• Journal of The Korean Society of Inherited Metabolic disease
• /
• v.2 no.1
• /
• pp.77-79
• /
• 2002

The urea cycle, consisting of a series of six enzymatic reactions, plays key roles to prevent the accumulation of toxic nitrogenous compound and synthesize arginine de novo. Five well characterized diseases have been described, resulting from an enzymatic defect in the biosynthesis of one of the normally expressed enzyme. This presentation will focus on two representative diseases; ornithine transcarbamylase(OTC) deficiency and citrullinemia(argininosuccinate synthetase deficiency). OTC deficiency is one of the most common inborn error of urea cycle, which is inherited in X-linked manner. We identified 17 different mutations in 20 unrelated Korean patients with OTC deficiency; L9X, R26P, R26X, T44I, R92X, G100R, R141Q, G195R, M205T, H214Y, D249G, R277W, F281S, 853 del C, R320X, V323M and 10 bp del at nt. 796-805. These mutations occur at well conserved nucleotide sequences across species or CpG hot spot. The L9X and R26X lead to the disruption of leader sequences, required for directing mitochondrial localization of the OTC precursor. Their phenotypes are severe, and neonatal onset. The G100R, R277W and V323M mutations were uniquely identified in patients with late onset OTC deficiency. The other genotypes are associated with neonatal onset. Out of 20 patients with OTC deficiency, only 6 patients are alive; two were liver transplanted, and normal in growth and development at 2, 4 years after transplantation respectively. Citrullinemia is an autosomal recessive disease, caused by the mutations in the argininosuccinate synthetase(ASS) gene. We identified in 3 major mutations in 11 unrelated Korean patients with citrullinemia; G324S, $IVS6^{-2}$ A to G, and 67 bp ins at nt 1125-1126. Among these, the 67 base pair insertion mutation is novel. The allele frequency of each mutation is; G324S(45%), IVS6-2 A to G(32%), and 67 base pair insertion(14%). All patients are diagnosed at neonatal or infantile age. Interestingly, two patients presented with stroke like episode. Out of 11 patients, 5 patients died. Among 6 patients alive, one patient was successfully liver transplanted.

• Molecules and Cells
• /
• v.27 no.2
• /
• pp.175-181
• /
• 2009

The myosin light chain kinase (MYLK) gene encodes both smooth muscle and nonmuscle cell isoforms. Recently, polymorphisms in MYLK have been reported to be associated with several diseases. To examine the genetic effects of polymorphisms on the risk of asthma and related phenotypes, we scrutinized MYLK by re-sequencing/genotyping and statistical analysis in Korean population (n = 1,015). Seventeen common polymorphisms located in or near exons, having pairwise $r^2$ values less than 0.25, were genotyped. Our statistical analysis did not replicate the associations with the risk of asthma and log-transformed total IgE levels observed among African descendant populations. However, two SNPs in intron 16 (+89872C> G and +92263T> C), which were in tight LD (|D'| = 0.99), revealed significant association with log-transformed blood eosinophil level even after correction multiple testing ($P=0.002/P^{corr}=0.01$ and $P=0.002/P^{corr}=0.01$, respectively). The log-transformed blood eosinophil levels were higher in individuals bearing the minor alleles for +89872C> G and +92263T> C than in those bearing other allele. In additional subgroup analysis, the genetic effects of both SNPs were much more apparent among asthmatic patients and atopic asthma patients. Among atopic asthma patients, the log-transformed blood eosinophil levels were proportionally increased by gene-dose dependent manner of in both +89872C> G and +92263T> C(P = 0.0002 and P = 0.00007, respectively). These findings suggest that MYLK polymorphisms might be among the genetic factors underlying differential increases of blood eosinophil levels among asthmatic patients. Further biological and/or functional studies are needed to confirm our results.

• Journal of Society of Preventive Korean Medicine
• /
• v.14 no.1
• /
• pp.111-123
• /
• 2010

