Pleiotropic association of LIPC variants with lipid and urinary 8-hydroxy deoxyguanosine levels in a Taiwanese population.

BACKGROUND: Hepatic lipase (HL, encoded by LIPC) is a glycoprotein primarily synthesized and secreted by hepatocytes. Previous studies had demonstrated that HL is crucial for reverse cholesterol transport and affects the metabolism, composition, and level of several lipoproteins. In current study, we investigated the association of LIPC (Lipase C, Hepatic Type) variants with circulating and urinary biomarker levels by using subgroup and mediation analyses. METHODS: A total of 572 participants from Taiwan were genotyped for three LIPC single nucleotide polymorphisms (SNPs) by using TaqMan assay. Fasting levels of glucose, lipid profile, inflammation markers, urine creatinine and 8-hydroxy deoxyguanosine (8-OHdG) were measured. The chi-square test, 2-sample t test and Analysis of variance (ANOVA) were used to examine differences among variables and genotype frequencies. RESULTS: SNPs rs2043085 and rs1532085 were significantly associated with urinary 8-OHdG levels, whereas all three SNPs were more significantly associated with Triglycerides (TG) or HDL-cholesterol (HDL-C) levels after additional adjustment for HDL-C or TG levels, respectively. Subgroup analyses revealed that the association of the LIPC SNPs with the levels of serum TG, HDL-C, and urinary 8-OHdG were predominantly observed in the men but not in the women. Differential associations of the LIPC SNPs with various lipid levels were observed in participants with different adiposity statuses. Mediation analyses indicated that TG levels acted as a suppressor masking the association of the LIPC genotypes with HDL-C levels, particularly in the men (Sobel test, all P < 0.01). CONCLUSION: Our data revealed that interaction and suppression effects mediated the pleiotropic association of the LIPC variants. The effects of the LIPC SNPs depended on sex, adiposity status, and TG levels. Thus, our findings can provide a method for identifying high-risk populations of cardiovascular diseases for clinical diagnosis.

Association of ABCG2 rs2231142-A allele and serum uric acid levels in male and obese individuals in a Han Taiwanese population.

BACKGROUND/PURPOSE: Recent studies suggest that hyperuricemia is a potential risk factor for cardiovascular disease (CVD). Hyperuricemia is highly heritable and is associated with sex and body weight. Previous genome-wide association studies have found that the ABCG2 single nucleotide polymorphism (SNP) rs2231142 is an important genetic factor for increased uric acid (UA) levels, and the degree of association between rs2231142 and hyperuricemia is affected by both sex and ethnicity. This investigation aimed to analyze the association between ABCG2 polymorphisms and UA levels, as well as their interactions with sex and obesity in Taiwanese. METHODS: Two genetic polymorphisms around the ABCG2 gene were genotyped in 459 patients. RESULTS: After adjusting for clinical covariates, the rs2231142 SNP was found significantly associated with UA levels using a dominant inheritance model. Patients carrying the rs2231142-A allele had a higher frequency of hyperuricemia than those with the rs2231142-CC allele. Subgroup analysis revealed an association of rs2231142 with UA levels in male or obese patients, and there was no association in nonobese female patients. CONCLUSION: The rs2231142 SNP is associated with serum UA levels and hyperuricemia in Taiwanese patients and it occurs predominantly in male or obese patients. Hyperuricemia might be controlled differently by sex and obesity.

Interactive effects of C-reactive protein levels on the association between APOE variants and triglyceride levels in a Taiwanese population.

BACKGROUND: Apolipoprotein E (APOE) plays a major role in lipid metabolism and inflammation. However, the association between APOE gene polymorphisms and serum triglyceride levels remains controversial. We tested the effects of APOE variants on triglyceride levels and their interactions with the inflammatory marker C-reactive protein (CRP) in a Taiwanese population. METHODS: Two APOE single nucleotide polymorphisms (SNPs) rs429358 and rs7412 were genotyped by TaqMan Assay using real time PCR in 595 healthy subjects attending the clinic for routine visits. RESULTS: After adjustment for clinical covariates, subjects carrying the rs429358-TT genotype and non-ε4 alleles were found to have higher CRP levels, whereas those with rs7412-CC genotype and non-ε2 alleles had significantly higher total and low-density lipoprotein cholesterol levels (all P < 0.01). Using subgroup and interaction analyses, we observed significantly lower triglyceride levels in subjects carrying the rs429358-TT genotype and non-ε4 alleles in the low CRP group (P = 2.71 × 10(-4) and P = 4.32 × 10(-4), respectively), but not in those in the high CRP group (interaction P = 0.013 and 0.045, respectively). In addition, multivariate stepwise linear regression analysis showed that subjects carrying the rs429358-TT genotype and non-ε4 alleles with low CRP levels had significantly lower triglyceride levels (P < 0.001 and P < 0.001, respectively). In addition, when combined with the risk alleles of GCKR, APOA5 and LPL gene variants, we observed that triglyceride levels increased significantly with the number of risk alleles (P = 2.9 × 10(-12)). CONCLUSIONS: The combination of SNPs and ε alleles at the APOE locus is involved in managing lipid and CRP levels in the Taiwanese population. APOE polymorphisms interact with CRP to regulate triglyceride levels, thus triglyceride concentration is influenced by both the genetic background of the APOE locus and the inflammatory status of a subject.

