Yu-Cho Woo

Serum Fibroblast Growth Factor-21 Levels Are Associated With Carotid Atherosclerosis Independent of Established Cardiovascular Risk Factors

Objective—Serum levels of fibroblast growth factor-21 (FGF21), a metabolic hormone, have been shown to be elevated in subjects with adverse lipid profiles, obesity, metabolic syndrome, impaired glucose tolerance, type 2 diabetes mellitus, and hypertension. Recently, elevated serum FGF21 levels have also been reported in subjects with coronary heart disease or carotid artery plaques. However, whether serum FGF21 is independently associated with atherosclerotic diseases remains unclear. In this study, we examined the relationship between serum FGF21 levels and carotid intima-media thickness (IMT) in a large cohort of Southern Chinese subjects. Approach and Results—The cohort consisted of 670 subjects who underwent carotid IMT measurement. Serum FGF21 levels were measured with an ELISA kit. Serum FGF21 levels positively correlated with carotid IMT in women (r=0.32; P<0.001), but not in men (r=0.06; P=0.305). On multiple linear regression analysis, elevated serum FGF21 level in women was an independent risk factor for increased carotid IMT (P=0.039), together with age (P<0.001) and hypertension (P=0.011), in a model comprising also waist circumference, smoking history, serum creatinine, high sensitive C-reactive protein, dysglycemia, and dyslipidemia (adjusted R2=35.8%; P<0.001). Elevated serum FGF21 levels were also a significant independent risk factor of carotid IMT on multiple stepwise regression analysis (P=0.01). Conclusions—The present study is the first demonstration that elevated serum FGF21 levels are associated with carotid atherosclerosis in humans, independent of established risk factors including adverse lipid profiles and C-reactive protein. The role of FGF21 as a biomarker or therapeutic target of atherosclerotic diseases warrants further investigation.

Elevated circulating adipocyte‐fatty acid binding protein levels predict incident cardiovascular events in a community‐based cohort: a 12‐year prospective study

Background Obesity is closely associated with various cardiovascular diseases (CVDs). Adipose tissue inflammation and perturbation of adipokine secretion may contribute to the pathogenesis of CVD. This study aimed to evaluate whether the 2 most abundant adipokines, adipocyte‐fatty acid binding protein (A‐FABP) and adiponectin, are independent risk factors predisposing to CVD. Method and Results We investigated prospectively the 12‐year development of CVD in relation to the baseline levels of A‐FABP and adiponectin in a population‐based community cohort comprising 1847 Chinese subjects recruited from the Hong Kong Cardiovascular Risk Factors Prevalence Study 2 (CRISPS 2) cohort without previous CVD. Baseline serum levels of A‐FABP, adiponectin, and C‐reactive protein (CRP), an established biomarker predictive of CVD, were measured. In all, 182 (9.9%) of the 1847 Chinese subjects developed CVD during a median follow‐up of 9.4 years. The CVD group had more traditional risk factors, higher baseline levels of A‐FABP and CRP (both P<0.001), but similar adiponectin levels (P=0.881) compared with the non‐CVD group. In Cox regression analysis including both biomarkers, the adjusted HR for A‐FABP and CRP for subjects above the optimal cutoff values were 1.57 (95% CI, 1.14 to 2.16; P=0.006) and 1.60 (95% CI, 1.12 to 2.27; P=0.01), respectively, after adjustment for traditional risk factors. The category‐free net reclassification index, but not the c‐statistic, showed improvement in predictive performance by the addition of A‐FABP to the traditional risk factor model (P=0.017). Conclusions Circulating A‐FABP level predicts the development of CVD after adjustment for traditional risk factors in a community‐based cohort. Its clinical use for CVD prediction warrants further validation.

