Young Koo Jee

Carbamazepine-induced severe cutaneous adverse reactions and HLA genotypes in Koreans

BACKGROUND Although the US FDA recommends screening for HLA-B*1502 allele in most of Asian ancestry before initiating carbamazepine therapy, the HLA associations with carbamazepine hypersensitivity in non-Chinese Asian populations remain unclear. This study investigated the association between the HLA class I genotype and carbamazepine-induced severe cutaneous adverse reaction (SCAR) in Koreans. METHODS Twenty-four patients who had developed carbamazepine-induced SCAR (7 Stevens-Johnson syndrome (SJS), 17 drug hypersensitivity syndrome (HSS)), 50 carbamazepine-tolerant controls from the Korean Pharmacogenetic Adverse Drug Reaction Research Network and data of 485 Korean general population from a previously published study were recruited. HLA-A, -B, and -C genotyping was performed by direct DNA sequence analysis. RESULTS Only one of the seven SJS patients was positive for the B*1502 allele, but the frequency of B*1511 was much higher in the patients with CBZ-SJS than in the CBZ-tolerant control patients (P=0.011, P(c)=not significant; OR=18.0(2.3-141.2)). The frequencies of A*3101 in carbamazepine-induced HSS and SCAR were significantly higher than those in carbamazepine-tolerant controls (P(c)=0.011, OR=8.8(2.5-30.7) and P(c)=0.013, OR=7.3(2.3-22.5), respectively). The frequencies of B*1511 in carbamazepine-SJS and A*3101 in carbamazepine-HSS/SCAR were significantly higher than those in the general population. CONCLUSIONS HLA-B*1502 does not seem to be an effective predictive marker for carbamazepine-induced SCAR, while HLA-B*1511 and A*3101 was associated with carbamazepine-induced SJS and HSS/SCAR respectively in the Korean population.

Positive and negative associations of HLA class I alleles with allopurinol-induced SCARs in Koreans.

Recent investigations suggest genetic susceptibility of allopurinol-induced severe cutaneous adverse reactions (SCARs). However, the strength of association was variable according to phenotypes and ethnic backgrounds. To explore genetic markers for allopurinol-induced SCARs in Koreans, we genotyped human leukocyte antigen (HLA) class I alleles of 25 cases of allopurinol-induced SCARs (20 cases of drug-induced hypersensitivity syndrome and five cases of Stevens–Johnson syndrome/toxic epidermal necrolysis) and 57 patients tolerant to allopurinol. Frequencies of B*5801 [92.0 vs. 10.5%, Pc=2.45×10−11, odds ratio (OR)=97.8], Cw*0302 (92.0 vs. 12.3%, Pc=9.39×10−11, OR=82.1), and A*3303 (88.0 vs. 26.3%, Pc=3.31×10−6, OR=20.5) were significantly higher in SCARs compared with tolerant controls. In contrast, A*0201 was not found in SCARs patients despite relatively high frequency in tolerant controls (29.8%). We found strong positive association of HLA-B*5801 and negative association of HLA-A*0201 with the development of allopurinol-induced SCARs in the Korean population.

EVpedia: a community web portal for extracellular vesicles research

MOTIVATION Extracellular vesicles (EVs) are spherical bilayered proteolipids, harboring various bioactive molecules. Due to the complexity of the vesicular nomenclatures and components, online searches for EV-related publications and vesicular components are currently challenging. RESULTS We present an improved version of EVpedia, a public database for EVs research. This community web portal contains a database of publications and vesicular components, identification of orthologous vesicular components, bioinformatic tools and a personalized function. EVpedia includes 6879 publications, 172 080 vesicular components from 263 high-throughput datasets, and has been accessed more than 65 000 times from more than 750 cities. In addition, about 350 members from 73 international research groups have participated in developing EVpedia. This free web-based database might serve as a useful resource to stimulate the emerging field of EV research. AVAILABILITY AND IMPLEMENTATION The web site was implemented in PHP, Java, MySQL and Apache, and is freely available at http://evpedia.info.

High prevalence of current asthma and active smoking effect among the elderly

Background Although asthma is a common cause of morbidity in adults, relatively few objectively measured population studies of asthma prevalence in adult populations have been conducted.

