A genome-wide association study of a coronary artery disease risk variant.

Although over 30 common genetic susceptibility loci have been identified to be independently associated with coronary artery disease (CAD) risk through genome-wide association studies (GWAS), genetic risk variants reported to date explain only a small fraction of heritability. To identify novel susceptibility variants for CAD and confirm those previously identified in European population, GWAS and a replication study were performed in the Koreans and Japanese. In the discovery stage, we genotyped 2123 cases and 3591 controls with 521 786 SNPs using the Affymetrix SNP Array 6.0 chips in Korean. In the replication, direct genotyping was performed using 3052 cases and 4976 controls from the KItaNagoya Genome study of Japan with 14 selected SNPs. To maximize the coverage of the genome, imputation was performed based on 1000 Genome JPT+CHB and 5.1 million SNPs were retained. CAD association was replicated for three GWAS-identified loci (1p13.3/SORT1 (rs599839), 9p21.3/CDKN2A/2B (rs4977574), and 11q22.3/ PDGFD (rs974819)) in Koreans. From GWAS and a replication, SNP rs3782889 showed a strong association (combined P=3.95 × 10(-14)), although the association of SNP rs3782889 doesn't remain statistically significant after adjusting for SNP rs11066015 (proxy SNP with BRAP (r(2)=1)). But new possible CAD-associated variant was observed for rs9508025 (FLT1), even though its statistical significance did marginally reach at the genome-wide a significance level (combined P=6.07 × 10(-7)). This study shows that three CAD susceptibility loci, which were previously identified in European can be directly replicated in Koreans and also provides additional evidences implicating suggestive loci as risk variants for CAD in East Asian.

Genetic variants in the IL12B gene are associated with inflammatory bowel diseases in the Korean population.

BACKGROUND AND AIM: Recent genomic studies have identified genetic variants in the IL12B gene, which encodes the p40 subunit shared by interleukin 12 and interleukin 23, as susceptibility loci for inflammatory bowel disease (IBD). The study aimed to identify additional novel genetic variants in IL12B and investigated whether variants confer susceptibility to the development of Crohn's disease (CD) or ulcerative colitis (UC) in the Korean population. METHODS: To detect single nucleotide polymorphisms (SNPs) in IL12B, direct sequencing of all coding exons, exon-intron boundaries, promoter region, and 5' untranslated region was performed in 24 randomly selected samples. Selected haplotype-tagging SNPs were subsequently genotyped in 493 IBD patients (245 patients with CD and 248 with UC) and 504 healthy controls. RESULTS: Two haplotype-tagging SNPs (rs2288831 and rs919766) were selected through direct sequencing and were genotyped. Of them, SNP rs2288831 in the IL12B gene was significantly associated with CD susceptibility in allelic association analysis (odds ratio = 1.30; 95% confidence interval 1.04-1.62; P = 0.019). This significant association with CD was also observed for a haplotype consisting of SNP rs919766 and rs2288831 (odds ratio = 1.29; 95% confidence interval 1.03-1.60; P = 0.025). However, none of IL12B SNPs were associated with UC susceptibility. Finally, no specific associations between genetic variants and disease phenotype of CD were identified. CONCLUSIONS: This study is first to identify SNP rs2288831 in the IL12B gene as a susceptible variation for CD. Further studies in other ethnic groups are warranted to validate the association of this genetic variant with IBD.

Common variants in RYR1 are associated with left ventricular hypertrophy assessed by electrocardiogram.

AIMS: To identify the genetic risk factors that influence the development of electrocardiographic (ECG) left ventricular hypertrophy (LVH), a major risk factor for cardiovascular (CV) morbidity and mortality. METHODS AND RESULTS: We performed a genomewide association study (GWAS) of ECG-LVH, in which the community-based Korea Association REsource (KARE) study (8432 controls and 398 cases) was analysed by Affymetrix SNP array 5.0. The GWAS results were validated in hospital-based samples (597 controls and 207 cases). Fourteen single-nucleotide polymorphisms (SNPs) in eight genetic loci (5q35.1, 6p22.3-22.1, 8q24.2, 11p15, 11q21-22.1, 14q12, 17q11.2, and 19q13.1) were associated with ECG-LVH in the original GWAS study (P < 1 × 10(-5)). Of these SNPs, 12 were genotyped in the hospital sample. There was consistent association with the 19q13.1 region which contains RYR1 gene. The most significant SNP in the region was rs10500279, which had genomewide significance in the combined GWAS/replication sample [odds ratio = 1.58 (confidence interval: 1.35-1.85), P = 1.0 × 10(-8)]. Mutations in RYR1, which encodes a major Ca(2+) channel in the skeletal muscle, have been reported to correlate with CV diseases. CONCLUSION: We performed the first GWAS for ECG-LVH, implicating the skeletal muscle Ca(2+) channel protein RYR1 as a genetic risk factor. These results might increase our understanding of the development of ECG-LVH.