Circulating Fibroblast Growth Factor 21 Levels Predict Progressive Kidney Disease in Subjects With Type 2 Diabetes and Normoalbuminuria

BACKGROUND Elevated fibroblast growth factor 21 (FGF21) levels have been suggested, from cross-sectional studies, as an indicator of subclinical diabetic nephropathy. We investigated whether serum FGF21 was predictive of the development of diabetic nephropathy. METHOD Baseline serum FGF21 levels were measured in 1136 Chinese type 2 diabetic subjects recruited from the Hong Kong West Diabetes Registry. The role of serum FGF21 in predicting decline in estimated glomerular filtration rate (eGFR) over a median follow-up of 4 years was analyzed using Cox regression analysis. RESULTS At baseline, serum FGF21 levels increased progressively with eGFR category (P for trend <.001). Among 1071 subjects with baseline eGFR ≥ 30 mL/min/1.73 m(2), serum FGF21 levels were significantly higher in those with eGFR decline during follow-up (n = 171) than those without decline (n = 900) (P < .001). In multivariable Cox regression analysis, baseline serum FGF21 was independently associated with eGFR decline (hazard ratio, 1.21; 95% confidence interval [CI], 1.01-1.43; P = .036), even after adjustment for baseline eGFR. In a subgroup of 559 subjects with baseline eGFR ≥ 60 mL/min/1.73 m(2) and normoalbuminuria, serum FGF21 level remained an independent predictor of eGFR decline (hazard ratio, 1.36; 95% CI, 1.06-1.76; P = .016). Integrated discrimination improvement (IDI) suggested that the inclusion of baseline serum FGF21 significantly improved the prediction of eGFR decline (IDI, 1%; 95% CI, 0.1-3.0; P = .013) in this subgroup, but not in the initial cohort involving all subjects. CONCLUSIONS Elevated serum FGF21 levels may be a useful biomarker for predicting kidney disease progression, especially in the early stages of diabetic nephropathy.

Exome-wide association analysis reveals novel coding sequence variants associated with lipid traits in Chinese

Blood lipids are important risk factors for coronary artery disease (CAD). Here we perform an exome-wide association study by genotyping 12,685 Chinese, using a custom Illumina HumanExome BeadChip, to identify additional loci influencing lipid levels. Single-variant association analysis on 65,671 single nucleotide polymorphisms reveals 19 loci associated with lipids at exome-wide significance (P<2.69 × 10−7), including three Asian-specific coding variants in known genes (CETP p.Asp459Gly, PCSK9 p.Arg93Cys and LDLR p.Arg257Trp). Furthermore, missense variants at two novel loci—PNPLA3 p.Ile148Met and PKD1L3 p.Thr429Ser—also influence levels of triglycerides and low-density lipoprotein cholesterol, respectively. Another novel gene, TEAD2, is found to be associated with high-density lipoprotein cholesterol through gene-based association analysis. Most of these newly identified coding variants show suggestive association (P<0.05) with CAD. These findings demonstrate that exome-wide genotyping on samples of non-European ancestry can identify additional population-specific possible causal variants, shedding light on novel lipid biology and CAD.

Elevated Circulating Pigment Epithelium-Derived Factor Predicts the Progression of Diabetic Nephropathy in Patients With Type 2 Diabetes

Context: Pigment epithelium-derived factor (PEDF), a circulating glycoprotein with antiangiogenic, antioxidative, and anti-inflammatory properties, protects against diabetic nephropathy (DN) in animal models. Objective: We investigated whether circulating PEDF predicted the progression of DN in a 4-year prospective study. Design, Setting, and Participants: Baseline plasma PEDF levels were measured in type 2 diabetic subjects recruited from the Hong Kong West Diabetes Registry. The role of PEDF in predicting chronic kidney disease (CKD) and albuminuria progression was analyzed using Cox regression analysis. Main Outcome Measure: We evaluated CKD progression, defined as deterioration in CKD staging and a 25% or greater drop in estimated glomerular filtration rate (eGFR) according to International Society of Nephrology statements. Results: At baseline, plasma PEDF levels increased progressively with CKD staging (P for trend <.001; n = 1136). Among 1071 subjects with baseline CKD stage ≤3, plasma PEDF levels were significantly higher in those with CKD progression (n = 171) during follow-up than those without (P < .001). Baseline PEDF was independently associated with CKD progression (hazard ratio = 2.76; 95% confidence interval = 1.39–5.47; P = .004), adjusted for age, sex, waist circumference, diabetes duration, hemoglobin A1c, systolic blood pressure, use of antihypertensive drugs, C-reactive protein, and eGFR. Elevated baseline PEDF was also associated with the development of microalbuminuria/albuminuria in a subgroup with normoalbuminuria and eGFR >60 mL/min/1.73 m2 (n = 462) at baseline (hazard ratio = 2.75; 95% confidence interval = 1.01–7.49; P < .05), even after adjustment for potential confounders. Conclusions: Elevated PEDF levels may represent a compensatory change in type 2 diabetic patients with renal disease and appear to be a useful marker for evaluating the progression of DN.

