SLC10A1 rs2296651 variant (S267F mutation) predicts biochemical traits, hepatitis B virus infection susceptibility and the risk of gallstone disease.

Sodium taurocholate co-transporting polypeptide (NTCP), a bile acid transporter, plays a crucial role in regulating bile acid levels and influencing the risk of HBV infection. Genetic variations in the SLC10A1 gene, which encodes NTCP, affect these functions. However, the impact of SLC10A1 gene variants on the metabolic and biochemical traits remained unclear. We aimed to investigate the association of SLC10A1 gene variants with the clinical and biochemical parameters, and the risk of different HBV infection statuses and gallstone disease in the Taiwanese population. Genotyping data from 117,679 Taiwan Biobank participants were analyzed using the Axiom genome-wide CHB arrays. Regional-plot association analysis demonstrated genome-wide significant association between the SLC10A1 rs2296651 genotypes and lipid profile, gamma glutamyl transferase (γGT) level and anti-HBc-positivity. Genotype-phenotype association analyses revealed significantly lower total cholesterol, low-density lipoprotein (LDL) cholesterol and uric acid levels, a higher γGT level and a higher gallstone incidence in rare rs2296651-A allele carrier. Participants with the rs2296651 AA-genotype exhibited significantly lower rates of anti-HBc-positivity and HBsAg-positivity. Compared to those with the GG-genotype, individuals with non-GG-genotypes had reduced risks for various HBV infection statuses: the AA-genotype showed substantially lower risks, while the GA-genotype demonstrated modestly lower risks. Predictive tools also suggested that the rs2296651 variant potentially induced protein damage and pathogenic effects. In conclusion, our data revealed pleiotropic effects of the SLC10A1 rs2296651 genotypes on the levels of biochemical traits and the risk of HBV infection and gallstone disease. This confirms SLC10A1's versatility and implicates its genotypes in predicting both biochemical traits and disease susceptibility.

Exploring PCSK9 Genetic Impact on Lipoprotein(a) via Dual Approaches: Association and Mendelian Randomization.

Previous investigations have suggested an association between the PCSK9 common polymorphism E670G and Lipoprotein(a) (Lp(a)) levels, as well as a link between plasma PCSK9 levels and Lp(a) concentrations. However, the causal relationship between plasma PCSK9 and Lp(a) levels remains uncertain. In this study, we explored the association between PCSK9 E670G polymorphism and Lp(a) levels in 614 healthy Taiwanese individuals. Employing a two-sample Mendelian randomization (MR) analysis using openly accessible PCSK9 and Lp(a) summary statistics from the genome-wide association studies (GWAS) and UK Biobank, we aimed to determine if a causal link exists between plasma PCSK9 levels and Lp(a) concentrations. Our findings reveal that the E670G G allele is independently associated with a decreased likelihood of developing elevated Lp(a) levels. This association persists even after adjusting for common cardiovascular risk factors and irrespective of lipid profile variations. The MR analysis, utilizing six PCSK9 GWAS-associated variants as instrumental variables to predict plasma PCSK9 levels, provides compelling evidence of a causal relationship between plasma PCSK9 levels and Lp(a) concentration. In conclusion, our study not only replicates the association between the PCSK9 E670G polymorphism and Lp(a) levels but also confirms a causative relationship between PCSK9 levels and Lp(a) concentrations through MR analysis.

Repetition of Paclitaxel-Coated Devices for the Treatment of Lower Extremity Artery Disease: Mortality Outcomes and Predictors.

Background: A recent meta-analysis reported late excess mortality in patients treated with paclitaxel-coated devices (PCDs) for symptomatic femoropopliteal disease. However, this finding is controversial. Objectives: To investigate the impact on mortality and predictors of repeat exposure to PCDs in patients with lower extremity peripheral arterial disease (LE-PAD). Methods: We analyzed registry patient-level data from two centers. A total of 214 patients were enrolled, and stratified based on terciles of cumulative dose of paclitaxel. We treated 134 patients with a single PCD exposure and 80 with multiple PCD exposures. We used the follow-up index (FUI) in Kaplan-Meier survival estimates to minimize potential selection bias. We used Cox proportional hazard and splines models to determine the predictors of mortality and assess their relationships with mortality. Results: The mean cumulative dose of paclitaxel was significantly different among groups (6.40 mg vs. 15.06 mg vs. 38.57 mg, p < 0.001). The 5-year FUI (0.93 ± 0.19 vs. 0.94 ± 0.18 vs. 0.95 ± 0.15, p = 0.836) and survival rates were not different (65.4% vs. 51.9% vs. 72.0%, p = 0.148). There was no dose-response association between paclitaxel dosage and death (p = 0.297). The predictors of death were congestive heart failure, stroke, dialysis dependence, neutrophil-lymphocyte ratio (NLR) > 3, age > 71 years, and body mass index (BMI) < 20 kg/m2. Spline model analysis validated the non-linear associations between mortality, age, BMI, and NLR. Conclusions: Repeated PCD exposure for LE-PAD did not result in excess late mortality. Predictors of mortality might change over time, and continuous variables had non-linear relationships with death.