Backgrounds : Stroke is characterized by loss of brain functions due to a disturbance in the blood vessels supplying blood to the brain, and classified into hemorrhage and ischemia. Stroke is known to be affected by genetic factors and other diseases such as hypertension and cardiovascular diseases. However, the distinctive association between stroke and genetic variations has not discovered yet. Objectives : This study investigated the effects of fibrinogen level and genetic variations in FGA (Fibrinogen alpha chain) gene on stroke in Korean stroke patients and controls. Methods : DNA samples from 674 stroke patients diagnosed by Oriental medical hospitals and 267 controls were used in this study. Two common single nucleotide polymorphism(SNP) with high minor allele frequency(MAF), rs2070011G/A of promoter region and nonsynonymous rs6050A/G of exon 5 in FGA gene, were targeted for Taqman genotyping. Because the TOAST classification is important to the factors and symptoms of stroke, ischemic patients were further classified into five subtypes using diagnosis and clinical data. One-way ANOVA and chi-square test were used for clinical data and genetic association, respectively. Haploview v4.1 program was used for linkage disequilibrium(LD), haplotype and haplotype block analysis. Results : The levels of red blood cells and fibrinogen from clinical data were shown to be significant factors for the sub-groups of TOAST classification. No significant associations of stroke, hemorrhage, ischemic and subtypes of TOAST with rs2070011 and rs6050 of FGA gene were found(P > 0.05). However, rs2070011 in promoter region and nonsynonymous rs6050 in exon 5 which produce the amino acid change from threonine to alanine showed a haplotype block and three haplotypes of A-G, G-A, A-A, suggesting that rs2070011 and rs6050 might be co-segregated in generic recombination. Although A-A haplotype of stroke patients showed 64-69% low frequency compared to controls, there was no significant association between stroke and haplotype(P > 0.05). Conclusion : This study showed that there was no significant association between stroke and two SNP of rs2070011G/A and nonsynonymous rs6050A/G in FGA gene. However, these two SNP compose a haplotype block and three haplotypes of A-G, G-A, A-A. This finding suggests that rs2070011 and rs6050 are so close as to be positioned as linkage disequilibrium. Nevertheless, no significant association between haplotypes and stroke was found.

• Journal of Genetic Medicine
• /
• v.14 no.1
• /
• pp.8-17
• /
• 2017

Purpose: Pulse wave velocity (PWV) is an indicator of arterial stiffness, and is considered a marker of vascular damage. However, a genome-wide association study analyzing single nucleotide polymorphisms (SNPs) associated with brachial-ankle PWV (baPWV) has not been conducted in healthy populations. We performed this study to identify SNPs associated with baPWV in healthy populations in Korea. Materials and Methods: Genomic SNPs data for 2,407 individuals from three sites were analyzed as part of the Korean Genomic Epidemiologic Study. Without replication samples, we performed multivariable analysis as a post hoc analysis to verify the findings in site adjusted analysis. Healthy subjects aged between 40 and 70 years without self-reported history or diagnosis of hypertension, diabetes, hyperlipidemia, heart disease, cerebrovascular disease and cancer were included. We excluded subjects with a creatinine level >1.4 mg/dL (men) and 1.2 mg/dL (women). Results: In the site-adjusted association analysis, significant associations (P<$5{\times}10^{-8}$) with baPWV were detected for only 5 SNPs with low minor allele frequency. In multivariable analysis adjusted by age, sex, height, body mass index, mean arterial pressure, site, smoking, alcohol, and exercise, 11 SNPs were found to be associated (P<$5{\times}10^{-8}$) with baPWV. The 5 SNPs (P<$5{\times}10^{-8}$) linked to three genes (OPCML, PRR35 and RAB40C) were common between site-adjusted analysis and multivariable analysis. However, meta-analysis of the result from three sites for the 11 SNPs showed no significant associations. Conclusion: Using the recent standard for genome-wide association study, we did not find any evidence of significant association signals with baPWV.

• Genomics & Informatics
• /
• v.20 no.3
• /
• pp.29.1-29.12
• /
• 2022

Several studies have shown associations between irinotecan toxicity and UGT1A genetic variations in colorectal and lung cancer, but only limited data are available for gastric cancer patients. We evaluated the frequencies of UGT1A polymorphisms and their relationship with clinicopathologic parameters in 382 Korean gastric cancer patients. Polymorphisms of UGT1A1*6, UGT1A1*27, UGT1A1*28, UGT1A1*60, UGT1A7*2, UGT1A7*3, and UGT1A9*22 were genotyped by direct sequencing. In 98 patients treated with irinotecan-containing regimens, toxicity and response were compared according to the genotype. The UGT1A1*6 and UGT1A9*22 genotypes showed a higher prevalence in Korean gastric cancer patients, while the prevalence of the UG1A1*28 polymorphism was lower than in normal Koreans, as has been found in other studies of Asian populations. The incidence of severe diarrhea after irinotecan-containing treatment was more common in patients with the UGT1A1*6, UGT1A7*3 and UGT1A9*22 polymorphisms than in controls. The presence of the UGT1A1*6 allele also showed a significant association with grade III-IV neutropenia. Upon haplotype and diplotype analyses, almost every patient bearing the UGT1A1*6 or UGT1A7*3 variant also had the UGT1A9*22 polymorphism, and all severe manifestations of UGT1A polymorphism-associated toxicity were related to the UGT1A9*22 polymorphism. By genotyping UGT1A9*22 polymorphisms, we could identify high-risk gastric cancer patients receiving irinotecan-containing chemotherapy, who would experience severe toxicity. When treating high-risk patients with the UGT1A9*22 polymorphism, clinicians should closely monitor them for signs of toxicity such as severe diarrhea or neutropenia.

