Won-Kee Lee

Serum irisin levels in new-onset type 2 diabetes

AIMS Irisin has been identified as a novel myokine that drives brown-fat-like conversion of white adipose tissue. In this cross-sectional study, we investigated whether serum irisin levels are decreased in patients with type 2 diabetes (T2D) compared with control subjects with normal glucose tolerance (NGT), and assessed the association between serum irisin levels and various metabolic parameters. METHODS The study population was selected from a population-based study and included 104 subjects with NGT and 104 subjects with new-onset T2D. Serum irisin and adiponectin levels and metabolic parameters were measured. Multivariate logistic regression analysis was performed to assess the association between irisin levels and newly diagnosed T2D. RESULTS Serum irisin levels were significantly decreased in the new-onset T2D group compared with the NGT control group (p=0.003). In a multivariable model adjusted for various metabolic parameters, increased irisin levels were associated with reduced odds (OR 0.64, 95% CI 0.47-0.88, p=0.006) of prevalent newly diagnosed T2D. Furthermore, multiple regression analysis showed that 2 h plasma glucose was an independent variable influencing serum irisin levels (p=0.004). CONCLUSION In the present study, we found that serum irisin levels were decreased in T2D patients and inversely associated with newly diagnosed T2D, suggesting that irisin may play a crucial role in glucose intolerance and T2D.

Association of a common AGO1 variant with lung cancer risk: a two-stage case-control study.

Based on the important role of microRNA (miRNA) biosynthesis genes in carcinogenesis, we hypothesized that polymorphisms in the miRNA biosynthesis genes may modulate susceptibility to lung cancer. To test this hypothesis, we conducted a two‐stage study to evaluate the associations between single nucleotide polymorphisms (SNPs) in the miRNA biosynthesis genes and the risk of lung cancer. In stage 1 of the study, 24 SNPs in the 11 miRNA biosynthesis genes (DROSHA, DGCR8, RAN, XPO5, DICER, AGO1, AGO2, HIWI, GEMIN3, GEMIN4, and TRBP) were genotyped in 100 lung cancer patients and 100 healthy controls using a sequenome mass spectrometry‐based genotyping assay. One promising SNP (AGO1 rs636832A > G) was selected for stage 2 of the study, and genotyped by a melting‐curve analysis using fluorescence‐labeled hybridization probes in an independent set of 552 cases and 552 controls. The AGO1 rs636832A > G exhibited highly consistent results between the two stages of the study. In combined analysis, the 636832A > G was associated with a significantly decreased risk of lung cancer in a dose‐dependent manner (Ptrend = 6.0 × 10−4). Individuals with at least one rs636832G allele were at a significantly decreased risk of lung cancer compared with those with the AA genotype (adjusted odds ratio = 0.67, 95% confidence interval = 0.53–0.84, P = 4.0 × 10−4). This finding suggests that the AGO1 rs636832A > G might be a useful marker for determining the susceptibility to lung cancer and that the AGO1 gene might be involved in the development of lung cancer.

Polymorphisms in the CASPASE Genes and Survival in Patients With Early-Stage Non–Small-Cell Lung Cancer

PURPOSE This study was conducted to determine the impact of potentially functional polymorphisms in the CASPASE (CASP) genes on the survival of early-stage non-small-cell lung cancer (NSCLC) patients. PATIENTS AND METHODS Four hundred eleven consecutive patients with surgically resected NSCLC were enrolled. Nine potentially functional polymorphisms in the CASP3, CASP7, CASP8, CASP9, and CASP10 genes were investigated. The genotype and haplotype associations with overall survival (OS) and disease-free survival (DFS) were analyzed. RESULTS Patients with the rs2227310 GG genotype had a significantly decreased OS and DFS compared with patients with the CC + CG genotype (adjusted hazard ratio [aHR] for OS, 1.67; 95% CI, 1.19 to 2.35; P = .003; aHR for DFS, 1.62; 95% CI, 1.19 to 2.22; P = .002). The rs4645981C>T genotype also had a significant effect on OS and DFS (under a recessive model; aHR for OS, 2.00; 95% CI, 1.04 to 3.85; P = .04; aHR for DFS, 2.76; 95% CI, 1.58 to 4.80; P = .0003). When the rs2227310 and rs4645981 genotypes were combined, patients with one or two bad genotypes had worse OS and DFS compared with those who had zero bad genotypes (aHR for OS, 1.75; 95% CI, 1.25 to 2.45; P = .001; aHR for DFS, 1.66; 95% CI, 1.23 to 2.26; P = .001). CONCLUSION The CASP7 rs2227310 and CASP9 rs4645981 polymorphisms may affect survival in early-stage NSCLC. The analysis of these polymorphisms can help identify patients at high risk for a poor disease outcome.