Association of a genetic variant of BTN2A1 with metabolic syndrome in East Asian populations.

BACKGROUND: The authors previously showed that the C→T polymorphism (rs6929846) of butyrophilin, subfamily 2, member A1 gene (BTN2A1) was significantly associated with myocardial infarction in Japanese individuals. Given that metabolic syndrome (MetS) is an important risk factor for myocardial infarction, the association of the rs6929846 of BTN2A1 with myocardial infarction might be attributable, at least in part, to its effect on susceptibility to MetS. AIM: The aim of the present study was to examine the relation of the rs6929846 of BTN2A1 to MetS in East Asian populations. METHODS: The study population comprised 5210 Japanese or Korean individuals (3982 individuals with MetS, 1228 controls) from three independent subject panels. Japanese subject panels A and B comprised 1322 individuals with MetS and 654 controls, and 1909 individuals with MetS and 170 controls, respectively, whereas the Korean population samples comprised 751 individuals with MetS and 404 controls. RESULTS: Comparison of genotype distributions using the χ(2) test revealed that the genotype distributions and allele frequencies of rs6929846 were significantly (p<0.05) associated with MetS in Japanese subject panels A (T allele frequency: MetS, 0.091; controls, 0.054; p=6.1×10(-5)) and B (T allele frequency: MetS, 0.091; controls, 0.039; p=0013) but not in the Korean population samples (T allele frequency: MetS, 0.102; controls, 0.125; p=0.0997). Multivariable logistic regression analysis with adjustment for covariates revealed that the rs6929846 of BTN2A1 was significantly (p<0.017) associated with MetS in Japanese subject panel A (p=0.0055, OR 1.97) and in all individuals (p=0.0038, OR 1.38), with the T allele representing a risk factor for this condition. CONCLUSION: BTN2A1 may be a susceptible gene for MetS in Japanese individuals.

A novel mutation in the SCN5A gene is associated with Brugada syndrome.

Brugada syndrome (BS) is an inherited cardiac disorder associated with a high risk of sudden cardiac death and is caused by mutations in the SCN5A gene encoding the cardiac sodium channel alpha-subunit (Na(v)1.5). The aim of this study was to identify the genetic cause of familial BS and characterize the electrophysiological properties of a novel SCN5A mutation (W1191X). Four families and one patient with BS were screened for SCN5A mutations by PCR and direct sequencing. Wild-type (WT) and mutant Na(v)1.5 channels were expressed in tsA201 cells, and the sodium currents (I(Na)) were analyzed using the whole-cell patch-clamp technique. A novel mutation, W1191X, was identified in a family with BS. Expression of the WT or the mutant channel (Na(v)1.5/W1191X) co-transfected with the beta(1)-subunit in tsA201 cells resulted in a loss of function of Na(v)1.5 channels. While voltage-clamp recordings of the WT channel showed a distinct acceleration of Na(v)1.5 activation and fast inactivation kinetics, the Na(v)1.5/W1191X mutant failed to generate any currents. Co-expression of the WT channel and the mutant channel resulted in a 50% reduction in I(Na). No effect on activation and inactivation were observed with this heterozygous expression. The W1191X mutation is associated with BS and resulted in the loss of function of the cardiac sodium channel.

Genetic polymorphism in the pregnancy-associated plasma protein-A associated with acute myocardial infarction.