Differential Genetic and Epigenetic Effects of the KLF14 Gene on Body Shape Indices and Metabolic Traits.

The KLF14 gene is a key metabolic transcriptional transregulator with monoallelic maternal expression. KLF14 variants are only associated with adipose tissue gene expression, and KLF14 promoter methylation is strongly associated with age. This study investigated whether age, sex, and obesity mediate the effects of KLF14 variants and DNA methylation status on body shape indices and metabolic traits. In total, the data of 78,742 and 1636 participants from the Taiwan Biobank were included in the regional plot association analysis for KLF14 variants and KLF14 methylation, respectively. Regional plot association studies revealed that the KLF14 rs4731702 variant and the nearby strong linkage disequilibrium polymorphisms were the lead variants for lipid profiles, blood pressure status, insulin resistance surrogate markers, and metabolic syndrome mainly in female participants and for body shape indices mainly in obese women. Significant age-dependent associations between KLF14 promoter methylation levels and body shape indices, and metabolic traits were also noted predominantly in female participants. KLF14 variants and KLF14 hypermethylation status were associated with metabolically healthy and unhealthy phenotypes, respectively, in obese individuals, and only the KLF14 variants demonstrated a significant association with both higher adiposity and lower cardiometabolic risk in the same allele, revealing uncoupled excessive adiposity from its cardiometabolic comorbidities, especially in obese women. Variations of KLF14 are associated with body shape indices, metabolic traits, insulin resistance, and metabolically healthy status. Differential genetic and epigenetic effects of KLF14 are age-, sex- and obesity-dependent. These results provided a personalized reference for the management of cardiometabolic diseases in precision medicine.

Common and Rare PCSK9 Variants Associated with Low-Density Lipoprotein Cholesterol Levels and the Risk of Diabetes Mellitus: A Mendelian Randomization Study.

PCSK9 is a candidate locus for low-density lipoprotein cholesterol (LDL-C) levels. The cause-effect relationship between LDL-C levels and diabetes mellitus (DM) has been suggested to be mechanism-specific. To identify the role of PCSK9 and genome-wide association study (GWAS)-significant variants in LDL-C levels and the risk of DM by using Mendelian randomization (MR) analysis, a total of 75,441 Taiwan Biobank (TWB) participants was enrolled for a GWAS to determine common and rare PCSK9 variants and their associations with LDL-C levels. MR studies were also conducted to determine the association of PCSK9 variants and LDL-C GWAS-associated variants with DM. A regional plot association study with conditional analysis of the PCSK9 locus revealed that PCSK9 rs10788994, rs557211, rs565436, and rs505151 exhibited genome-wide significant associations with serum LDL-C levels. Imputation data revealed that three rare nonsynonymous mutations-namely, rs151193009, rs768846693, and rs757143429-exhibited genome-wide significant association with LDL-C levels. A stepwise regression analysis indicated that seven variants exhibited independent associations with LDL-C levels. On the basis of two-stage least squares regression (2SLS), MR analyses conducted using weighted genetic risk scores (WGRSs) of seven PCSK9 variants or WGRSs of 41 LDL-C GWAS-significant variants revealed significant association with prevalent DM (p = 0.0098 and 5.02 × 10-7, respectively), which became nonsignificant after adjustment for LDL-C levels. A sensitivity analysis indicated no violation of the exclusion restriction assumption regarding the influence of LDL-C-level-determining genotypes on the risk of DM. Common and rare PCSK9 variants are independently associated with LDL-C levels in the Taiwanese population. The results of MR analyses executed using genetic instruments based on WGRSs derived from PCSK9 variants or LDL-C GWAS-associated variants demonstrate an inverse association between LDL-C levels and DM.