Polymorphisms in Matrix Metalloproteinase-1, -9 and -12 Genes and the Risk of Chronic Obstructive Pulmonary Disease in a Korean Population

Background: Although a few studies have been conducted to evaluate the association of polymorphisms in matrix metalloproteinase (MMP) genes with chronic obstructive pulmonary disease (COPD), the results have been inconsistent. Objectives: To investigate the association of 3 polymorphisms of MMP genes (MMP-1 –1607G→GG, MMP-9 –1562C→T and MMP-12 N357S), which have been reported to be associated with COPD-related phenotypes, with the risk of COPD in a Korean population. Methods: The genotypes of the 3 polymorphisms were determined in 301 patients with COPD and 333 healthy controls. Results: Of the 3 polymorphisms studied, only the distribution of the MMP-9 –1562C→T genotypes was significantly different between the cases and controls (p = 0.01), with the frequency of the variant T allele being significantly lower in the cases than in the controls (10.4 vs. 15.7%; p = 0.006). Individuals with at least 1 variant T allele were at a significantly decreased risk of COPD when compared with those with homozygous wild-type alleles (adjusted odds ratio = 0.69; 95% CI = 0.45–0.98; p = 0.04). Conclusions: These findings suggest that the MMP-9 –1562C→T polymorphism could be used as a marker for determining the genetic susceptibility to COPD in a Korean population.

Prognostic implications of computed tomographic right ventricular dilation in patients with acute pulmonary embolism

INTRODUCTION Whether right ventricular (RV) dilation on computerized tomography (RVD-CT) is a useful predictor for clinical outcomes of acute pulmonary embolism (PE) remains debatable. Furthermore, data regarding the best combination of prognostic markers for predicting the adverse outcome of PE are limited. MATERIALS AND METHODS The authors retrospectively reviewed 657 consecutive patients hospitalized at a tertiary referral center with a diagnosis of PE based on multi-detector row CT scan. RESULTS Patients were allocated into an adverse outcome group (11% [n = 69]) or a low risk group (89% [n = 588]). Multivariate analysis showed that RVD-CT (RV/left ventricle [LV] diameter ratio ≥ 1), high pulmonary embolism severity index (PESI) score (class IV-V), high N-terminal-pro-B-type natriuretic peptide (NT-proBNP,≥ 1,136 pg/ml), and elevated troponin I (≥ 0.05 ng/ml) significantly predicted an adverse outcome (odds ratio [OR] 6.26, 95% confidence interval [CI] 2.74-14.31, p < 0.001; OR 4.71, 95% CI 2.00-11.07, p < 0.001; OR 2.71, 95% CI 1.15-6.39, p = 0.023; and OR 3.00, 95% CI 1.27-7.07, p = 0.012, respectively). The addition of RVD-CT to PESI, NT-proBNP, troponin I or their combinations enhanced the positive predictive values and positive likelihood ratios of an adverse outcome. CONCLUSIONS RVD-CT could be an independent prognostic factor of adverse outcomes in patients with acute PE, and provides additional prognostic value when combined with other prognostic factors.

AKT1 polymorphisms and survival of early stage non-small cell lung cancer†

This study was conducted to investigate the impact of polymorphisms in the AKT1 gene on the survival of early stage non‐small cell lung cancer (NSCLC) patients.