BACKGROUND: Pregnancy-associated plasma protein-A (PAPP-A) is a high-molecular-weight, zinc-binding matrix metalloproteinase that is known to be abundantly expressed in ruptured plaques. Previous studies have shown PAPP-A to be a significant marker of plaque instability and cardiovascular events in patients with acute coronary syndromes. Because the activity of PAPP-A may be modulated by genetic variants in the PAPP-A genes, we tried to determine the association of PAPP-A gene with acute myocardial infarction (AMI). METHODS: We analyzed four single nucleotide polymorphisms (SNPs) of PAPP-A gene variants and seven other polymorphisms of cytokine genes that have been reported to have functional significance (RANTES G-403A, MCP1 G-2518A, CRP A2147G, CRP G-717A, AGER G557A, LTA T26A, IL-6 G-572C) for possible association with AMI in 170 unrelated AMI patients and unrelated age-matched controls, respectively. RESULTS: The average age of the study population was 62.2+/-11.4 years in AMI patients and 62.6+/-10.4 years in healthy controls. Multiple logistic regression analysis with risk factors such as age, male sex, smoking, hypertension, diabetes mellitus, and dyslipidemia revealed the PAPP-A IVS6+95 C allele to be associated with an increased risk of AMI (dominancy: odds ratio, 2.13; 95% confidence interval, 1.12-4.07; P=0.022; codominancy: odds ratio, 1.89; 95% confidence interval, 1.14-3.16; P=0.015). CONCLUSIONS: We found, for the first time, that PAPP-A IVS6+95 C allele is an independent risk factor for AMI even after adjustment for traditional risk factors. The determination of such genotype contributing to AMI could provide a new tool for identifying high-risk individuals.

Cordycepin inhibits lipopolysaccharide-induced inflammation by the suppression of NF-kappaB through Akt and p38 inhibition in RAW 264.7 macrophage cells.

Cordyceps militaris, a caterpillar-grown traditional medicinal mushroom, produces an important bioactive compound, cordycepin (3'-deoxyadenosine). Cordycepin is reported to possess many pharmacological activities including immunological stimulating, anti-cancer, anti-virus and anti-infection activities. The molecular mechanisms of cordycepin on pharmacological and biochemical actions of macrophages in inflammation have not been clearly elucidated yet. In the present study, we tested the role of cordycepin on the anti-inflammation cascades in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophage cells. In LPS-activated macrophage, nitric oxide (NO) production was inhibited by butanol fraction of C. militaris and the major component of C. militaris butanol faction was identified as cordycepin by high performance liquid chromatography. To investigate the mechanism by which cordycepin inhibits NO production and inducible nitric oxide synthase (iNOS) expression, we examined the activation of Akt and MAP kinases in LPS-activated macrophage. Cordycepin markedly inhibited the phosphorylation of Akt and p38 in dose-dependent manners in LPS-activated macrophage. Moreover, cordycepin suppressed tumor necrosis factor (TNF-alpha) expression, IkappaB alpha phosphorylation, and translocation of nuclear factor-kappaB (NF-kappaB). The expressions of cycloxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) were significantly decreased in RAW 264.7 cell by cordycepin. Taken together, these results suggest that cordycepin inhibits the production of NO production by down-regulation of iNOS and COX-2 gene expression via the suppression of NF-kappaB activation, Akt and p38 phosphorylation. Thus, cordycepin may provide a potential therapeutic approach for inflammation-associated disorders.

Forensic genetic analysis of mitochondrial DNA hypervariable region I/II sequences: an expanded Korean population database.

We have analyzed variation of the mitochondrial DNA (mtDNA) hypervariable segments I and II (HVS-I and HVS-II) in 185 randomly chosen individuals from Korea to provide an expanded and reliable Korean database. Combined sequence comparison of HVS-I and HVS-II led to the identification of 167 different haplotypes characterized by 154 variable sites. One hundred and fifty-one of the haplotypes were individual-specific, 14 were found in two individuals and 2 were found in three individuals. A pairwise comparison of the 185 HVS-I/II sequences found an average of 10.11 +/- 4.63 differences between individuals. The random match probability and gene diversity for the combined hypervariable regions were estimated at 0.66% and 0.9988, respectively. Analyzing the expanded database including three previously reported data sets and the present data using haplogroup-based comparisons and comparison with closely related sequences allowed errors to be detected and eliminated, thus considerably improving data quality. Sample division comparisons based on PhiST genetic distance measures revealed no significant population differentiation in the distribution of mtDNA sequence variations between the present data set and a database in The Scientific Working Group on DNA Analysis Methods (SWGDAM), but did indicate differences from other sets of data. Based on the results of mtDNA profiles, almost all of the mtDNA types studied here could be classified into subsets of haplogroups common in east Asia, and show that the Koreans possess lineages from both the southern and the northern haplogroup complexes of east Asian populations. The new data, combined with other mtDNA sequences, demonstrate how useful comparison with closely related mtDNA sequences can be for improving database quality, as well as providing haplotype information for forensic and population genetic analyses in the Korean population.