Synergistic Effects of Weighted Genetic Risk Scores and Resistin and sST2 Levels on the Prognostication of Long-Term Outcomes in Patients with Coronary Artery Disease.

Resistin and soluble suppression of tumorigenicity 2 (sST2) are useful predictors in patients with coronary artery disease (CAD). Their serum levels are significantly attributed to variations in RETN and IL1RL1 loci. We investigated candidate variants in the RETN locus for resistin levels and those in the IL1RL1 locus for sST2 levels and evaluated the prognostication of these two biomarkers and the corresponding variants for long-term outcomes in the patients with CAD. We included 4652, 557, and 512 Chinese participants from the Taiwan Biobank (TWB), cardiovascular health examination (CH), and CAD cohorts, respectively. Candidate variants in RETN and IL1RL1 were investigated using whole-genome sequence (WGS) and genome-wide association study (GWAS) data in the TWB cohort. The weighted genetic risk scores (WGRS) of RETN and IL1RL1 with resistin and sST2 levels were calculated. Kaplan-Meier curves were used to analyze the prognostication of resistin and sST2 levels, WGRS of RETN and IL1RL1, and their combinations. Three RETN variants (rs3219175, rs370006313, and rs3745368) and two IL1RL1 variants (rs10183388 and rs4142132) were independently associated with resistin and sST2 levels as per the WGS and GWAS data in the TWB cohort and were further validated in the CH and CAD cohorts. In combination, these variants explained 53.7% and 28.0% of the variation in resistin and sST2 levels, respectively. In the CAD cohort, higher resistin and sST2 levels predicted higher rates of all-cause mortality and major adverse cardiac events (MACEs) during long-term follow-up, but WGRS of RETN and IL1RL1 variants had no impact on these outcomes. A synergistic effect of certain combinations of biomarkers with RETN and IL1RL1 variants was found on the prognostication of long-term outcomes: Patients with high resistin levels/low RETN WGRS and those with high sST2 levels/low IL1RL1 WGRS had significantly higher all-cause mortality and MACEs rates, and those with both these combinations had the poorest outcomes. Both higher resistin and sST2 levels, but not RETN and IL1RL1 variants, predict poor long-term outcomes in patients with CAD. Furthermore, combining resistin and sST2 levels with the WGRS of RETN and IL1RL1 genotyping exerts a synergistic effect on the prognostication of CAD outcomes. Future studies including a large sample size of participants with different ethnic populations are needed to verify this finding.

Pleiotropic Effects of APOB Variants on Lipid Profiles, Metabolic Syndrome, and the Risk of Diabetes Mellitus.

Apolipoprotein B (ApoB) plays a crucial role in lipid and lipoprotein metabolism. The effects of APOB locus variants on lipid profiles, metabolic syndrome, and the risk of diabetes mellitus (DM) in Asian populations are unclear. We included 1478 Taiwan Biobank participants with whole-genome sequence (WGS) data and 115,088 TWB participants with Axiom genome-wide CHB array data and subjected them to genotype-phenotype analyses using APOB locus variants. Five APOB nonsynonymous mutations, including Asian-specific rs144467873 and rs13306194 variants, were selected from participants with the WGS data. Using a combination of regional association studies, a linkage disequilibrium map, and multivariate analysis, we revealed that the APOB locus variants rs144467873, rs13306194, and rs1367117 were independently associated with total, low-density lipoprotein (LDL), and non-high-density lipoprotein (non-HDL) cholesterol levels; rs1318006 was associated with HDL cholesterol levels; rs13306194 and rs35131127 were associated with serum triglyceride levels; rs144467873, rs13306194, rs56213756, and rs679899 were associated with remnant cholesterol levels; and rs144467873 and rs4665709 were associated with metabolic syndrome. Mendelian randomization (MR) analyses conducted using weighted genetic risk scores from three or two LDL-cholesterol-level-associated APOB variants revealed significant association with prevalent DM (p = 0.0029 and 8.2 × 10-5, respectively), which became insignificant after adjustment for LDL-C levels. In conclusion, these results indicate that common and rare APOB variants are independently associated with various lipid levels and metabolic syndrome in Taiwanese individuals. MR analyses supported APOB variants associated with the risk of DM through their associations with LDL cholesterol levels.

