Hyun-Young Lee

CysLTR1 promoter polymorphism and requirement for leukotriene receptor antagonist in aspirin-intolerant asthma patients

OBJECTIVESnLeukotriene receptor antagonists (LTRA), such as montelukast, have been used as a first-line treatment for patients with aspirin-intolerant asthma (AIA). This study evaluated associations between the clinical requirement for LTRA and genetic polymorphisms of the ALOX5, LTC4S, COX-2, CysLTR1 and TBXA2R genes in the arachidonic acid cascade in the long-term management of 89 AIA patients from a Korean population.nnnMETHODSnAsthma control status was monitored for 1 year with maintenance medications of inhaled corticosteroid and oral LTRA, and AIA patients were classified into three groups according to the mean montelukast dose required per month to maintain asthma control for 1 year: group I (> or = 200 mg montelukast/month; n = 37), group II (5-150 mg/month; n = 25) and group III (< 5 mg/month; n = 27). Genetic polymorphisms in the arachidonic acid cascade were determined using a single-base extension method.nnnRESULTSnWe found that there was a significant difference in the genotype frequency of the CysLTR1 promoter polymorphism -634C > T among the three groups (p = 0.007 for group I vs group II, p = 0.017 for group I vs group III), while there were no significant associations between LTRA requirements and polymorphisms of the other genes. The patients with the variant genotype (CT or TT) of the -634C = T CysLTR1 promoter polymorphism showed a higher expression level than those with the common genotype (CC).nnnCONCLUSIONnThese findings indicate that the CysLTR1 promoter polymorphism is a useful genetic marker for predicting LTRA requirements in the long-term management of AIA patients.

Differential Contribution of the CysLTR1 Gene in Patients with Aspirin Hypersensitivity

In this study, we compared the roles of CysLT receptor type 1 (CysLTR1) and leukotriene C4 synthase (LTC4S) gene polymorphisms in two major aspirin-related allergic diseases, aspirin-intolerant asthma (AIA) and aspirin-induced chronic urticaria/angioedema (AICU). CysLTR1-634C>T and LTC4S-444A>C polymorphisms were genotyped and its functional effect on the promoter activity was compared. As in vivo functional study, changes of peripheral mRNA level of CysLTR1 were measured by real-time PCR before and after aspirin challenge. A significant association was found for the CysLTR1 promoter polymorphism and the AIA phenotype compared to AICU (Pu2009=u20090.015). In U937 cells, the variant genotype reporter construct showed significantly higher promoter activity than the common genotype (Pu2009<u20090.05). The CysLTR1 mRNA levels increased significantly after aspirin challenge in AIA patients (Pu2009=u20090.013). In conclusion, the CysLTR1 polymorphism may contribute to develop to the AIA phenotype and be used as a genetic marker for differentiating two major aspirin hypersensitivity phenotypes.

Association of Four-locus Gene Interaction with Aspirin-intolerant Asthma in Korean Asthmatics

IntroductionAspirin-intolerant asthma (AIA), a major clinical presentation of aspirin hypersensitivity, affects 10% of adult asthmatics. The genetic risk factors involved in the susceptibility to AIA have recently been investigated, but multilocus single-nucleotide polymorphisms (SNPs) associated with this susceptibility has not been evaluated.MethodsWe examined 246 asthmatic patients: 94 having aspirin intolerance and 152 having aspirin tolerance. We selected 23 SNPs of 13 candidate genes and genotyped each SNP using a primer extension method. Multilocus genetic interactions were examined using multifactor dimensionality reduction (MDR) to test all multilocus SNP combinations to identify a useful SNP set for predicting the AIA phenotype.ResultsWe identified the best model using the MDR method, which consisted of a four-locus gene–gene interaction with 65.16% balanced accuracy and a cross-validation consistency of 70% in predicting AIA disease risk among asthmatic patients. This model included four SNPs such as B2ADR 46A>G, CCR3–520T>G, CysLTR1–634C>T, and FCER1B–109T>C.DiscussionThese results suggest that a multilocus SNP acts in combination to influence the susceptibility to aspirin intolerance in asthmatics and could be a useful genetic marker for the diagnosis of AIA.

Effect of DA-9701, a novel prokinetic agent, on stress-induced delayed gastric emptying and hormonal changes in rats

Backgroundu2002 DA‐9701 is a novel prokinetic agent formulated with Pharbitis Semen and Corydalis Tuber. This study aimed to evaluate the effect of DA‐9701 on stress‐induced delay in gastric emptying and changes in plasma adrenocorticotropic hormone and ghrelin levels in rats.