Association between Serine/Threonine Kinase 39 Gene Polymorphism, Hypertension, and Other Cardiovascular Risk Factors in Koreans.

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. RESULTS: 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. CONCLUSION: 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.

Adiponectin and progression of arterial stiffness in hypertensive patients.

BACKGROUND: Recent studies suggest that adiposity is associated with arterial stiffness. However, it is unclear which adipokine or what adiposity related parameters are related with the progression of arterial stiffness. We hypothesized that in hypertensive patients, initial levels of adipokines such as adiponectin and resistin are related to the progression of arterial stiffness, which has been proven to be associated with increased risk of cardiovascular events. METHODS: One hundred forty one consecutive patients with treated essential hypertension (81 men, 57.7±8.2 years) were enrolled. Pulse wave velocity (PWV) was measured at baseline, and after 24 months. Clinical variables and laboratory findings at the time of initial enrollment were analyzed to reveal the determinants of arterial stiffening. RESULTS: Mean heart to femoral PWV (hfPWV) was 992±202 cm/s at baseline, and 1021±263 cm/s at 24 months follow up. hfPWV progressed in seventy two patients (51.1%) during follow up period. In patients with hfPWV progression, mean plasma adiponectin level was significantly lower than patients with nonprogression (progressor: 5.18±3.21 µg/ml, non-progressor: 7.02±5.19 µg/ml, p=0.013). Multivariate regression analysis revealed plasma adiponectin level to being an independent predictor of hfPWV changes (ß=-0.018, p=0.032) when controlled for age, gender, SBP changes, BP control and HOMA. CONCLUSIONS: Plasma adiponectin levels are associated with progression of arterial stiffness in hypertensive patients. These findings may be one explanation for the high association between adiposity and arterial stiffness in hypertensive patients.

Association between CDH13 variants and cardiometabolic and vascular phenotypes in a Korean population.

PURPOSE: 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. RESULTS: 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). CONCLUSION: 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.

Associations between genetic variants in the IRGM gene and inflammatory bowel diseases in the Korean population.

BACKGROUND: Recent European ancestry genome-wide association studies have identified genetic variants of IRGM as significant susceptibility loci for Crohn's disease (CD). Therefore, we investigated whether genetic variants of IRGM confer genetic susceptibility to CD or ulcerative colitis (UC) and evaluated the genotype-phenotype associations in the Korean population. METHODS: This study included 510 inflammatory bowel disease (IBD) patients (253 patients with CD and 257 with UC) and 520 healthy controls in Koreans. Initially, we performed direct sequencing analysis to identify unique IRGM single nucleotide polymorphisms (SNPs). Three selected haplotype-tagging SNPs and one risk locus (rs72553867, rs10065172, rs4958847, and rs12654043) within the IRGM were then geno-typed in patients and controls. RESULTS: IRGM SNP rs10065172 was significantly associated with CD susceptibility in terms of allelic frequency (P = 0.004; odds ratio [OR] = 1.42) and genotype frequency (dominant model, P = 0.008; OR = 1.62). We also found a relationship between SNP rs72553867 and CD susceptibility in the analysis of allelic frequency (P = 0.0117; OR = 0.67) and genotype frequency (dominant model, P = 0.002; OR = 0.55). In addition, we observed that the association of CD with rs10065172 became stronger in patients with younger age at diagnosis (≤ 20 years) or male gender. However, there was no significant association between the four SNPs and UC susceptibility. CONCLUSIONS: This is the first study to identify SNP rs10065172 and rs72553867 in IRGM as principal CD susceptibility loci in an Asian population.

The Relationship Between Gastric Myoelectric Activity and SCN5A Mutation Suggesting Sodium Channelopathy in Patients With Brugada Syndrome and Functional Dyspepsia - A Pilot Study.

BACKGROUND/AIMS: SCN5A encodes the cardiac-specific Na(V)1.5 sodium channel, and Brugada syndrome is a cardiac conduction disorder associated with sodium channel α-subunit (SCN5A) mutation. The SCN5A-encoded Na(V)1.5 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Association of CYP2C19*2 and *3 genetic variants with essential hypertension in Koreans.