Combined Use of Serum Adiponectin and Tumor Necrosis Factor-Alpha Receptor 2 Levels Was Comparable to 2-Hour Post-Load Glucose in Diabetes Prediction

Background Adipose tissue inflammation and dysregulated adipokine secretion are implicated in obesity-related insulin resistance and type 2 diabetes. We evaluated the use of serum adiponectin, an anti-inflammatory adipokine, and several proinflammatory adipokines, as biomarkers of diabetes risk and whether they add to traditional risk factors in diabetes prediction. Methods We studied 1300 non-diabetic subjects from the prospective Hong Kong Cardiovascular Risk Factor Prevalence Study (CRISPS). Serum adiponectin, tumor necrosis factor-alpha receptor 2 (TNF-α R2), interleukin-6 (IL-6), adipocyte–fatty acid binding protein (A-FABP) and high-sensitivity C-reactive protein (hsCRP) were measured in baseline samples. Results Seventy-six participants developed diabetes over 5.3 years (median). All five biomarkers significantly improved the log-likelihood of diabetes in a clinical diabetes prediction (CDP) model including age, sex, family history of diabetes, smoking, physical activity, hypertension, waist circumference, fasting glucose and dyslipidaemia. In ROC curve analysis, “adiponectin + TNF-α R2” improved the area under ROC curve (AUC) of the CDP model from 0.802 to 0.830 (P = 0.03), rendering its performance comparable to the “CDP + 2-hour post-OGTT glucose” model (AUC  = 0.852, P = 0.30). A biomarker risk score, derived from the number of biomarkers predictive of diabetes (low adiponectin, high TNF-α R2), had similar performance when added to the CDP model (AUC  = 0.829 [95% CI: 0.808–0.849]). Conclusions The combined use of serum adiponectin and TNF-α R2 as biomarkers provided added value over traditional risk factors for diabetes prediction in Chinese and could be considered as an alternative to the OGTT.

High-Intensity Focused Ultrasound for Treatment of Symptomatic Benign Thyroid Nodules: A Prospective Study

Purpose To evaluate first-year efficacy and changes in pressure symptoms and health-related quality of life (HRQOL) after ultrasonographically (US) guided high-intensity focused ultrasound (HIFU) ablation of symptomatic benign thyroid nodules. Materials and Methods After ethics approval and informed consent were obtained, a prospective trial was conducted. Patients with a symptomatic benign thyroid nodule were given a choice of HIFU treatment or active surveillance. Clinical and US examinations, pressure symptom scores (visual analog scale), and HRQOL questionnaires (short form-12 survey) were evaluated at baseline and at 3, 6, and 12 months. The primary outcome was change in nodule volume after 12 months. The percentage of change in nodule volume was defined as the baseline volume minus the volume at 12 months divided by the baseline volume times 100. Ablation success was defined as a reduction in volume of greater than 50%. Nodule volume was compared by using the paired t test. Continuous variables were compared by using the Mann-Whitney U test, and categorical variables were compared by using χ2 tests. Results Twenty-two patients underwent HIFU and 22 underwent active surveillance. Mean age was 53.11 years (range, 28-76 years) and 55.19 years (range, 41-70 years), respectively. The ratio of men to women was 2:20 and 1:21, respectively. The 12-month mean volume reduction ± standard deviation in the HIFU group was significant (68.87% ± 15.27 [range, 47.35%-94.89%], P < .001) but not in the surveillance group (-2.11% ± 6.29 [range, -15.64% to 12.70%], P > .05). Preablation nodule volume was the only determinant of ablation success (odds ratio, 1.877; 95% confidence interval [CI]: 1.085, 3.249; P = .024). At 12 months, patients in the HIFU group had less swelling (P < .001), lower pressure symptom scores (P < .001), and higher physical composite scores (P = .006). Physical composite scores significantly correlated with 6-month reduction in nodule size (r = 0.768; 95% CI: 0.660, 0.930; P < .001) and 12-month reduction in nodule size (r = 0.704; 95% CI: 0.680, 940; P < .001). Conclusion HIFU ablation of symptomatic benign thyroid nodules not only induced significant shrinkage but also improved pressure symptom scores and HRQOL throughout a 12-month period.