Repression of Interleukin-5 Transcription by the Glucocorticoid Receptor Targets GATA3 Signaling and Involves Histone Deacetylase Recruitment

Glucocorticoids are the mainstay of asthma therapy and mediate the repression of a number of cytokine genes, such as Interleukin (IL)-4, -5, -13, and granulocyte macrophage colony-stimulating factor (GM-CSF), which are central to the pathogenesis of asthmatic airway inflammation. The glucocorticoid receptor (GR) mediates repression by a number of diverse mechanisms. We have previously suggested that one such repressive activity is by direct binding of GR to elements within the GM-CSF enhancer that are recognized by the nuclear factor of activated T cells·activator protein 1 (NF-AT·AP-1) complex. We reasoned that, because many cytokine genes activated in asthma are transcriptionally regulated by the recruitment of this complex to DNA, their binding sites might provide a target for GR to mediate its repressive effects. Here, we show that transcriptional repression of the Interleukin-5 gene involves recruitment of GR to a DNA region located within the IL-5 proximal promoter, which is bound by NF-AT and AP-1 proteins. GR recruitment had a profound effect upon the activation capacity of GATA3, which has a binding site close to the NF-AT·AP-1 domain in both IL-5 and IL-13 promoters. Repression by GR involves co-repressor recruitment, because treatment of transfected cells with the deacetylase inhibitor trichostatin A caused a partial relief of repression. Additionally, repression could be augmented by co-transfection of cells with a histone deacetylase (HDAC1). These data suggest that the local recruitment of GR causes repression by inhibiting transcriptional activation by GATA3, a key tissue-specific determinant of expression of Th2 cytokines.

HLA-B*5901 is strongly associated with methazolamide-induced Stevens-Johnson syndrome/toxic epidermal necrolysis

AIMS The carbonic anhydrase inhibitor methazolamide infrequently causes Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). An association between these diseases and the HLA-B59 serotype has been suggested in case reports. This study examined the disease-associated B*59 allele and investigated the association of these diseases with other HLA class I alleles. METHODS We performed high-resolution HLA-A, -B and -C genotyping in five patients with methazolamide-induced SJS/TEN using a PCR-sequencing-based typing method and analyzed the association between HLA-class I alleles and occurrence of methazolamide-induced SJS/TEN. RESULTS B*5901 and Cw*0102 alleles were observed in all patients and A*2402 was observed in four patients. The B*5901 allele showed the strongest association with methazolamide-induced SJS/TEN (p < 0.001; odds ratio: 249.8; 95% CI: 13.4-4813.5), followed by Cw*0102 (p = 0.004; odds ratio: 22.1; 95% CI: 1.2-414.3), when compared with the general population as a control. The frequency of the patients carrying B*5901, Cw*0102 and A*2402 simultaneously was significantly higher than that in the general population (p < 0.001; odds ratio: 110.1; 95% CI: 11.7-1038.6). CONCLUSION A strong association was observed between HLA-B*5901 and methazolamide-induced SJS/TEN in Korean patients. HLA-B*5901 may be a useful screening marker for predicting methazolamide-induced SJS/TEN in patients of Korean and Japanese ancestry.

Prevalence of childhood asthma based on questionnaires and methacholine bronchial provocation test in Korea

Background In most epidemiological survey studies, only subjective symptoms and past medical history of asthma have been used as diagnostic criteria. Even though a questionnaire survey can be performed in a large population study at low cost, limitations such as lack of objectivity and poor predictability in non‐specific bronchial hyperresponsiveness cannot be avoided.

Association between polymorphisms in prostanoid receptor genes and aspirin-intolerant asthma.

Background Genetic predisposition is linked to the pathogenesis of aspirin-intolerant asthma. Most candidate gene approaches have focused on leukotriene-related pathways, whereas there have been relatively few studies evaluating the effects of polymorphisms in prostanoid receptor genes on the development of aspirin-intolerant asthma. Therefore, we investigated the potential association between prostanoid receptor gene polymorphisms and the aspirin-intolerant asthma phenotype. Methods We screened for genetic variations in the prostanoid receptor genes PTGER1, PTGER2, PTGER3, PTGER4, PTGDR, PTGIR, PTGFR, and TBXA2R using direct sequencing, and selected 32 tagging single nucleotide polymorphisms among the 77 polymorphisms with frequencies >0.02 based on linkage disequilibrium for genotyping. We compared the genotype distributions and allele frequencies of three participant groups (108 patients with aspirin-intolerant asthma, 93 patients with aspirin-tolerant asthma, and 140 normal controls). Results Through association analyses studies of the 32 single nucleotide polymorphisms, the following single nucleotide polymorphisms were found to have significant associations with the aspirin-intolerant asthma phenotype: −616C>G (P=0.038) and −166G>A (P=0.023) in PTGER2; −1709T>A (P=0.043) in PTGER3; −1254A>G (P=0.018) in PTGER4; 1915T>C (P=0.015) in PTGIR; and −4684C>T (P=0.027), and 795T>C (P=0.032) in TBXA2R. In the haplotype analysis of each gene, the frequency of PTGIR ht3[G-G-C-C], which includes 1915T>C, differed significantly between the aspirin-intolerant asthma patients and aspirin-tolerant asthma patients (P=0.015). Conclusion These findings suggest that genetic polymorphisms in PTGER2, PTGER3, PTGER4, PTGIR, and TBXA2R play important roles in the pathogenesis of aspirin-intolerant asthma.