Accordion Stent Deformation upon Retrieval of a Side-Branch Protective Guidewire.

UNLABELLED: In this case we herein report a dangerous complication from primary percutaneous coronary intervention, where an unnoticed loop of the guidewire was inadvertently made around the stent during provisional stenting. Since the guidewire and the stent were entangled, efforts to retrieve the guidewire only exacerbated the problem by compressing the stent like an accordion. We review those factors that may have influenced stent compression in our case, as well as possible ways to avoid it from occurring in the future. KEY WORDS: Catheterization; Coronary stenosis; Embolism; Myocardial infarction; Percutaneous coronary intervention; Stents.

Risk of Glaucoma Associated with Components of Metabolic Disease in Taiwan: A Nationwide Population-Based Study.

PURPOSE: This retrospective cohort study was conducted to determine the glaucoma risk associated with metabolic disease (MetD) using insurance claims data of Taiwan. METHODS: From the database, we identified patients with newly diagnosed hypertension, diabetes and/or hyperlipidemia from the years 2000 to 2002 as the MetD cohort (N = 42,036) and an age-gender-diagnosis-date matched control cohort without MetD with a two-fold sample size than that of the MetD cohort. Both cohorts were followed until the development of glaucoma, death, or withdrawal, until 31 December 2013. The incidence of glaucoma, and the Cox method estimated hazard ratio (HR) of glaucoma were calculated. Results showed that the incidence of glaucoma was two-fold higher in the MetD cohort than in the controls (1.99 versus 0.99 per 1000 person-years), with an adjusted HR of 1.66 (95% CI: 1.50-1.85). The glaucoma incidence was higher in patients with diabetes than those with hypertension and hyperlipidemia (2.38 versus 1.95 and 1.72 per 1000 person-years, respectively). The incidence increased to 5.67 per 1000 person-years in patients with all three comorbidities, with an aHR of 4.95 (95% CI: 2.35-10.40). We also found higher incidence rates of primary open-angle glaucoma and primary angle-closure glaucoma with aHRs of 2.03 and 1.44, respectively. It was concluded that glaucoma risk increased with the number of MetD. Health providers need to monitor patients with MetD to prevent glaucoma.

Establishment of an Immunocompetent Metastasis Rat Model with Hepatocyte Cancer Stem Cells.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer mortality. Cancer stem cells (CSCs) are responsible for the maintenance, metastasis, and relapse of various tumors. The effects of CSCs on the tumorigenesis of HCC are still not fully understood, however. We have recently established two new rat HCC cell lines HTC and TW-1, which we isolated from diethylnitrosamine-induced rat liver cancer. Results showed that TW-1 expressed the genetic markers of CSCs, including CD133, GSTP1, CD44, CD90, and EpCAM. Moreover, TW-1 showed higher tolerance to sorafenib than HTC did. In addition, tumorigenesis and metastasis were observed in nude mice and wild-type rats with TW-1 xenografts. Finally, we combined highly expressed genes in TW-1/HTC with well-known biomarkers from recent HCC studies to predict HCC-related biomarkers and able to identify HCC with AUCs > 0.9 after machine learning. These results indicated that TW-1 was a novel rat CSC line, and the mice or rat models we established with TW-1 has great potential on HCC studies in the future.

Visual Subfield Progression in Glaucoma Subtypes.

PURPOSE: To investigate visual field progression pattern and factors associated with progression in patients with primary open-angle glaucoma (POAG), normal-tension glaucoma (NTG), and chronic angle-closure glaucoma (CACG). METHODS: The raw data of the 30-2 Humphrey Field Analyzer from glaucoma patients with definite visual field progression were processed with pointwise linear regression (PLR) analysis. The rate of change of retinal threshold sensitivity in the ten glaucoma hemifield test (GHT) zones, the upper and the lower hemifields, and the whole field was evaluated and was correlated with patients' basic demographic data. RESULTS: An average follow-up of 6.94 ± 2.69 years that showed the rate of change of visual field threshold sensitivity was correlated with the peak posttreatment intraocular pressure (IOP) and the long-term IOP fluctuations in all GHT zones except in the inferior arcuate area. The baseline IOP, the trough posttreatment IOP, the refractive status, and the CCT were not correlated with VF progression. CONCLUSION: The rate of visual field progression was correlated with the peak posttreatment IOP and the long-term IOP fluctuation but with subfield differences.