• Journal of The Korean Society of Inherited Metabolic disease
• /
• v.16 no.2
• /
• pp.79-85
• /
• 2016

Purpose: This study aimed to analyze genetic mutations, clinical manifestations, and treatment of patients with benign HPA in Korea. Methods: This case series study involved ten HPA patients who were referred to our hospital because of high phenylalanine concentration. We investigated their demographic features, clinical manifestations, and mutations of the PAH gene through direct DNA sequencing. Results: Among ten patients with benign HPA, two pairs of patients were related (father-daughter, mother-daughter relationship) cases, and all of them showed no specific clinical manifestations or notable past history. Their plasma phenylalanine levels ranged between 1.2 and 4.2 mg/dL. In the tetrahydrobiopterin (BH4) loading test, all patients were nonresponsive to BH4. In the confirmation test of PAH mutation analysis, we identified eleven different alleles out of twelve. The most common allele was R53H (c.158G> A). In addition, two novel PAH gene mutations, V423A (c.1268T>C) and V51A (c.152T>C), were identified. Although the patients did not receive any pharmacologic treatment or continuous phenylalanine restriction dietary therapy, their neurocognitive development was normal. Moreover, on serial outpatient follow-up tests, all patients maintained phenylalanine levels below 6 mg/dL. Conclusion: This study is the first in Korea to analyze benign HPA patients. All patients with benign HPA could maintain phenylalanine levels below 6 mg/dL with normal neurocognitive development, without continuous therapy. Therefore, performing mutation analysis and distinguishing benign HPA from phenylketonuria (PKU) are important to help improve life quality in patients with benign HPA by avoiding unnecessary lifelong therapy.

• Journal of Genetic Medicine
• /
• v.5 no.1
• /
• pp.34-40
• /
• 2008

Purpose : Preeclampsia is a major cause of maternal and perinatal mortality and morbidity and is considered to be a multifactorial disorder involving a genetic predisposition and environmental factors. Endothelin-1 (ET-1) is a potent vasoconstrictor peptide, and alterations in the ET-1 system are thought to play a role in triggering the vasoconstriction seen with preeclampsia. The aim of this study was to examine the frequency of the 4 common single-nucleotide polymorphisms (SNPs) (c.1370T>G, c.137_139delinsA, c.3539+2T>C, and c.5665G>T) of the ET-1 gene in normotensive and preeclamptic pregnancies and to investigate whether these SNPs are associated with preeclampsia in pregnant Korean women. Methods : We analyzed blood samples from 206 preeclamptic and 216 normotensive pregnancies using a commercially available SNapShot kit and an ABI Prism 3100 Genetic analyzer. Results : There were no significant differences in genotype or allele frequencies of the 4 SNPs in the ET-1 gene between preeclamptic and normotensive pregnancies. The respective frequencies of the 3 haplotypes (TDTG, GDCT, and TICT; >10% haplotype frequency) were 61%, 13% and 13%, respectively, in preeclampsic pregnancies and 62%, 14% and 12%, respectively, in normotensive pregnancies. The frequencies of these haplotypes were similar for both groups. Using multiple logistic regression analysis, we did not observe an increase in the risk of preeclampsia for the 4 SNPs of the ET-1 gene under either a recessive or dominant model. Conclusion : This study suggests that the 4 SNPs of the ET-1 gene are not associated with an increased risk for preeclampsia in pregnant Korean women.

• Clinical and Experimental Pediatrics
• /
• v.52 no.3
• /
• pp.356-363
• /
• 2009

Purpose : A polymorphism in the IGF-I gene promoter region is known to be associated with serum IGF-I levels, birth weight, and body length, suggesting that IGF-I gene polymorphism might influence postnatal growth. The present study aimed to investigate the role of this polymorphic cytosine-adenine (CA) repeat of the IGF-I gene in children with idiopathic short stature. Methods : The study involved 131 children (72 boys and 59 girls) diagnosed with idiopathic short stature, aged 715 years. Genomic DNA was extracted from anticoagulated peripheral whole blood. The primers were designed to cover the promoter region containing the polymorphic CA repeat. Data were analyzed using GeneMapper software. The correlations between age and serum IGF-I levels were analyzed using Spearmans correlation coefficient. Results : The CA repeat sequences ranged from 15 to 22, with 19 CA repeats the most common with an allele frequency of 40.6%. Homozygous for 19 CA repeat was 13.0%, heterozygous for 19 CA repeat was 56.5%, and 19 CA non-carrier was 30.5%. The three different genotype groups showed no significant differences in height, body weight and body mass index, and serum IGF-I levels. The serum IGF-I level and age according to the IGF-I genotypes were significantly correlated in the entire group, 19 CA repeat carrier group, and the non-carrier group. The three groups also showed no significant differences in the first year responsiveness to GH treatment. Conclusion : There were no significant different correlations between 19 CA repeat polymorphism and serum IGF-I levels according to genotype. Our results suggest that the IGF-I 19 CA repeat gene polymorphism is not functional in children with idiopathic short stature.