Circulating chemerin level is associated with metabolic, biochemical and haematological parameters-A population-based study.

OBJECTIVE: This study aims to analyse the association of chemerin levels with several metabolic, biochemical and haematological parameters in a large Taiwanese population with relative healthy status. DESIGN: Cross-sectional study. METHODS: Data of 4101 healthy participants without history of hypertension, diabetes, dyslipidaemia and renal insufficiency from Taiwan Biobank were analysed. The demographic, biochemical and haematologic parameters were retrieved from the database. Chemerin levels were measured using commercially available enzyme-linked immunosorbent assay. Univariate and multivariate analysis was performed to test the independent correlates of chemerin. RESULTS: In the univariate analysis, circulating chemerin levels were positively associated with body mass index (BMI), waist circumference, waist-to-hip ratio (WHR), systolic (SBP) and diastolic blood pressure (DBP), haemoglobin A1C (HbA1C), total cholesterol, triglyceride, low-density lipoprotein cholesterol (LDL-C), creatinine, uric acid, alanine aminotransferase (ALT), gamma-glutamyl transferase (γ-GT), leucocyte and platelet counts both in men and women and negatively associated with high-density lipoprotein cholesterol (HDL-C), estimated glomerular filtration rate (eGFR) and total bilirubin. In the multivariate analysis, BMI, HbA1C, triglyceride, uric acid, γ-GT and platelet counts predicted chemerin levels independently both in men and in women with positive correlation, while eGFR, total bilirubin and HDL-C predicted circulating chemerin levels independently with negative correlation. CONCLUSIONS: Chemerin level is independently associated with multiple metabolic, biochemical and haematological parameters. This study provides further evidence on the molecular basis linking obesity with several human diseases.

Combined corrected QT interval and growth differentiation factor-15 level has synergistic predictive value for long-term outcome of angiographically confirmed coronary artery disease.

BACKGROUND: The corrected QT interval (QTc) predicts prognosis for the general population and patients with coronary artery disease (CAD). Growth differentiation factor-15 (GDF-15) is a biomarker of myocardial fibrosis and left ventricular (LV) remodelling. The interaction between these two parameters is unknown. SUBJECTS AND METHODS: This study included 487 patients with angiographically confirmed CAD. QTc was calculated using the Bazett formula. Multiple biochemistries and GDF-15 levels were measured. The primary endpoint was total mortality, and the secondary endpoints comprised the combination of total mortality, myocardial infarction and hospitalisation for heart failure and stroke. RESULTS: The mean follow-up period was 1029 ± 343 days (5-1692 days), during which 21 patients died and 47 had secondary endpoints. ROC curve analysis for the optimal cut-off value of primary endpoint is 1.12 ng/mL for GDF-15 (AUC = 0.787, P = 9.0 × 10-6 ) and 438.5 msec for QTc (AUC = 0.698, P = .002). Utilising linear regression, QTc has a positive correlation with Log-GDF-15 (r = .216, P = 1.0 × 10-6 ). Utilising Kaplan-Meier analysis, both QTc interval and GDF-15 level are significant predictors for primary end point (P = .000194, P = 2.0 × 10-6 , respectively) and secondary endpoint (P = .00028, P = 6.15 × 10-8 , respectively). When combined these two parameters together, a significant synergistic predictive power was noted for primary and secondary endpoint (P = 2.31 × 10-7 , P = 1.26 × 10-8 , respectively). This combined strategy also showed significant correlation with the severity of CAD (P < .001). CONCLUSION: In Chinese patient with angiographically confirmed CAD, a combined strategy utilising an ECG parameter (QTc) and a circulating biomarker (GDF-15) has good correlation with the severity of CAD, and improves the predictive power for total mortality.

Pleiotropic Effects of Functional MUC1 Variants on Cardiometabolic, Renal, and Hematological Traits in the Taiwanese Population.