Effect of β2-Adrenergic Receptor Polymorphism in Asthma Control of Patients Receiving Combination Treatment

Purpose Combination treatment of inhaled corticosteroid (ICS) plus long-acting β2-agonist (LABA) is widely used as a maintenance regimen for the management of asthma. This study evaluated the effect of the β2-adrenergic receptor (ADRB2) polymorphism on lung function and asthma control with regular use of combination treatment of an inhaled ICS plus LABA. Materials and Methods 43 Korean asthmatics who were symptomatic despite regular ICS use for at least 3 months were enrolled. For a 2-week run-in period, they received ICS (budesonide 800 µg/day) plus terbutaline (5 µg prn). as needed. During the 24-week active treatment period, they received budesonide 160 µg and formoterol 4.5 µg b.i.d. as maintenance and rescue medication. Pulmonary function and quality of life scores were monitored every 8 weeks; morning/evening peak expiratory flow meter (PEFR) was recorded daily. Patients were genotyped for ADRB2 Arg16Gly using single base extension methodology. Results During the run-in period, there were no significant between-group differences in lung function; after 8 weeks of active treatment, Arg/Arg patients had significantly higher forced expiratory volume in 1 secord (FEV1) and maximal mid-expiratory flow (MMEF) (p = 0.023 and p = 0.021, respectively), and better asthma control and quality of life after 24 weeks (p = 0.016 and p = 0.028, respectively). During treatment, there was a greater improvement in morning/evening PEFR in Arg/Arg patients. Conclusion Asthmatic patients with the Arg/Arg genotype at codon 16 of ADRB2 achieve better asthma control with long-term regular use of combined budesonide and formoterol treatment, suggesting that the ADRB2 genotype may dictate choice of treatment strategy.

Inter-alpha-trypsin inhibitor heavy chain H4 as a diagnostic and prognostic indicator in patients with hepatitis B virus-associated hepatocellular carcinoma.

OBJECTIVESnInter-alpha-trypsin inhibitor heavy chain H4 (ITIH4) is associated with various diseases. We evaluated the diagnostic and prognostic significance of serum ITIH4 levels in healthy controls and patients with chronic hepatitis B (CHB), hepatitis B virus (HBV)-related liver cirrhosis, and HBV-related hepatocellular carcinoma (HCC).nnnDESIGN AND METHODSnThe study enrolled 300 individuals (50 healthy controls, 50 with CHB, 100 with HBV-associated cirrhosis, and 100 with HBV-associated HCC). Serum ITIH4 levels were determined by western blot analysis and expressed in densitometry units (DU).nnnRESULTSnITIH4 levels were higher in CHB (mean: 252.96 DU) and liver cirrhosis (mean: 206.43 DU) patients than in healthy controls (mean: 75.92 DU) and HCC patients (mean: 92.86 DU) (P<0.001). The area under the receiver operating characteristic curve was 0.71 for the diagnosis of HCC in patients with HBV-related liver disease. Multivariate Cox regression analysis showed that large tumor size (≥5 cm) was independently associated with overall survival (hazard ratio 5.894, 95% confidence interval 1.373-25.300, P=0.017). A Kaplan-Meier survival analysis showed significantly worse survival among HCC patients with both low ITIH4 (<80 DU) and a large tumor size compared to that among other HCC patients (P<0.001), and among patients with high AFP (>200 ng/mL) and low ITIH4 compared to that among other HCC patients (P=0.041).nnnCONCLUSIONSnSerum ITIH4 levels are reduced in HCC patients compared to that in CHB and cirrhosis patients, and low serum ITIH4 levels are associated with shorter survival in HBV-associated HCC patients.

Genetic polymorphisms in the Wnt/β-catenin pathway genes as predictors of tumor development and survival in patients with hepatitis B virus-associated hepatocellular carcinoma

OBJECTIVESnWnt/β-catenin signaling has a pivotal role in the pathogenesis of hepatocellular carcinoma (HCC). The present study aimed to determine whether genetic variation in the Wnt/β-catenin signaling pathway is associated with the development and/or progression of HCC and the survival of patients with hepatitis B virus (HBV)-associated HCC.nnnDESIGN AND METHODSnWe assessed seven single nucleotide polymorphisms (SNPs) of the AXIN1, AXIN2, CTNNB1, and WNT2 genes in 245 patients with HBV-associated HCC and 483 chronic HBV carriers without HCC. We analyzed the association of each SNP with HCC development or progression and overall survival.nnnRESULTSnThe CTNNB1 rs3864004 A allele was associated with a decreased risk of HCC development (P=0.049). Haplotype analysis revealed a significantly higher frequency of CTNNB1 G-A/G-A haplotype at rs3864004 and rs4135385 positions in patients with HCC than in chronic HBV carriers without HCC (P=0.042). The AXIN1 rs1805105 T>C SNP was associated with small tumor size and early tumor stage and the WNT2 rs39315 G allele was associated with advanced tumor stage in HCC. In Kaplan-Meier analysis, carriers of the AXIN1 rs214252 C allele showed longer survival than those with the TT genotype (P=0.020). In multivariate Cox regression analysis, absence of CTNNB1 haplotype A-A at rs3864004 and rs4135385 positions and advanced tumor stage were independent poor predictors of patient survival in patients with HCC.nnnCONCLUSIONnThese findings suggest that the genetic polymorphisms in CTNNB1 gene might affect tumor development and survival in patients with HBV-associated HCC.