Association of Neovascular Glaucoma with Risk of Stroke: A Population-Based Cohort Study.

Neovascular glaucoma (NVG), caused by ocular ischemia, is a serious ocular disease complicated by intractably increased intraocular pressure. Cerebrovascular accidents are classified into ischemic and hemorrhagic stroke. Based on the similar pathogenic mechanisms of NVG and ischemic stroke, we investigated the relationship between NVG and stroke by using a nationally representative sample. This study included 416 NVG patients and 4160 controls. Medical comorbidities were also evaluated. The cumulative incidence of ischemic stroke was 15.6% higher in the NVG cohort than in the control cohort (p < 0.001); the incidence density rates of stroke were 3.80 and 1.19 per 10,000 person-years in the NVG and control cohorts, respectively. According to the multivariable Cox regression results, the estimated adjusted hazard ratio (aHR) of stroke was 2.07 (95% confidence interval (CI) = 1.41-3.02) for the NVG cohort. Furthermore, the NVG cohort was 2.24-fold more likely to develop ischemic stroke (95% CI = 1.51-3.32). The risk of ischemic stroke was higher in patients with hypertension (aHR = 2.09, 95% CI = 1.55-2.82) and in patients with diabetic retinopathy (aHR = 1.69, 95% CI = 1.05-2.72). Notably, patients with NVG have a higher risk of ischemic stroke, but not hemorrhagic stroke.

Rescue vitrectomy with blocked artery massage and bloodletting for branch retinal artery occlusion.

A 61-year-old male suffered from sudden blurred vision and superior visual field defect oculus dexter. His vision was counting fingers at 20 cm. Fundoscopy demonstrated inferior pale retina and a large embolus located at the proximal inferior retinal artery. Branch retinal artery occlusion (BRAO) was diagnosed. Initial paracentesis, topical brimonidine tartrate, oral pentoxifylline, and hyperbaric oxygen therapy were performed but showed limited improvement. Hence, he received 25-gauge vitrectomy, artificial posterior vitreous detachment, blocked retinal artery massage, and bloodletting 5 days after onset. After the surgery, his vision improved to 20/25. Fundoscopy showed reperfused retina, and optical coherence tomography revealed resolved retinal edema. RAO is an ophthalmological emergency; however, no standard guideline is available. Vitrectomy with blocked retinal artery massage and bloodletting showed favorable results in this case of BRAO with a large embolus. More prospective clinical trials are needed for setting up the standard treatment.

A GDF15 3' UTR variant, rs1054564, results in allele-specific translational repression of GDF15 by hsa-miR-1233-3p.

Growth differentiation factor 15 (GDF15) is a strong predictor of cardiovascular events and mortality in individuals with or without cardiovascular diseases. Single nucleotide polymorphisms (SNPs) in microRNA (miRNA) target sites, also known as miRSNPs, are known to enhance or weaken miRNA-mRNA interactions and have been linked to diseases such as cardiovascular disease and cancer. In this study, we aimed to elucidate the functional significance of the miRSNP rs1054564 in regulating GDF15 levels. Two rs1054564-containing binding sites for hsa-miR-873-5p and hsa-miR-1233-3p were identified in the 3' untranslated region (UTR) of the GDF15 transcript using bioinformatics tools. Their activities were further characterized by in vitro reporter assays. Bioinformatics prediction suggested that miRNA binding sites harboring the rs1054564-G allele had lower free energies than those with the C allele and therefore were better targets with higher affinities for both hsa-miR-873-5p and hsa-miR-1233-3p. Reporter assays showed that luciferase activity was significantly decreased by rs1054564-G-containing 3' UTRs for both miRNAs (P < 0.05) and was restored by miRNA inhibitors. Comparing the fold suppression of the two miRNAs, only that of hsa-miR-1233-3p showed significant changes between the rs1054564-G- and C-containing 3' UTRs (P = 0.034). In addition, western blots showed that transfection of both miRNA mimics significantly decreased endogenous GDF15 expression in a melanoma cell line (P < 0.05). Taken together, our findings demonstrate that GDF15 is a target of hsa-miR-873-5p and hsa-miR-1233-3p and that the rs1054564-C allele partially abolishes hsa-miR-1233-3p-mediated translational suppression of GDF15. These results suggest that rs1054564 confers allele-specific translational repression of GDF15 via hsa-miR-1233-3p. Our work thus provides biological insight into the previously reported clinical association between rs1054564 and plasma GDF15 levels.

