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1.  Association between CDH13 Variants and Cardiometabolic and Vascular Phenotypes in a Korean Population 
Yonsei Medical Journal  2013;54(6):1305-1312.
Although some CDH13 single nucleotide polymorphisms (SNPs) have been shown to be determinants of blood adiponectin levels, the clinical implications of CDH13 variants are not yet completely understood. The purpose of this study was to evaluate the effects of SNPs of CDH13 on metabolic and vascular phenotypes.
Materials and Methods
We included 238 hypertensive subjects and 260 age- and sex-matched controls. Seven tagging-SNPs were identified in the CDH13 gene by whole gene sequencing. The association between these SNP variants and the risk of hypertension, metabolic traits, and carotid intima-media thickness (IMT) was examined.
Minor allele carriers of rs12444338 had a lower risk of hypertension, but the association turned out just marginal after adjusting confoudners. Blood glucose levels were higher in the minor allele carriers of c.1407C>T (p=0.01), whereas low-density lipoprotein-cholesterol levels were greater in those of rs6565105 (p=0.02). The minor allele of rs1048612 was associated with a higher body mass index (p=0.01). In addition, the mean carotid IMT was significantly associated with rs12444338 (p=0.02) and rs1048612 (p=0.02).
These results provide evidence that CDH13 variants are associated with metabolic traits and carotid atherosclerosis in Koreans. This study shows the multifaceted effects of CDH13 variants on cardiometabolic risk.
PMCID: PMC3809859  PMID: 24142632
CDH13 protein; human; hypertension; atherosclerosis; glucose; cholesterol
2.  The apolipoprotein A5 −1131T>C promoter polymorphism in Koreans: Association with plasma APOA5 and serum triglyceride concentrations, LDL particle size and coronary artery disease 
The association between −1131T>C single nucleotide polymorphism (SNP) of the apolipoprotein A5 gene (APOA5) and hypertriglyceridemia raised the possibility that this SNP could be related to coronary artery disease (CAD) risk. Therefore, we investigated the association of this APOA5 −1131T>C SNP with circulating concentrations of APOA5, triglyceride and CAD in Koreans.
CAD patients (n = 741) and age-, sex-matched healthy controls (n = 741) were genotyped for the APOA5 −1131T>C SNP. The main outcome measures were the odds ratio (OR) on CAD risk and lipid variables, APOA5 concentration and LDL particle size.
The presence of the minor allele at the −1131T>C SNP was associated with an increased risk of CAD [OR 1.34 (95% CI, 1.09–1.65), P = 0.007] after adjusting for BMI, alcohol consumption, systolic blood pressure and diastolic blood pressure. There was an association between the APOA5 concentration and the −1131T>C genotype in controls (T/T: 245 ± 7 ng/ml, T/C: 220 ± 6, C/C: 195 ± 12; P = 0.001) and CAD patients (T/T: 218 ± 8 ng/ml, T/C: 185 ± 7, C/C: 169 ± 12; P < 0.001). Subjects with T/C or C/C in control and CAD patient groups showed higher triglyceride than those with T/T genotype. Also, the −1131T>C polymorphism was associated with LDL particle size (P = 0.003), with the T/C or C/C controls having smaller size than the T/T controls.
The APOA5 −1131C allele is associated with reduced APOA5 concentration and with increased CAD risk. This is consistent with the observed association between the −1131C SNP, increased triglycerides as well as small LDL particle size.
PMCID: PMC4428346  PMID: 19159622
APOA5 −1131T>C polymorphism; Coronary artery disease; Triglycerides; Apolipoprotein A5 concentration; LDL particle size
3.  Association between Serine/Threonine Kinase 39 Gene Polymorphism, Hypertension, and Other Cardiovascular Risk Factors in Koreans 
Korean Circulation Journal  2013;43(1):13-22.