Altered Systemic Adipokines in Patients with Chronic Urticaria

Background: Increasing evidence suggests that adipokines affect immune responses and chronic urticaria (CU) is associated with an altered immune response related to chronic systemic inflammation. Our objectives were to investigate whether adipokines are involved in CU pathogenesis and to outline relationships between adipokines and urticaria severity and quality of life. Methods: Serum adiponectin, leptin, lipocalin-2 (LCN2), interleukin (IL)-10, IL-6, and tumor necrosis factor (TNF)-α concentrations were measured by enzyme-linked immunosorbent assays in 191 CU patients and 89 healthy controls. The effect of LCN2 on N-formyl-methionine-leucine-phenylalanine (fMLP)-induced neutrophil chemotaxis was assessed using migration assays. CU severity was assessed based on the urticaria activity score (UAS). To explore relationships between adipokines and UAS and the chronic urticaria-specific quality of life (CU-QoL) questionnaire, a structural equation model was used. Results: Mean levels of serum LCN2, TNF-α, IL-6, and IL-10 were significantly higher in CU patients than in controls. Adiponectin levels were significantly lower in patients with CU than in controls. While serum IL-6 levels were significantly higher in refractory CU patients, compared to responsive CU individuals, LCN2 levels were significantly lower. LCN2 inhibited fMLP-induced neutrophil migration. LCN2 showed a direct relationship with UAS (β = -0.274, p < 0.001), and UAS was found to contribute to CU-QoL (β = 0.417, p < 0.001). Conclusions: Our results highlighted an imbalance in pro- and anti-inflammatory adipokines in CU patients. We suggest that LCN2 could be a differential marker for disease activity and the clinical responses to antihistamine treatment in CU patients. Modulation of systemic inflammation may be a therapeutic strategy for treating severe, refractory CU.

Epidemiology of Chronic Urticaria in Korea Using the Korean Health Insurance Database, 2010-2014

Purpose There are very few epidemiological studies on chronic urticaria (CU). We aimed to investigate the prevalence of CU and to depict demographics and medication patterns for the disease in a nationwide population-based study. Methods Data on urticaria (L50 of the International Classification of Diseases, 10th revision) from 2010 to 2014 were obtained from the Korean Health Insurance Review and Assessment Service. Algorithms designed to evaluate prescription drug claims for antihistamines were applied to identify CU. Results The crude prevalence of CU was 2,256.5 per 100,000 person-years and tended to increase every year. The age-standardized prevalence of CU was significantly higher in females than in males (2,466.8 vs 1,819.2 per 100,000 person-years, P<0.001). Age-specific prevalence was highest for older adults over the age of 65 years and lowest for ages 10-29 years. The median duration of CU was 591 days, and symptoms lasted for at least 1 year in 61.9% of patients. Gastrointestinal disease was the most common comorbidity in adults, whereas allergic rhinitis and common cold were more prevalent in children with CU. Around a third of CU patients were taking antihistamine treatment alone, and 70% were treated with both antihistamines and systemic corticosteroids. Cyclosporine was prescribed for 0.02% of CU patients. Conclusions The present study outlines recent longitudinal epidemiological data on the prevalence of CU in Korea. In light of limitations on the use of claims data, including no specific disease code for CU and a possible discordance between drug claims and the presence of urticaria symptoms, further investigations are necessary to describe the exact epidemiologic profile of CU patients.

No effect of the estrogen receptor α gene polymorphisms in the etiology of precocious puberty in girls.

Estrogen plays a crucial role in the development and function in reproductive physiology. Estrogens regulate cellular activity through binding to estrogen receptor α (ERα) and β (ERβ). ERα polymorphisms have been associated with changes in age at menarche, menopause onset, and fertility. The aim of this study is to investigate the relationship of ERα gene polymorphisms with central precocious puberty (CPP) in girls. Two hundred and one (201) Korean girls with idiopathic CPP were included in this study along with 100 healthy Korean female adults with pubertal maturation within normal age who served controls. Auxological and endocrine parameters were measured, and both patients and controls were genotyped for PvuII (397 T→C) and XbaI (351 A→G) polymorphisms in the ERα gene. A significantly lower incidence of the CC genotype with PvuII polymorphism were noted among CPP girls than controls (11.9% vs. 22%, P=0.021). However, the clinical parameters did not differ among the 3 genotypes. In addition, there was no significant difference in patients with the XbaI polymorphism compared to controls. The present study reveals that neither PvuII nor XbaI polymorphisms in the ERα gene are associated with onset and progression of puberty. However, further studies are needed to validate the exact function of these polymorphisms.