in β-catenin phosphorylation. Increased Wnt/β-catenin activity was attenuated by antagonist of receptor 5-HT7 (SB-258719) in HCC cell lines and patient-derived primary tumour tissues in the presence of 5-HT. SB-258719 also reduced tumour growth in vivo. This study provides evidence of Wnt/β-catenin signalling activation by 5-HT and may represent a potential therapeutic target for hepatocarcinogenesis. Show less
To explore the association of the APOA5 gene c.553G>T polymorphism with hypertriglyceridemia (HTG) susceptibility and altered triglyceride levels. We searched the PubMed, Google Scholar, and CNKI data Show more
To explore the association of the APOA5 gene c.553G>T polymorphism with hypertriglyceridemia (HTG) susceptibility and altered triglyceride levels. We searched the PubMed, Google Scholar, and CNKI databases for published studies relating to analyses of these associations. Case-control and comparative studies of the association between the APOA5 c.553G>T variant and altered triglyceride levels were included. In total, the meta-analysis involved 10 studies on HTG, which provided 2219 cases and 3401 controls. To measure the correlation between the c.553G>T polymorphism and HTG susceptibility, odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. The overall OR was calculated using a random-effects model. Compared with APOA5 c.553 GG carriers, c.553T carriers displayed an increased risk of HTG in the Asian population, with an overall random effects OR of 3.55 (95% CI: 2.46-5.13) in the dominant model. There was significant heterogeneity among the studies (P Our results suggest that APOA5 c. 553T is an independent risk factor for HTG and increased triglyceride levels in the Asian population. APOA5 c. 553T could be employed as a genetic risk marker for HTG and increased triglyceride levels. Show less
Self-renewal is a hallmark of both hematopoietic stem cells (HSCs) and leukemia stem cells (LSCs); therefore, the identification of mechanisms that are required for LSC, but not HSC, function could pr Show more
Self-renewal is a hallmark of both hematopoietic stem cells (HSCs) and leukemia stem cells (LSCs); therefore, the identification of mechanisms that are required for LSC, but not HSC, function could provide therapeutic opportunities that are more effective and less toxic than current treatments. Here, we employed an in vivo shRNA screen and identified jumonji domain-containing protein JMJD1C as an important driver of MLL-AF9 leukemia. Using a conditional mouse model, we showed that loss of JMJD1C substantially decreased LSC frequency and caused differentiation of MLL-AF9- and homeobox A9-driven (HOXA9-driven) leukemias. We determined that JMJD1C directly interacts with HOXA9 and modulates a HOXA9-controlled gene-expression program. In contrast, loss of JMJD1C led to only minor defects in blood homeostasis and modest effects on HSC self-renewal. Together, these data establish JMJD1C as an important mediator of MLL-AF9- and HOXA9-driven LSC function that is largely dispensable for HSC function. Show less
Determination of the exogenous factors that regulate differentiation of neural stem/progenitor cells into neurons, oligodendrocytes and astrocytes is an important step in the clinical therapy of spina Show more
Determination of the exogenous factors that regulate differentiation of neural stem/progenitor cells into neurons, oligodendrocytes and astrocytes is an important step in the clinical therapy of spinal cord injury (SCI). The Notch pathway inhibits the differentiation of neural stem/progenitor cells and Lingo-1 is a strong negative regulator for myelination and axon growth. While Lingo-1 shRNA and N-[N-(3, 5-difluorophenacetyl)-1-alanyl]-S-Phenylglycinet-butylester (DAPT), a Notch pathway inhibitor, have been used separately to help repair SCI, the results have been unsatisfactory. Here we investigated and elucidated the preliminary mechanism for the effect of Lingo-1 shRNA and DAPT on neural stem/progenitor cells differentiation. We found that neural stem/progenitor cells from E14 rat embryos expressed Nestin, Sox-2 and Lingo-1, and we optimized the transduction of neural stem/progenitor cells using lentiviral vectors encoding Lingo-1 shRNA. The addition of DAPT decreased the expression of Notch intracellular domain (NICD) as well as the downstream genes Hes1 and Hes5. Expression of NeuN, CNPase and GFAP in DAPT treated cells and expression of NeuN in Lingo-1 shRNA treated cells confirmed differentiation of neural stem/progenitor cells into neurons, oligodendrocytes and astrocytes. These results revealed that while Lingo-1 shRNA and Notch signaling inhibitor DAPT both promoted differentiation of neural stem cells into neurons, only DAPT was capable of driving neural stem/progenitor cells differentiation into oligodendrocytes and astrocytes. Since we were able to show that both Lingo-1 shRNA and DAPT could drive neural stem/progenitor cells differentiation, our data might aid the development of more effective SCI therapies using Lingo-1 shRNA and DAPT. Show less
Gastric cancer is not a single disease, and its subtype classification is still evolving. Next-generation sequencing studies have identified novel genetic drivers of gastric cancer, but their use as m Show more