Estrogen-Related Receptor γ Plays a Key Role in Vascular Calcification Through the Upregulation of BMP2 Expression

Objective—Vascular calcification which refers to ectopic mineralization in vascular cells is associated with several conditions, such as chronic kidney disease, atherosclerosis, and diabetes mellitus. Estrogen-related receptor (ERR)&ggr; is a member of the orphan nuclear receptor superfamily, which plays diverse roles in regulating homeostatic and metabolic processes. However, the role of ERR&ggr; in vascular calcification has not been investigated to date. The aim of the present study was to examine the role of ERR&ggr; in vascular calcification. Approach and Results—Vascular calcification was induced by treating rat aortic vascular smooth muscle cells with calcification medium. ERR&ggr; expression in vascular smooth muscle cells was induced during calcification medium–induced vascular calcification. Adenovirus-mediated overexpression of ERR&ggr; in vascular smooth muscle cells resulted in the upregulation of the expression of osteogenic genes, including runt-related transcription factor 2, osteopontin, and Msx2, and the downregulation of &agr;-smooth muscle actin. Adenovirus-mediated overexpression of ERR&ggr; induced bone morphogenetic protein 2 (BMP2) expression, leading to increased phosphorylation of the intracellular BMP2 effector proteins SMAD1/5/8. Collectively, these data suggested that ERR&ggr; promotes dedifferentiation of vascular smooth muscle cells to an osteogenic phenotype during the vascular calcification process. Inhibition of endogenous ERR&ggr; expression or activity using a specific siRNA or the selective inverse agonist GSK5182 attenuated vascular calcification and osteogenic gene expression in vitro and in vivo. Conclusions—The present results indicate that ERR&ggr; plays a key role in vascular calcification by upregulating the BMP2 signaling pathway, suggesting that inhibition of ERR&ggr; is a potential therapeutic strategy for the prevention of vascular calcification.

Dual roles of a variable number of tandem repeat polymorphism in the TERT gene in lung cancer

This study was conducted to determine the impact of a functional tandem repeat minisatellite (MNS16A) polymorphism in the telomerase reverse transcriptase (TERT) gene on the risk of lung cancer, as well as on survival of patients with non‐small‐cell lung cancer (NSCLC). The effect of the MNS16A variable number of tandem repeat (VNTR) polymorphism on the risk of lung cancer was evaluated in a case–control study that consisted of 937 lung cancer patients and 943 healthy controls. The effect of the polymorphism on survival outcome was evaluated in 703 patients with surgically resected NSCLC. Compared with the VNTR‐302 allele, the VNTR‐243 allele was associated with a significantly increased risk of lung cancer (adjusted odds ratio, 1.55; 95% confidence interval [CI], 1.07–2.25; P = 0.02). In addition, the genotypes carrying at least one VNTR‐243 allele were associated with a significantly increased risk of lung cancer compared with the genotypes with no VNTR‐243 allele (adjusted odds ratio, 1.61; 95% CI, 1.09–2.38; P = 0.02). In contrast to the effect of the polymorphism on the risk of lung cancer, the genotypes carrying at least one VNTR‐243 allele were associated with a significantly better overall survival in patients with surgically resected NSCLC (adjusted hazard ratio, 0.51; 95% CI, 0.28–0.93; P = 0.03). These findings suggest that the MNS16A VNTR polymorphism in the TERT gene has dual, conflicting roles in lung carcinogenesis. This polymorphism may increase the risk of lung cancer development, and may improve survival in lung cancer patients. (Cancer Sci 2011; 102: 144–149)

Polymorphisms in the FAS and FASL Genes and Survival of Early Stage Non–small Cell Lung Cancer

Purpose: This study was conducted to investigate the impact of functional polymorphisms in the FAS and FASL genes on the survival of early stage non–small cell lung cancer (NSCLC) patients. Experimental Design: Three hundred and thirty-eight consecutive patients with surgically resected NSCLC were enrolled. The FAS -1377G>A (rs2234767) and -670A>G (rs1800682) and FASL -844C>T (rs763110) polymorphisms were investigated. Immunohistochemistry was used to assess FAS protein expression in tumors. The genotype and haplotype associations with survival were analyzed using Cox proportional hazards model, Kaplan-Meier method, and the log-rank test. Results: Patients with the GG and combined AG + GG genotypes of the FAS -670A>G locus had a significantly decreased survival when compared with patients with the AA genotype [adjusted hazard ratio = 1.71, 95% confidence interval (95% CI) = 1.06-2.77, and P = 0.03; and adjusted hazard ratio = 1.48, 95% CI = 1.01-2.20, and P = 0.047, respectively]. In addition, the FAS -1377G/-670G and -1377A/-670G haplotypes exhibited a significantly lower survival compared with the -1377G/-670A haplotype (adjusted hazard ratio = 1.87, 95% CI = 1.20-2.91, and P = 0.006; and adjusted hazard ratio = 1.31, 95% CI = 1.05-1.65, P = 0.02, respectively). Strongly positive FAS immunostaining was significantly less frequent in patients with the FAS -670 AG + GG genotype than in patients with the -670 AA genotype (4.5% versus 10.8%; P = 0.04). Conclusion: The FAS -670A>G polymorphism may affect survival in early-stage NSCLC. The analysis of the FAS -670A>G polymorphism can help identify patients at high risk for a poor disease outcome.