Background and Objectives
Although the association between single nucleotide polymorphisms (SNPs) of Serine/Threonine Kinase 39 (STK39) and hypertension has been reported, the prior studies have been inconsistent. The aim of this study is to evaluate the association between rs3754777 and rs6749447, the two SNPs of STK39, and hypertension and other cardiovascular risk factors in Koreans, residing in the Republic of Korea.
Subjects and Methods
We included 238 hypertensive patients and 260 controls. The associations between genotype and haplotype combination and hypertension were examined. In addition, possible SNP-related differences in the adjusted blood pressure and other cardiovascular risk factors were analyzed.
There was no significant association between the two SNPs and hypertension. However, the carriers of AA genotype of rs3754777 showed lower blood glucose and cholesterol levels, particularly in females. Genotype of rs6749447 was associated with the waist circumference, triglyceride, and high density lipoprotein-cholesterol levels, only in gender-stratified analysis. The effects of haplotype combinations on risk factors were compatible with genotype effects of each SNP.
Associations between the two SNPs of STK39, rs3754777 and rs6749447, and hypertension were not significant. However, the two SNPs showed genotype-related differences in blood glucose, lipids, and waist circumference, especially in women. Further studies are needed to clarify the effect of STK39 variants in these cardiovascular risk factors.
PMCID: PMC3569562  PMID: 23408757
STK39 protein, human; Hypertension; Cholesterol; Waist circumference; Glucose
4.  Association of CYP2C19*2 and *3 Genetic Variants with Essential Hypertension in Koreans 
Yonsei Medical Journal  2012;53(6):1113-1119.
The cytochrome P450 2C19 (CYP2C19) metabolizes arachidonic acid to produce epoxyicosanoid acids, which are involved in vascular tone and regulation of blood pressure. Recent findings suggest that CYP2C19 gene might be considered as a novel candidate gene for treatment of cardiovascular disease. The aim of the present study was to evaluate the association between two variants, CYP2C19*2 (681G>A) and CYP2C19*3 (636G>A) and the development of essential hypertension (EH) in Koreans.
Materials and Methods
We carried out an association study in a total of 1190 individuals (527 hypertensive subjects and 663 unrelated healthy controls). The CYP2C19 polymorphisms were genotyped using the SNaPShot™ assay.
The distribution of alleles and genotypes of CYP2C19*3 showed significant difference between hypertensive patients and normal controls (p=0.011 and p=0.013, respectively). Logistic regression analysis indicated that the CYP2C19*3 (636A) allele carriers were significantly associated with EH [odds ratio, 0.691; 95% confidence interval (CI), 0.512-0.932, p=0.016], in comparison to wild type homozygotes (CYP2C19*1/*1). Neither genotype nor allele distribution of CYP2C19*2 polymorphism showed significant differences between hypertensive and control groups (p>0.05).
Our present findings strengthen the evidence of an association between CYP2C19 gene polymorphism and EH prevalence. In particular, the CYP2C19*3 defective allele may contribute to reduced risk for the development of EH.
PMCID: PMC3481368  PMID: 23074110
Essential hypertension; CYP2C19; polymorphism; association study; Koreans
5.  The Relationship Between Gastric Myoelectric Activity and SCN5A Mutation Suggesting Sodium Channelopathy in Patients With Brugada Syndrome and Functional Dyspepsia - A Pilot Study 
SCN5A encodes the cardiac-specific NaV1.5 sodium channel, and Brugada syndrome is a cardiac conduction disorder associated with sodium channel α-subunit (SCN5A) mutation. The SCN5A-encoded NaV1.5 channel is also found on gastrointestinal smooth muscle and interstitial cells of Cajal. We investigated the relationship between functional dyspepsia (FD) and SCN5A mutation to evaluate sodium channelopathy in FD.
Patients with Brugada syndrome or FD were examined using upper endoscopy, electrogastrography (EGG), FD symptom questionnaire based on Rome III criteria and genetic testing for SCN5A mutation. Symptom scores of FD and EGG findings were analyzed according to SCN5A mutation.