Spider mite allergy in apple-cultivating farmers: European red mite (Panonychus ulmi) and two-spotted spider mite (Tetranychus urticae) may be important allergens in the development of work-related asthma and rhinitis symptoms

BACKGROUND Recent investigations have suggested that the citrus red mite (Panonychus citri) is the most important allergen affecting citrus-cultivating farmers with asthma, allergic rhinitis, or both. OBJECTIVE We sought to evaluate type I hypersensitivity to spider mites, particularly the European red mite (Panonychus ulmi) and the two-spotted spider mite (Tetranychus urticae), and to determine the relationship between hypersensitivity to spider mites and respiratory dysfunction. METHODS We performed a cross-sectional survey. Questionnaires were given, and skin prick tests for 11 inhalant allergens common in Korea and 2 species of spider mites (European red mite and two-spotted spider mite) were performed in 725 apple-cultivating farmers in Korea. RESULTS Results of skin prick tests in the apple farmers indicated that European red mite (23.2%) was the most common sensitizing allergen, followed by Tyrophagus putrescentiae (21.2%), two-spotted spider mite (16.6%), Dermatophagoides farinae (16.3%), D pteronyssinus (14.4%), cockroach (13.1%), and Hop Japanese (Humulus Japonicus) pollen (12.0%). Positive skin responses (mean wheal size >/=3 mm) to one or more of 13 inhalant allergens were found in 48.2% of farmers tested, whereas 40 subjects (8.6%) had an isolated skin response to the spider mites. Among 119 farmers with work-related asthmatic symptoms, the positive skin response rates to European red mite and two-spotted spider mite were 40.4% and 27.0%, respectively. These figures were significantly higher than those found among farmers without work-related symptoms (19.1% and 14.1%, respectively; P <.01). The prevalence of work-related asthma symptoms was higher in farmers with positive skin responses to spider mites than in those with negative skin responses to spider mites and those with positive skin responses to any allergen tested (31.4% vs 15.0% vs 21.0%, respectively; P <.05). CONCLUSION Spider mites, particularly European red mite and 2-spotted spider mite, are common sensitizing allergens in apple-cultivating farmers. These spider mites may be important causative allergens in the development of work-related respiratory symptoms in these workers.

Genetic polymorphisms of drug-metabolizing enzymes and anti-TB drug-induced hepatitis

AIMS Although some genetic risk factors have been reported for the development of hepatitis due to anti-TB drugs, an extensive candidate gene approach evaluating drug-metabolizing enzymes has not been attempted. This study aimed to investigate the association of genetic polymorphisms in drug-metabolizing enzymes with anti-TB drug-induced hepatitis. MATERIALS & METHODS We compared genotype distributions of tagging SNPs in promoter, exons and haplotypes in seven drug-metabolizing enzyme genes (CYP2C9, CYP2C19, CYP2D6, CYP2E1, NAT2, UGT1A1 and UGT1A3) between 67 cases and 159 controls. RESULTS Among four tagging SNPs of N-acetyltransferase 2 (NAT2), -9796T>A in promoter and R197Q were significantly associated (p = 0.0016 and p = 0.0007, respectively). NAT2 haplotype 2 [A-A-A-G] carrying A allele of -9796T>A and A allele of R197Q showed significant association (p = 0.0004). However, there was no significant association between genotypes of other enzyme-metabolizing genes and anti-TB drug-induced hepatitis. The constructs containing -9796A of NAT2 showed significantly lower luciferase activity (p < 0.01), suggesting decreased expression of NAT2. The variant alleles and haplotype 2 showed significantly higher peak serum levels of isoniazid, lower acetyl isoniazid:isoniazid ratio and lower isoniazid clearance compared with wild-types. CONCLUSION These findings suggest that genetic variants in the promoter and exons of NAT2 increase the risk of anti-TB drug-induced hepatitis by modifying acetylation phenotypes and/or gene expression of NAT2, and there is no essential role for genetic mutation of the other metabolizing enzymes in the development of this adverse reaction.