MUC1 is a transmembrane mucin involved in carcinogenesis and cell signaling. Functional MUC1 variants are associated with multiple metabolic and biochemical traits. This study investigated the association of functional MUC1 variants with MUC1 DNA methylation and various metabolic, biochemical, and hematological parameters. In total, 80,728 participants from the Taiwan Biobank were enrolled for association analysis using functional MUC1 variants and a nearby gene regional plot association study. A subgroup of 1686 participants was recruited for MUC1 DNA methylation analysis. After Bonferroni correction, we found that two MUC1 variants, rs4072037 and rs12411216, were significantly associated with waist circumference, systolic blood pressure, hemoglobin A1C, renal functional parameters (blood urea nitrogen, serum creatinine levels, and estimated glomerular filtration rate), albuminuria, hematocrit, hemoglobin, red blood cell count, serum uric acid level, and gout risk, with both favorable and unfavorable effects. Causal inference analysis revealed that the association between the variants and gout was partially dependent on the serum uric acid level. Both gene variants showed genome-wide significant associations with MUC1 gene-body methylation. Regional plot association analysis further revealed lead single-nucleotide polymorphisms situated at the nearby TRIM46-MUC1-THBS3-MTX1 gene region for the studied phenotypes. In conclusion, our data demonstrated the pleiotropic effects of MUC1 variants with novel associations for gout, red blood cell parameters, and MUC1 DNA methylation. These results provide further evidence in understanding the critical role of TRIM46-MUC1-THBS3-MTX1 gene region variants in the pathogenesis of cardiometabolic, renal, and hematological disorders.

[Effects of Motivational Interview and Mobile Social Network Support on Smoking Cessation in Male Patients With Coronary Heart Disease].

BACKGROUND: Patients with coronary heart disease (CHD) who quit smoking exhibit lower rates of heart attack recurrence and mortality than their peers who continue smoking. However, most male patients with CHD resume smoking after hospital discharge. PURPOSE: To explore the effectiveness of motivational interventions and mobile social network support on smoking cessation and other predictors of smoking cessation in male patients with CHD. METHODS: An experimental design was used, and a convenience sample was recruited from a cardiology ward of a hospital in northern Taiwan. The participants were randomly assigned to the experimental group (n = 57) and control group (n = 64). During hospitalization, each participant completed a questionnaire after undergoing cardiac catheterization. The questionnaire included a demographic datasheet, the Fagerström Test for Nicotine Dependence, and the contemplation ladder. Afterward, the experimental group received motivational interventions, filled out a self-efficacy scale and the contemplation ladder, and joined an online mobile social group (LINE) for three months. The control group received regular care and a smoking cessation booklet, and then filled out the self-efficacy scale and contemplation ladder. An intention-to-treat analysis was adopted to evaluate smoke cessation status. Information on post-discharge smoking status was collected from the participants via the Line communications app or phone calls at three-months after hospital discharge and was further confirmed using urinary cotinine levels. RESULTS: The results revealed that both groups registered improvements in motivation to quit smoking. This motivation was relatively higher in the experimental group after the intervention than in the control group. The smoking cessation rate in the experimental group (35.09%) was higher than that in the control group (17.19%). However, the intergroup difference in the cessation rate only approached statistical significance (OR: 2.34; p = .055) after controlling for the baseline difference between the two groups. Controlling for the effects of the intervention, age of smoking initiation, first diagnosis of CHD, and self-efficacy were identified as predictors of smoking cessation. CONCLUSIONS / IMPLICATIONS FOR PRACTICE: Healthcare providers are encouraged to provide motivational interviews to enhance the motivation of their patients to quit smoking as well as to incorporate self-efficacy into related interventions to increase the smoking cessation rate.

Association Rule Mining and Prognostic Stratification of 2-Year Longevity in Octogenarians Undergoing Endovascular Therapy for Lower Extremity Arterial Disease: Observational Cohort Study.