A genetic variation in microRNA target site of KRT81 gene is associated with survival in early stage non-small cell lung cancer

BACKGROUND MicroRNAs (miRNAs) have a key role in carcinogenesis through negative regulation of their target genes. Therefore, genetic variations in miRNAs or their target sites may affect miRNA-mRNA interactions, thereby result in altered expression of target genes. This study was conducted to investigate the associations between single-nucleotide polymorphisms (SNP) located in the miRNA target sites (poly-miRTSs) and survival of patients with early-stage non-small-cell lung cancer (NSCLC). METHODS Using public SNP database and miRNA target sites prediction program, 354 poly-miRTSs were selected for genotyping. Among these, 154 SNPs applicable to Sequenoms MassARRAY platform were investigated in 357 patients. A replication study was carried out on an independent patient population (n = 479). Renilla luciferase assay and reverse transcription-polymerase chain reaction were conducted to examine functional relevance of potentially functional poly-miRTSs. RESULTS Of the 154 SNPs analyzed in a discovery set, 14 SNPs were significantly associated with survival outcomes. Among these, KRT81 rs3660G>C was found to be associated with survival outcomes in the validation cohort. In the combined analysis, patients with the rs3660 GC + CC genotype had a significantly better overall survival compared with those with GG genotype [adjusted hazard ratio (aHR) for OS, 0.65; 95% confidence interval (CI) 0.50-0.85; P = 0.001]. An increased expression of the reporter gene for the C allele of rs3660 compared with the G allele was observed by luciferase assay. Consistently, the C allele was associated with higher relative expression level of KRT81 in tumor tissues. CONCLUSION The rs3660G>C affects KRT81 expression and thus influences survival in early-stage NSCLC. The analysis of the rs3660G>C polymorphism may be useful to identify patients at high risk of a poor disease outcome.BACKGROUND MicroRNAs (miRNAs) have a key role in carcinogenesis through negative regulation of their target genes. Therefore, genetic variations in miRNAs or their target sites may affect miRNA-mRNA interactions, thereby result in altered expression of target genes. This study was conducted to investigate the associations between single-nucleotide polymorphisms (SNP) located in the miRNA target sites (poly-miRTSs) and survival of patients with early-stage non-small-cell lung cancer (NSCLC). METHODS Using public SNP database and miRNA target sites prediction program, 354 poly-miRTSs were selected for genotyping. Among these, 154 SNPs applicable to Sequenoms MassARRAY platform were investigated in 357 patients. A replication study was carried out on an independent patient population (n = 479). Renilla luciferase assay and reverse transcription-polymerase chain reaction were conducted to examine functional relevance of potentially functional poly-miRTSs. RESULTS Of the 154 SNPs analyzed in a discovery set, 14 SNPs were significantly associated with survival outcomes. Among these, KRT81 rs3660G>C was found to be associated with survival outcomes in the validation cohort. In the combined analysis, patients with the rs3660 GC + CC genotype had a significantly better overall survival compared with those with GG genotype [adjusted hazard ratio (aHR) for OS, 0.65; 95% confidence interval (CI) 0.50-0.85; P = 0.001]. An increased expression of the reporter gene for the C allele of rs3660 compared with the G allele was observed by luciferase assay. Consistently, the C allele was associated with higher relative expression level of KRT81 in tumor tissues. CONCLUSION The rs3660G>C affects KRT81 expression and thus influences survival in early-stage NSCLC. The analysis of the rs3660G>C polymorphism may be useful to identify patients at high risk of a poor disease outcome.