The Effect of Age and Initial Central Retinal Thickness on Earlier Need of Repeat Ozurdex Treatment for Macular Edema Due to Retinal Vein Occlusion: A Retrospective Case Series.

PURPOSE: To evaluate the effects of dexamethasone intravitreal implant (Ozurdex) and identify risk factors for repeated treatment in patients with macula edema due to branch retinal vein occlusion (BRVO) or central retinal vein occlusion (CRVO). METHODS: Patients followed up for at least 6 months were enrolled from 2013 to 2016. Dexamethasone intravitreal implant was given as the baseline treatment. For evaluation of dexamethasone intravitreal implant effects and complications, the demographics, medical history, best-corrected visual acuity (BCVA), intraocular pressure, and central retinal thickness (CRT) were recorded. Multivariate Cox proportional hazard model and logistic regression were used to identify factors for repeated treatment. RESULTS: Twenty-three BRVO and 11 CRVO patients were enrolled. There were 15 males and 19 females. Fifteen (44.12%) patients needed only one dexamethasone intravitreal implant. The peak CRT and BCVA significantly improved. Comparing single-injection with multiple-injection group, age and initial CRT more than 400 µm were significantly higher in the multiple-injection group. From multivariate logistic regression and Cox proportional hazards analysis, patients with age older than 55 years and initial CRT more than 400 µm had higher risk for multiple injections. CONCLUSIONS: Patients receiving as-needed schedule of dexamethasone intravitreal implant had significant peak CRT and BCVA improvement. Age older than 55 years and initial CRT more than 400 µm were significant risk factors associated with repeated dexamethasone intravitreal implant treatment.

Association between NF-κB Pathway Gene Variants and sICAM1 Levels in Taiwanese.

Intercellular adhesion molecule-1 (ICAM1) is crucial to the development and progression of atherosclerosis. Recent genome-wide association studies (GWAS) have revealed that single nucleotide polymorphisms (SNPs) in two of the nuclear factor-κB (NF-κB) pathway genes, NFKBIK and RELA, are associated with soluble ICAM1 (sICAM1) levels. However, neither of these two gene variants is found in the Asian populations. This study aimed to elucidate whether other candidate gene variants involved in the NF-κB pathway may be associated with sICAM1 levels in Taiwanese. After excluding carriers of the ICAM1 rs5491-T allele, three SNPs in the ICAM1 gene and eight SNPs in six of the NF-κB pathway genes (NFKB1, PDCD11, TNFAIP3, NKAPL, IKBKE, and PRKCB) were analyzed for their association with sICAM1 levels in 480 individuals. Our data showed that two SNPs, rs5498 of ICAM1 and rs1635 of NKAPL, were significantly associated with sICAM1 levels (P = 0.002 and 0.004, respectively) in the Taiwanese population. Using a multivariate analysis, rs5498 and rs1635 as well as the previously reported ABO genotypes and rs12051272 of the CDH13 gene were independently associated with sICAM1 levels (P = 0.001, 0.001, 0.006 and 0.031, respectively). An analysis with combined risk alleles of four candidate SNPs in the ICAM1, NKAPL, ABO, and CDH13 genes showed an increase in sICAM1 levels with added numbers of risk alleles and weighted genetic risk score. Our findings thus expanded the repertoire of gene variants responsible for the regulation of sICAM1 levels in the Asian populations.

Acute angle closure in the setting of high axial myopia: A case report.

Acute angle closure is common in hyperopic eyes but uncommon in myopic eyes. Here, we report a case of angle closure attack in a 59-year-old female patient with high axial myopia. The patient presented without underlying medical history or drug history with marked congestion and progressively blurred vision in her right eye (RE) for 1 week. Initial intraocular pressure (IOP) was 40 mmHg in the RE and 19 mmHg in the left eye. Slit lamp examination revealed a very shallow anterior chamber in both eyes and marked corneal microcytic edema in the RE. Acute angle closure of the RE was diagnosed. Conservative IOP-lowering management followed by laser iridotomy was effective in managing acute high IOP crisis; however, early cataract extraction was necessary for long-term IOP control. Clinicians should be mindful of the possibility of acute angle closure even in highly axially myopic eyes.

Association Between Glaucoma and the Risk of Dementia.