Serum fibroblast growth factor 21 is a superior biomarker to other adipokines in predicting incident diabetes

Fibroblast growth factor 21 (FGF21) improves glucose and lipid metabolism, but high circulating levels are found in type 2 diabetes, suggesting FGF21 resistance. Serum FGF21 predicts incident diabetes, but its performance compared to established and emerging predictors is not known. We aimed to study the performance of FGF21 in diabetes prediction, relative to other adipokines and established risk factors including 2‐h plasma glucose (2hG) during the oral glucose tolerance test (OGTT).

Impact of Genetic Loci Identified in Genome-Wide Association Studies on Diabetic Retinopathy in Chinese Patients With Type 2 Diabetes

Purpose Diabetic retinopathy (DR) is a common microvascular complication of type 2 diabetes (T2DM). Genome-wide association studies (GWAS) had identified novel DR-susceptibility genetic variants in various populations. We examined the associations of these DR-associated single nucleotide polymorphisms (SNPs) with severe DR in a Chinese T2DM cohort. Methods Cross-sectional case-control studies on sight-threatening DR (STDR) and proliferative DR (PDR) were performed. We genotyped 38 SNPs showing top association signals with DR in previous GWAS in 567 STDR cases, including 309 with PDR and 1490 non-DR controls. Multiple logistic regression models with adjustment for conventional risk factors, including age, sex, duration of diabetes, and presence of hypertension, were employed. Results The strongest association was found at INSR rs2115386, an intronic SNP of INSR: Padjusted = 9.13 × 10-4 (odds ratio [OR],1.28; 95% confidence interval [95%CI], 1.11-1.48) for STDR, and Padjusted= 1.12 × 10-4 (OR [95%CI],1.44 [1.20-1.74]) for PDR. rs599019 located downstream of COLEC12 (Padjusted = 0.019; OR [95%CI],1.19 [1.03-1.38]) and rs4462262 located at an intergenic region between ZWINT and MRPS35P3 (Padjusted = 0.041; OR [95%CI],1.38[1.01-1.89]) also were significantly associated with STDR, but not with PDR alone. On the other hand, MYT1L-LOC729897 rs10199521 (Padjusted = 0.022; OR [95%CI],1.25 [1.03-1.51]) and API5 rs899036 (Padjusted = 0.049; OR [95%CI],1.36 [1.00-1.85]) showed significant independent associations only with PDR. Similar results were obtained when hemoglobin A1c also was included in the adjustment models. Conclusions We demonstrated the significant and independent associations of several GWAS-identified SNPs with DR in Chinese T2DM patients with severe DR. The findings on INSR rs2115386 are supportive of the role of insulin resistance, or the compensatory hyperinsulinemia, in the pathogenesis of DR.

Vocal cord paresis following single-session high intensity focused ablation (HIFU) treatment of benign thyroid nodules: incidence and risk factors

Abstract Background: Vocal cord paresis (VCP) may occur following high intensity focused ultrasound (HIFU) of thyroid nodules. We hypothesised its occurrence relates to the distance of the focus point (FP) of the HIFU beams from the recurrent laryngeal nerve (RLN) and the thermal power that this point received. Their relationships were examined. Methods: One hundred and three patients who underwent HIFU for symptomatic benign thyroid nodule from October 2015 to March 2017 were analysed. All treatment images were captured and were later watched by 2 reviewers to identify three FPs closest to the tracheoesophageal groove (TEG) on transverse sonographic view. TEG was taken as the RLN position. After identifying these FPs, their distance (mm) from the TEG, thermal power (W) used and depth from skin (mm) were recorded. These parameters were compared between those with and without VCP. VCP was defined as a cord with reduced or no movement. Results: Four (3.9%) patients suffered from a unilateral VCP afterwards but they all recovered fully within 6 weeks. There were no significant differences in baseline characteristics and treatment efficacy between the two groups. The distance from TEG (OR = 1.706, 95%CI = 1.001 to 2.915, p = 0.050) was the only significant factor for VCP. None of the other variables including thermal power were significant. Conclusions: The incidence of VCP was 3.9% (4/103) and they completely recovered within 6 weeks. The distance between the FP and the TEG was the only related factor for VCP. The safe distance between FP and TEG should be ≥1.1 cm.