BACKGROUND: Two-year longevity is a crucial consideration in revascularization strategies for patients with symptomatic lower extremity arterial disease (LEAD). However, factors associated with 2-year longevity and risk stratification in octogenarians or nonagenarians have been underreported. OBJECTIVE: This paper aims to investigate the associated variables and stratify the 2-year prognosis in older patients with LEAD. METHODS: We performed logistic regression and association rule mining based on the Apriori algorithm to discover independent variables and validate their associations with 2-year longevity. Malnutrition, inflammation, and stroke factors were identified. C statistics and Kaplan-Meier analysis were used to assess the impact of different numbers of malnutrition, inflammation, and stroke factors on 2-year longevity. RESULTS: We recruited a total of 232 octogenarians or nonagenarians (mean age 85 years, SD 4.2 years) treated with endovascular therapy. During the study period, 81 patients died, and 27 of those (33%) died from a cardiac origin within 2 years. Association rules analysis showed the interrelationships between 2-year longevity and the neutrophil-lymphocyte ratio (NLR) and nutritional status as determined by the Controlling Nutritional Status (CONUT) score or Geriatric Nutritional Risk Index (GNRI). The cut-off values of NLR, GNRI, and CONUT were ≥3.89, ≤90.3, and >3, respectively. The C statistics for the predictive power for 2-year longevity were similar between the CONUT score and the GNRI-based models (0.773 vs 0.760; P=.57). The Kaplan-Meier analysis showed that 2-year longevity was worse as the number of malnutrition, inflammation, and stroke factors increased from 0 to 3 in both the GNRI-based model (92% vs 68% vs 46% vs 12%, respectively; P<.001) and the CONUT score model (87% vs 75% vs 49% vs 10%, respectively; P<.001). The hazard ratio between those with 3 factors and those without was 18.2 (95% CI 7.0-47.2; P<.001) in the GNRI and 13.6 (95% CI 5.9-31.5; P<.001) in the CONUT score model. CONCLUSIONS: This study demonstrated the association and crucial role of malnutrition, inflammation, and stroke factors in assessing 2-year longevity in older patients with LEAD. Using this simple risk score might assist clinicians in selecting the appropriate treatment.

Contemporary cardiovascular outcomes in Taiwanese patients undergoing endovascular therapy for symptomatic lower extremity peripheral arterial disease.

BACKGROUND/PURPOSE: To investigate contemporary cardiovascular (CV) outcomes in Taiwanese patients with symptomatic low extremity peripheral artery disease treated with endovascular therapy. METHODS: An observational cohort study with up to 155 months of follow-up was conducted using a single-center registry database between July 2005 and June 2017. Long-term outcomes and predictors of future CV events were analyzed in 936 patients with 1246 affected legs. RESULTS: This study cohort comprised 21% claudicants and 79% critical limb ischemia (CLI) patients. Compared with claudicants, CLI patients had higher rates of medical comorbidities, tissue inflammation, and lesion complexities. During the study period, 349 patients died (130 CV deaths and 219 non-CV deaths), 306 had non-fatal CV events. The rates of 5-year freedom from all-cause mortality, major CV events (MACEs), and non-fatal CV events were 54.9%, 67.1%, and 56.6% respectively. For CLI patients, independent factors for all-cause mortality were age (odds ratio [OR] 1.03), atrial fibrillation (OR 1.79), albumin (OR 0.62), hematocrit (OR 0.96), body mass index (OR 0.94), C-reactive protein (OR 1.18), dialysis (OR 2.16), and non-ambulance (OR 2.05). Congestive heart failure, dialysis, and non-ambulance independently predicted the MACEs (OR 2.04, 1.93, and 1.67, respectively). For claudicants, coronary artery disease (CAD) was the essential factor for all-cause mortality (OR 2.24), MACE (OR 2.76) and non-fatal CV events (OR 1.82). CONCLUSION: Long-term survival and MACE-free rates were significantly worse in CLI patients than in claudicants. Malnutrition and inflammation were associated with long-term survival. CAD, low hematocrit, dialysis, CHF, and ambulatory status predicted future CV events.

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.

Circulating Chemerin Levels, but not the RARRES2 Polymorphisms, Predict the Long-Term Outcome of Angiographically Confirmed Coronary Artery Disease.

Chemerin, a novel adipokine, has been associated with metabolic, inflammatory, and atherosclerotic diseases. We aimed to determine the genetic basis of chemerin levels by conducting a genome-wide association study (GWAS) and to investigate the role of RARRES2 polymorphisms and circulating chemerin levels in the long-term outcome of coronary artery disease (CAD). A total of 2197 participants from the Taiwan Biobank (TWB) were recruited for the GWAS analysis, and 481 patients with angiographically confirmed CAD were enrolled for long-term outcome analysis. One locus of genome-wide significance with a single independent association signal was identified in the GWAS for chemerin levels with the peak association at the RARRES2 gene promoter region polymorphism rs3735167 (p = 2.35 × 10-21). In the CAD population, borderline significance was noted between RARRES2 polymorphisms and chemerin levels, whereas high chemerin levels were associated with obesity, female sex, diabetes mellitus, hypertension, current smoking, high platelet and leukocyte counts, anemia, impaired renal function, high C-reactive protein (CRP) levels, and multi-vessel disease. Kaplan⁻Meier survival curves indicated that the patients with high chemerin and CRP levels, but not those with RARRES2 polymorphisms, had a lower survival rate and higher combined cerebral and cardiovascular event rates. Combined chemerin and CRP levels further revealed a stepwise increase in poor clinical outcomes from low- to high-risk subgroups. In conclusion, rs3735167 is the lead RARRES2 polymorphism for chemerin levels in Taiwanese. Chemerin levels, but not the rs3735167 genotypes, predicted the long-term outcome of CAD, especially when combined with CRP levels.

