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Ko S.-Y.,University of Ulsan | Oh H.-B.,University of Ulsan | Park C.-W.,University of Ulsan | Lee H.C.,University of Ulsan | Lee J.-E.,DNA Link
Clinical Microbiology and Infection | Year: 2012

Direct sequencing and reverse hybridization are currently the main methods for detecting drug-resistance mutations of hepatitis B virus (HBV). However, these methods do not enable haplotype analysis so they cannot be used to determine whether the mutations are co-located on the same viral genome. This limits the accurate identification of viral mutants that are resistant to drugs with a high genetic barrier. In our current study, ultra-deep pyrosequencing (UDPS) was used to detect HBV drug-resistance mutations in 25 entecavir-treated and five treatment-naive patients. Of the 25 entecavir-treated patients, 18 had experienced virological breakthrough and two exhibited reduced susceptibility to entecavir. The results obtained by UDPS were compared with those of direct sequencing, and the haplotypes of the drug-resistant HBV mutants were analysed. The average number of reads per patient covering the region in which drug-resistance mutations are located was 1735 (range 451-4526). UDPS detected additional drug-resistance mutations not detected by direct sequencing in 19 patients (mutation frequency range 1.1-23.8%). Entecavir-resistance mutations were found to be co-located on the same viral genome in all 20 patients displaying virological breakthrough or reduced susceptibility to entecavir. In conclusion, UDPS was not only sensitive and accurate in identifying drug-resistance mutations of HBV but also enabled haplotype analysis of the mutants. This method may offer significant advantages in explaining and predicting the responses of patients with HBV to antiviral therapy. © 2012 The Authors. Clinical Microbiology and Infection © 2012 European Society of Clinical Microbiology and Infectious Diseases.

Kim J.-J.,University of Ulsan | Lee H.-I.,University of Ulsan | Park T.,Seoul National University | Kim K.,Seoul National University | And 8 more authors.
Journal of Human Genetics | Year: 2010

Height is a complex genetic trait that involves multiple genetic loci. Recently, 44 loci associated with height were identified in Caucasian individuals by large-scale genome-wide association (GWA) studies. To identify genetic variants influencing height in the Korean population, we analyzed GWA data from 8842 Korean individuals and identified 15 genomic regions with one or more sequence variants associated with height (P<1 × 10-5). Of these, eight loci were newly identified in Koreans (SUPT3H, EXT1, FREM1, PALM2-AKAP2, NUP37-PMCH, IGF1, KRT20 and ANKRD60). The 15 significant loci account for approximately 1.0% of height variation, with a 3.7-cm difference between individuals with ≤8 height-increasing alleles (5.1%) and ≥19 height-increasing alleles (4.2%). We also examined the associations between height loci and idiopathic short stature (ISS). Five loci (SPAG17, KBTBD8, HHIP, HIST1H1D and ACAN) were significantly associated with ISS (uncorrected P<0.05), indicating that height-associated genes in the adult population are involved in extreme cases of short stature in children. This study validates previous reports of loci associated with human height and identified novel candidate regions involved in human growth and development. © 2010 The Japan Society of Human Genetics. All rights reserved.

Kim J.-J.,University of Ulsan | Hong Y.M.,Ewha Womans University | Sohn S.,Ewha Womans University | Jang G.Y.,Korea University | And 20 more authors.
Human Genetics | Year: 2011

Kawasaki disease (KD) is an acute self-limited vasculitis of infants and children that manifests as fever and signs of mucocutaneous inflammation. Coronary artery aneurysms develop in approximately 15-25% of untreated children. Although the etiology of KD is largely unknown, epidemiologic data suggest the importance of genetic factors in the susceptibility to KD. In order to identify genetic variants that influence KD susceptibility, we performed a genome-wide association study (GWAS) using Affymetrix SNP array 6.0 in 186 Korean KD patients and 600 healthy controls; 18 and 26 genomic regions with one or more sequence variants were associated with KD and KD with coronary artery lesions (CALs), respectively (p < 1 × 10-5). Of these, one locus on chromosome 1p31 (rs527409) was replicated in 266 children with KD and 600 normal controls (odds ratio [OR] = 2.90, 95% confidence interval [CI] = 1.85-4.54, P combined = 1.46 × 10-6); and a PELI1 locus on chromosome 2p13.3 (rs7604693) was replicated in 86 KD patients with CALs and 600 controls (OR = 2.70, 95% CI = 1.77-4.12, P combined = 2.00 × 10-6). These results implicate a locus in the 1p31 region and the PELI1 gene locus in the 2p13.3 region as susceptibility loci for KD and CALs, respectively. © 2011 Springer-Verlag.