A total of 17 patients (4 Brugada syndrome and 13 FD) participated in the study. An SCN5A mutation was noted in 75.0% of the patients with Brugada syndrome and in 1 (7.7%) of the patients with FD. Of 4 patients with SCN5A mutation, 2 (50%) had FD. Postprandial tachygastria and bradygastria were noted in 2 (50%) and 1 (25%) of the patients with SCN5A mutation, respectively. The EGG findings were not significantly different between positive and negative mutation in 17 patients.
Although we did not find statistically significant results, we suggest that it is meaningful to attempt to identify differences in symptoms and gastric myoelectric activity according to the presence of an SCN5A mutation by EGG analysis. The relationship between FD and sodium channelopathy should be elucidated in the future by a large-scale study.
PMCID: PMC3271254  PMID: 22323988
Brugada syndrome; Channelopathy; Functional gastrointestinal disorder; SCN5A
6.  Association of a polymorphism of BTN2A1 with dyslipidemia in East Asian populations 
We previously identified rs6929846 of the butyrophilin, subfamily 2, member A1 gene (BTN2A1) as a susceptibility locus for myocardial infarction in Japanese individuals by a genome-wide association study. The aim of the present study was to examine the relation of the rs6929846 polymorphism of BTN2A1 to dyslipidemia in Japanese and Korean populations, given that dyslipidemia is an important risk factor for myocardial infarction. A total of 10,953 individuals from three independent subject panels were examined. The relations of the rs6929846 polymorphism of BTN2A1 to serum concentrations of triglycerides, high-density lipoprotein (HDL)-cholesterol and low-density lipoprotein (LDL)-cholesterol were examined in each subject panel. The C→T polymorphism (rs6929846) of BTN2A1 was significantly associated with serum concentrations of triglycerides in Japanese subject panels A (P=0.0004) and B (P=0.0010), and in the Korean population (P=0.0095), with the minor T allele being related to an increased serum concentration of triglycerides. The rs6929846 was associated with serum concentrations of HDL-cholesterol in Japanese subject panels A (P=0.0047) and B (P=0.0015), with the T allele being related to a decreased serum concentration of HDL-cholesterol, but not in the Korean population. This polymorphism was associated with the serum concentration of LDL-cholesterol only in Japanese subject panel B (P=0.0059), with the T allele being related to an increased serum concentration of LDL-cholesterol. The results suggest that BTN2A1 may be a susceptibility gene for hypertriglyceridemia in East Asian populations and for low serum HDL-cholesterol in the Japanese population.
PMCID: PMC3440727  PMID: 22977569
genetics; polymorphism; dyslipidemia; hyperlipidemia hypercholesterolemia
7.  Carriage of the V279F Null Allele within the Gene Encoding Lp-PLA2 Is Protective from Coronary Artery Disease in South Korean Males 
PLoS ONE  2011;6(4):e18208.
The Asia-specific PLA2G7 994G-T transversion leads to V279F substitution within the lipoprotein-associated phospholipase-A2 (Lp-PLA2) and to absence of enzyme activity in plasma. This variant offers a unique natural experiment to assess the role of Lp-PLA2 in the pathogenesis of coronary artery disease (CAD) in humans. Given conflicting results from mostly small studies, a large two-stage case-control study was warranted.
Methodology/Principal Findings
PLA2G7 V279F genotypes were initially compared in 2890 male cases diagnosed with CAD before age 60 with 3128 male controls without CAD at age 50 and above and subsequently in a second independent male dataset of 877 CAD cases and 1230 controls. In the first dataset, the prevalence of the 279F null allele was 11.5% in cases and 12.8% in controls. After adjustment for age, body mass index, diabetes, smoking, glucose and lipid levels, the OR (95% CI) for CAD for this allele was 0.80 (0.66–0.97, p = 0.02). The results were very similar in the second dataset, despite lower power, with an allele frequency of 11.2% in cases and 12.5% in controls, leading to a combined OR of 0.80 (0.69–0.92), p = 0.002. The magnitude and direction of this genetic effect were fully consistent with large epidemiological studies on plasma Lp-PLA2 activity and CAD risk.