Feasibility and Mid-Term Outcomes of Drug-Coated Balloon Angioplasty Between Intermittent Claudication and Critical Limb Ischemia in Patients with Femoropopliteal Disease.

BACKGROUND: The efficacy of drug-coated balloons (DCBs) in critical limb ischemia (CLI) is unclear. To investigate the clinical characteristics and outcomes of DCBs in symptomatic femoropopliteal disease between patients with intermittent claudication (IC) and CLI. METHODS: Data were retrospectively collected from three centers in Taiwan on patients who received DCBs for femoropopliteal lesions between March 2013 and June 2017. We compared the clinical characteristics and outcomes regarding binary restenosis, amputation-free survival (AFS), and major adverse limb events (MALEs) between groups. Cox proportional hazards analysis was used to identify predictors of outcome endpoints. RESULTS: We enrolled a total of 200 affected limbs in 174 patients, including 83 limbs in 71 patients with IC and 117 limbs in 103 patients with CLI. Compared to the patients with claudication, those with CLI were older and had higher proportions of medical comorbidities, tissue inflammation, poor runoff, and vessel calcification. The 3-year rates of freedom from binary restenosis (57% vs. 59%, p = 0.781), and MALEs (77% vs. 67%, p = 0.507) were similar between the two groups. However, the 3-year AFS was significantly higher in the IC group compared to the CLI group (91% vs. 73%, p = 0.001). Lesion length and severe calcification independently predicted binary restenosis, and restenotic lesion predicted MALEs. Age, congestive heart failure, and dialysis were independently associated with AFS. CONCLUSIONS: Despite advanced limb ischemia and comorbidities, the mid-term outcomes in surviving CLI patients were similar to those in the IC patients after treatment with DCBs for femoropopliteal disease.

Drug-Coated Balloon vs. Conventional Balloon Angioplasty in Dialysis Patients With Symptomatic Femoropopliteal Disease　- A Matched Comparison.

BACKGROUND: Recent randomized trials have shown the treatment benefits of use of a drug-coated balloon (DCB) over conventional percutaneous transluminal angioplasty (PTA) in patients with femoropopliteal disease. However, the effectiveness and safety of DCB for dialysis patients remain unclear.Methods and Results:Consecutive dialysis patients, who underwent PTA or DCB for femoropopliteal disease, were assessed retrospectively via 2:1 propensity score matching. Effectiveness and safety endpoints, including binary restenosis, clinically driven target lesion revascularization (CD-TLR), amputations, major adverse cardiac events (MACE), and deaths, were compared between groups. A total of 278 dialysis patients with 339 limbs were eligible for matching: 84 limbs from 77 patients treated with PTA and 46 limbs from 37 patients treated with DCB were compared after matching. Baseline patient and lesion characteristics were not different between groups. Patients treated with DCB had significantly higher rates of freedom from binary restenosis (52.4% vs. 18.6%, P<0.001) and CD-TLR (56.4% vs. 25.9%, P=0.001) at 2 years compared with patients treated with PTA. Both groups had similar outcomes for amputation, MACE, and death. Cox proportional analysis showed that treatment with DCB was independently associated with a reduction of binary restenosis (hazard ratio [HR] 0.368, P=0.001) and CD-TLR (HR 0.390, P=0.004). CONCLUSIONS: This study suggested superior 2-year outcomes using DCB compared with PTA and similar safety profiles in dialysis patients with femoropopliteal disease.

Pleiotropic Associations of RARRES2 Gene Variants and Circulating Chemerin Levels: Potential Roles of Chemerin Involved in the Metabolic and Inflammation-Related Diseases.