Yoon K.-A.,Research Institute and Hospital | Park J.H.,Research Institute and Hospital | Han J.,Research Institute and Hospital | Park S.,National Cancer Control Research Institute | And 9 more authors.
Human Molecular Genetics | Year: 2010

Lung cancer is one of the most common cancers and the major cause of cancer death, both in Korea and worldwide, with non-small cell lung cancer (NSCLC) as the predominant histologic type. To identify genetic risk factors, we here conducted a genome-wide association study (GWAS) and a replication study in 1425 patients with NSCLC and 3011 controls from Korea. From the data for 2162 participants analyzed using the Affymetrix Genome-wide Human SNP array 5.0K, 168 single nucleotide polymorphisms (SNPs) were selected for validation. In the second stage, we were able to genotype 168 SNPs in 804 patients and 1470 controls to confirm the results of the GWAS. In the meta-analysis, rs2131877 at the chromosome 3q29 region was the most significant biomarker of lung cancer susceptibility in Koreans (P = 2.43 × 10-8). Four markers that were located within the chromosome 3q29 region were also associated with lung cancer susceptibility (trend P < 1.2 × 10-4), along with markers on 5p15 that were previously reported in populations of European descent. This high-density large-scale GWAS carried out in the Korean population suggests that 3q29 is a novel susceptibility region associated with lung cancer susceptibility in Koreans. © The Author 2010. Published by Oxford University Press. All rights reserved.

Ryu J.-S.,Inha University | Shin E.-S.,DNA Link | Nam H.-S.,Inha University | Yi H.-G.,Inha University | And 4 more authors.
Journal of Thoracic Oncology | Year: 2011

To determine whether genetic variations in CMPK1 or RRM1, which impact the pharmacodynamics of gemcitabine, differentially affect the outcomes of non-small cell lung cancer (NSCLC) patients treated with gemcitabine or taxane/cisplatinum. Methods: We conducted retrospective study evaluating the associations between overall survival in 298 NSCLC patients at stages IIIA/IIIB (140) and IV (158), treated with gemcitabine (139) or taxane (159)/cisplatinum and 14 tagging single-nucleotide polymorphisms (tSNPs): 4 in CMPK1 and 10 in RRM1. Results: The wild-type genotypes of CMPK1 IVS1+1057 and IVS1-928 were associated with shorter overall survival in patients treated with the gemcitabine/cisplatinum (adjusted hazards ratio = 1.97 and 1.89; Cox p Bonferroni = 0.008 and 0.020), whereas this effect was not observed in patients treated with taxane/cisplatinum. No associations were observed for the other 2 CMPK1 or 10 RRM1 tSNPs. Analysis of the interaction between the CMPK1 and RRM1 genes showed that the survival of patients with CMPK1 IVS1+1057 CC and RRM1 IVS1-2374 TT, IVS7+25 AA, IVS7-425 AA, or IVS8+287 TT was significantly shorter when they were treated with the gemcitabine/cisplatinum (adjusted hazards ratio = 3.00, 2.89, 3.14, and 3.00; Cox p Bonferroni = 0.007, 0.012, 0.006, and 0.007). However, these effects were not observed in patients treated with taxane/cisplatinum. Conclusions: These findings suggest that polymorphisms of CMPK1 and their combination with those of RRM1 are helpful in identifying patients who will benefit less from a gemcitabine/cisplatinum as the first-line regimen. Copyright © 2011 by the International Association for the Study of Lung Cancer.

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