We investigated the association of primary open-angle glaucoma (POAG) and primary angle-closure glaucoma (PACG) with the risk of dementia by evaluating their clinical and epidemiological similarities by using a nationally representative sample in Taiwan. Data were collected from the National Health Insurance Research Database of Taiwan. In total, 6509 patients with glaucoma (3304 with POAG and 3205 with PACG) were enrolled, and a comparison cohort of 26,036 individuals without glaucoma was established after matching for age and sex. The cumulative incidence curve of overall dementia for each cohort was evaluated. The risk of dementia was analyzed using univariate and multivariate Cox proportional hazard models after adjustment for demographic characteristics and comorbidities. The patients with glaucoma exhibited a significantly higher risk of dementia than the individuals without glaucoma did (hazard ratio [HR] = 1.13, 95% confidence interval [CI] = 1.01-1.27). The patients with POAG exhibited a 1.21-fold increased risk of dementia compared with the individuals without glaucoma (HR = 1.21, 95% CI = 1.02-1.43). However, the patients with PACG were not significantly associated with an increased risk of dementia compared with the individuals without glaucoma (HR = 1.09, 95% CI = 0.95-1.26). Patients with POAG aged ≥65 years were significantly associated with an increased risk of dementia compared with the individuals without glaucoma (HR = 1.28, 95% CI = 1.07-1.54). Females with POAG exhibited a 1.34-fold increased risk of dementia compared with females without glaucoma (95% CI = 1.06-1.69). This study demonstrated that patients with POAG but not those with PACG were associated with an increased risk of dementia compared with the general population.

Association Between Peripheral Vascular Endothelial Function and Progression of Open-Angle Glaucoma.

The aim of the study is to evaluate the relationship between Humphrey visual field progression and peripheral vascular endothelial function in patients with open-angle glaucoma (OAG), assessed by noninvasive endothelium-dependent flow-mediated vasodilation (FMD).Forty OAG patients, among which 22 had normal-tension glaucoma (NTG) and 18 had primary open-angle glaucoma (POAG) were enrolled. Each enrolled patient underwent a thorough ophthalmological examination including the Humphrey visual field test and measurement of FMD via high-resolution 2-dimensional ultrasonographic imaging of the brachial artery. Blood samples were evaluated for biochemistry and lipid profiles as well as levels of high-sensitivity C-reactive protein (hsCRP). The annual change of threshold sensitivity of the visual field in each test location were analyzed with pointwise linear regression. The correlation between long-term visual field progression and FMD was evaluated.A mean follow-up of 7.47 ±â€Š1.84 years revealed a faster progression rate over the superior visual field in all 40 OAG patients (superior field -0.24 ±â€Š0.67 dB/y, inferior field -0.10 ±â€Š0.59 dB/y, P = 0.37). However, only the annual sensitivity change of the inferior peripheral field showed correlation with baseline FMD. There was no significant difference in the change slope of visual field between NTG and POAG patients.A correlation between baseline brachial artery FMD and visual field progression was observed in the inferior peripheral field in patients with NTG and POAG. This result suggests that peripheral vascular endothelial dysfunction may be related to glaucoma progression.

The short coiled-coil domain-containing protein UNC-69 cooperates with UNC-76 to regulate axonal outgrowth and normal presynaptic organization in Caenorhabditis elegans.

BACKGROUND: The nematode Caenorhabditis elegans has been used extensively to identify the genetic requirements for proper nervous system development and function. Key to this process is the direction of vesicles to the growing axons and dendrites, which is required for growth-cone extension and synapse formation in the developing neurons. The contribution and mechanism of membrane traffic in neuronal development are not fully understood, however. RESULTS: We show that the C. elegans gene unc-69 is required for axon outgrowth, guidance, fasciculation and normal presynaptic organization. We identify UNC-69 as an evolutionarily conserved 108-amino-acid protein with a short coiled-coil domain. UNC-69 interacts physically with UNC-76, mutations in which produce similar defects to loss of unc-69 function. In addition, a weak reduction-of-function allele, unc-69(ju69), preferentially causes mislocalization of the synaptic vesicle marker synaptobrevin. UNC-69 and UNC-76 colocalize as puncta in neuronal processes and cooperate to regulate axon extension and synapse formation. The chicken UNC-69 homolog is highly expressed in the developing central nervous system, and its inactivation by RNA interference leads to axon guidance defects. CONCLUSION: We have identified a novel protein complex, composed of UNC-69 and UNC-76, which promotes axonal growth and normal presynaptic organization in C. elegans. As both proteins are conserved through evolution, we suggest that the mammalian homologs of UNC-69 and UNC-76 (SCOCO and FEZ, respectively) may function similarly.