Natural deficiency in Lp-PLA2 activity due to carriage of PLA2G7 279F allele protects from CAD in Korean men. These results provide evidence for a causal relationship between Lp-PLA2 and CAD, and support pharmacological inhibition of this enzyme as an innovative way to prevent CAD.
PMCID: PMC3071750  PMID: 21490708
8.  High frequencies of Y-chromosome haplogroup O2b-SRY465 lineages in Korea: a genetic perspective on the peopling of Korea 
Koreans are generally considered a Northeast Asian group, thought to be related to Altaic-language-speaking populations. However, recent findings have indicated that the peopling of Korea might have been more complex, involving dual origins from both southern and northern parts of East Asia. To understand the male lineage history of Korea, more data from informative genetic markers from Korea and its surrounding regions are necessary. In this study, 25 Y-chromosome single nucleotide polymorphism markers and 17 Y-chromosome short tandem repeat (Y-STR) loci were genotyped in 1,108 males from several populations in East Asia.
In general, we found East Asian populations to be characterized by male haplogroup homogeneity, showing major Y-chromosomal expansions of haplogroup O-M175 lineages. Interestingly, a high frequency (31.4%) of haplogroup O2b-SRY465 (and its sublineage) is characteristic of male Koreans, whereas the haplogroup distribution elsewhere in East Asian populations is patchy. The ages of the haplogroup O2b-SRY465 lineages (~9,900 years) and the pattern of variation within the lineages suggested an ancient origin in a nearby part of northeastern Asia, followed by an expansion in the vicinity of the Korean Peninsula. In addition, the coalescence time (~4,400 years) for the age of haplogroup O2b1-47z, and its Y-STR diversity, suggest that this lineage probably originated in Korea. Further studies with sufficiently large sample sizes to cover the vast East Asian region and using genomewide genotyping should provide further insights.
These findings are consistent with linguistic, archaeological and historical evidence, which suggest that the direct ancestors of Koreans were proto-Koreans who inhabited the northeastern region of China and the Korean Peninsula during the Neolithic (8,000-1,000 BC) and Bronze (1,500-400 BC) Ages.
PMCID: PMC3087676  PMID: 21463511
9.  Association of Plasma Retinol-Binding Protein 4, Adiponectin, and High Molecular Weight Adiponectin with Insulin Resistance in Non-Diabetic Hypertensive Patients 
Yonsei Medical Journal  2010;51(3):375-384.
The aim of this study was to determine whether retinol-binding protein 4 (RBP4), adiponectin and high molecular weight (HMW) adiponectin are associated with insulin resistance (IR) and metabolic parameters in non-diabetic hypertensive patients. Also, we sought to compare the predictive values of these adipocytokines for IR in non-diabetic hypertensive patients.
Materials and Methods
Analyses of RBP4, adiponectin, and HMW adiponectin were performed on 308 non-diabetic hypertensives (148 males, age 58 ± 10 years, 189 non-metabolic syndrome and 119 metabolic syndrome). The homeostasis model assessment (HOMA) index for IR, lipid profiles, and anthropometric measure-ments were assessed.
There was no significant difference in RBP4 levels according to the presence of metabolic syndrome, although adiponectin and HMW adiponectin were significantly lower in metabolic syndrome. Correlation analysis of log RBP4 with IR and metabolic indices revealed that there was no significant correlation of RBP4 with waist circumference (r = 0.056, p = 0.324), HDL cholesterol (r = 0.005, p = 0.934), ApoB/ApoAI ratio (r = 0.066, p = 0.270), and the HOMA index (r = 0.017, p = 0.756). However, adiponectin and HMW adiponectin showed significant correlations with the HOMA index (r = - 0.247, p < 0.001; r = - 0.296, p < 0.001) and metabolic parameters. With IR defined as HOMA index ≥ 2.5, HMW adiponectin did not demonstrate a superior predictive value for IR compared to adiponectin (AUC = 0.680 vs. 0.648, p = 0.083). The predictive value of RBP4 for IR was minimal (AUC = 0.534).