Chemerin, an adipokine and inflammatory mediator, is associated with metabolic, inflammation- and immune-mediated diseases. The genetic, clinical, and biomarker correlates of circulating chemerin levels have not been completely elucidated. We analyzed the determinants and correlates of retinoic acid receptor responder 2 (RARRES2; encoding chemerin) gene variants and chemerin levels in the Taiwanese population. In total, 612 individuals were recruited. Clinical and metabolic phenotypes, 13 inflammatory markers, 5 adipokines, and 6 single-nucleotide polymorphisms (SNPs) covering the RARRES2 region were analyzed. High chemerin levels and chemerin level tertiles were positively associated with multiple metabolic phenotypes and circulating inflammatory marker and adipokine levels and negatively associated with high-density lipoprotein cholesterol and adiponectin levels and estimated glomerular filtration rates (eGFRs). Genotype and haplotype analyses showed that RARRES2 SNPs were significantly associated with chemerin, fibrinogen, interleukin 6, and lipocalin 2 levels. Stepwise logistic regression analysis showed that C-reactive protein level, leptin level, triglyceride level, eGFR, rs3735167 genotypes, sex, and soluble P-selectin level were independently associated with chemerin levels. In conclusion, pleiotropic associations were noted between RARRES2 variants, circulating chemerin levels and multiple metabolic phenotypes and inflammatory marker levels. This study provides further evidence for the potential roles of chemerin in metabolic and inflammation-related diseases.

Clinical Outcomes of Repetition of Drug-Coated Balloon for Femoropopliteal Restenosis After Drug-Coated Balloon Treatment.

BACKGROUND: To compare the clinical outcomes of patients undergoing repeated drug-coated balloon (DCB) treatment for femoropopliteal (FP) DCB restenosis with those of patients without repetition-DCB.Methods and Results:From March 2013 to September 2014, 102 patients (118 affected legs) underwent DCB for symptomatic FP disease; 47 patients had restenosis, and 37 underwent reintervention over a 45-month follow-up. We compared the outcomes of repetition-DCB for DCB restenosis with those of patients without repetition. The baseline patient and lesion characteristics were similar between groups. The mean lesion length was 200.8±113.1 and 195.2±134.6 mm, P=0.894, respectively. In addition, the procedural and follow-up outcomes were not different. The rates of freedom from binary restenosis (70% vs. 14%, P=0.001) and clinically driven target lesion revascularization (CD-TLR) (78% vs. 38%, P=0.026) at 1 year were statistically different between groups. Cox regression analysis showed that repetition of DCB was the only predictor for freedom from binary restenosis (hazard ratio [HR]: 6.15, 95% confidence interval (CI) 1.60 to 23.6, P=0.008) and CD-TLR (HR: 5.37, 95% CI 1.32-22.0, P=0.019). CONCLUSIONS: For FP DCB restenosis, repetition of DCB can potentially improve vessel patency and significantly reduce the need for reintervention compared with conventional treatment. However, these observations require further confirmation in larger scale studies.

Growth Differentiation Factor 15 May Predict Mortality of Peripheral and Coronary Artery Diseases and Correlate with Their Risk Factors.

Plasma GDF15 concentrations were measured in 612 Taiwanese individuals without overt systemic disease. Clinical parameters, GDF15 genetic variants, and 22 biomarker levels were analyzed. We further enrolled 86 patients with PAD and 481 patients with CAD, who received endovascular intervention and coronary angiography, respectively, to examine the role of GDF15 level in predicting all-cause mortality. Significant associations were found between GDF15 genotypes/haplotypes and GDF15 levels. The circulating GDF15 level was positively associated with age, smoking, hypertension, and diabetes mellitus as well as circulating levels of lipocalin 2 and various biomarkers of inflammation and oxidative stress. Kaplan-Meier survival analysis showed that baseline GDF15 levels of above 3096 pg/mL and 1123 pg/mL were strong predictors of death for patients with PAD and CAD, respectively (P = 0.011 and P < 0.001). GDF15 more accurately reclassified 17.3% and 29.2% of patients with PAD and CAD, respectively (P = 0.0046 and P = 0.0197), compared to C-reactive protein. Both genetic and nongenetic factors, including cardiometabolic and inflammatory markers and adipokines, were significantly associated with GDF15 level. A high level of GDF15 was significantly associated with an increase of all-cause mortality in patients with high-risk PAD and in patients with angiographically documented CAD.