RBP4 was not associated with IR or metabolic indices and the predictive value for IR was minimal in hypertensives. HMW adiponectin didn't have a superior predictive value for IR compared to adiponectin. Therefore, we can suggest that RBP4 and HMW adiponectin don't have more additive information than adiponectin in non-diabetic hypertensives.
PMCID: PMC2852793  PMID: 20376890
Retinol-binding proteins; adiponectin; hypertension; insulin resistance
10.  Personalized Medicine in Coronary Artery Disease: Insights From Genomic Research 
Korean Circulation Journal  2009;39(4):129-137.
Prior clinical studies have demonstrated that a family history of coronary artery disease (CAD) is associated with future cardiovascular events. Although there are several Mendelian disorders that are associated with CAD, most common forms of CAD are believed to be multifactorial and the result of many genes with small individual effects. The identification of these genes and their variation would be very helpful for the prediction, prevention, and management of CAD; linkage analysis or candidate gene case-control studies have been largely unsuccessful. On the contrary, recent advances in genomic techniques have generated a large amount of deoxyribonucleic acid (DNA)-based information. The link between CAD and inflammation and biological pathways has been highlighted. In particular, several genome-wide association studies have replicated a novel gene marker on chromosome 9p21. The information gained from genomic studies, in combination with clinical data, is expected to refine personalized approaches to assess risk and guide management for CAD. Genetic risk scores derived from several functional single nucleotide polymorphisms (SNPs) or haplotypes in multiple genes may improve the prediction of CAD. Despite the complexity of CAD genetics, steady progress is expected.
PMCID: PMC2771813  PMID: 19949601
Coronary artery disease; Genomics; Genes; Risk; Polymorphism, single nucleotide
11.  Mitochondrial DNA Haplogroup Analysis Reveals no Association between the Common Genetic Lineages and Prostate Cancer in the Korean Population 
PLoS ONE  2008;3(5):e2211.
Mitochondrial DNA (mtDNA) variation has recently been suggested to have an association with various cancers, including prostate cancer risk, in human populations. Since mtDNA is haploid and lacks recombination, specific mutations in the mtDNA genome associated with human diseases arise and remain in particular genetic backgrounds referred to as haplogroups. To assess the possible contribution of mtDNA haplogroup-specific mutations to the occurrence of prostate cancer, we have therefore performed a population-based study of a prostate cancer cases and corresponding controls from the Korean population. No statistically significant difference in the distribution of mtDNA haplogroup frequencies was observed between the case and control groups of Koreans. Thus, our data imply that specific mtDNA mutations/lineages did not appear to have a significant effect on a predisposition to prostate cancer in the Korean population, although larger sample sizes are necessary to validate our results.
PMCID: PMC2376063  PMID: 18493608
12.  Lack of Association between Y-Chromosomal Haplogroups and Prostate Cancer in the Korean Population 
PLoS ONE  2007;2(1):e172.
The Y chromosome has recently been suggested to have an association with prostate cancer risk in human populations. Since this chromosome is haploid and lacks recombination over most of its length, haplotypes constructed from binary markers throughout the chromosome can be used for association studies. To assess the possible Y-chromosomal contribution to prostate cancer risk, we have therefore analyzed 14 Y-chromosomal binary markers in 106 prostate cancer cases and 110 controls from the Korean population. In contrast to previous findings in the Japanese population, no statistically significant difference in the distribution of Y-chromosomal haplogroup frequencies was observed between the case and control groups of Koreans. Thus, our data imply that the previously reported associations between Y-chromosomal lineages and a predisposition to, or protection against, prostate cancer might be explained by statistical fluctuations, or by genetic effects that are seen only in some environments.
PMCID: PMC1766463  PMID: 17245448

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