PURPOSE: 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. RESULTS: 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). CONCLUSION: 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.

The relationship between insulin-like growth factor-1 and metabolic syndrome, independent of adiponectin.

BACKGROUND: Insulin-like growth factor-1 (IGF-1) is associated with obesity and aging, and was recently linked to metabolic syndrome (MetS) and insulin resistance. However, little is known about the relationship between IGF-1 and adiponectin (adiponectin), another marker of MetS. METHODS: We measured the plasma IGF-1 and adiponectin levels of 3099 subjects (1869 males, 55.9±10.8 y). We applied the Korean-modified International Diabetes Foundation (k-IDF) criteria for determination of, and risk assessment for, MetS. RESULTS: K-IDF criteria-based MetS occurred in 37.0% (n=1146) of patients. IGF-1 (91.5 vs. 97.3 ng/ml, p<0.001) and adiponectin (3.95 vs. 4.23 µg/ml, p<0.001) were significantly lower in MetS patients than without MetS. Lower IGF-1 was associated with increasing numbers of MetS abnormalities, independent of adiponectin (p for trend<0.001, F=12.615, p<0.001 in ANCOVA). MetS prevalence in individuals with both high IGF-1 and adiponectin levels (6.7%, n=206) was significantly lower than in other groups. Both high IGF-1 and adiponectin group was associated with reduced MetS risk after adjusting for other confounding factors (OR 0.694, 95% CI 0.493-0.977, p=0.036). CONCLUSIONS: IGF-1 was associated with MetS independent of adiponectin in our study. The independent relationship between IGF-1 and MetS provides insight into the pathophysiologic mechanisms of MetS.

Synergistic effects of genetic variants of APOA5 and BTN2A1 on dyslipidemia or metabolic syndrome.

We previously showed that the -1131T→C polymorphism (rs662799) of the apolipoprotein A-V gene (APOA5) and the C→T polymorphism (rs6929846) of the butyrophilin, subfamily 2, member A1 gene (BTN2A1) were significantly associated with an increased serum concentration of triglycerides, a decreased serum concentration of high density lipoprotein (HDL)-cholesterol, and the prevalence of metabolic syndrome (MetS) in Japanese individuals. The purpose of the present study was to examine whether these polymorphisms synergistically affect the prevalence of dyslipidemia and MetS in East Asian populations. The study populations comprised 7471 Japanese and 3529 Korean individuals in the dyslipidemia study, and 3474 Japanese and 1671 Korean individuals in the MetS study. Multivariable logistic regression analysis of combined genotypes with adjustment for age, gender and diabetes mellitus revealed that rs662799 and rs6929846 significantly and synergistically affected dyslipidemia. Japanese or Korean individuals with the C allele of APOA5 and the T allele of BTN2A1 had a 2.05- or 1.92-fold increased risk for hypertriglyceridemia and a 1.82- or 1.56-fold increased risk for hypo-HDL-cholesterolemia, respectively, compared to those with the TT genotype of APOA5 and the CC genotype of BTN2A1. Similar analysis with adjustment for age and gender revealed that Japanese individuals, but not Korean individuals, with the C allele of APOA5 and the T allele of BTN2A1 had a 2.87-fold increased risk for MetS compared to those with the TT genotype of APOA5 and the CC genotype of BTN2A1. Genetic variants of APOA5 and BTN2A1 may synergistically affect the prevalence of dyslipidemia in East Asian populations and of MetS in Japanese individuals.

Association of cytochrome P450 2C19*2 polymorphism with clopidogrel response variability and cardiovascular events in Koreans treated with drug-eluting stents.

BACKGROUND: Although East Asians carry the cytochrome P450 (CYP) 2C19*2 allele more frequently than do Caucasians, the impact of the CYP2C19*2 allele on clopidogrel pharmacodynamics and clinical outcomes is unknown. OBJECTIVE: To evaluate the effect of CYP2C19 variants on clopidogrel pharmacodynamics and long-term prognosis in East Asian patients with drug-eluting stents (DES). METHODS: DES-treated patients taking dual antiplatelet therapy were enrolled from a Korean multicentre genetic registry. The CYP2C19*2 allele was genotyped using the Taqman method (n=2146), and on-treatment platelet reactivity was measured with the VerifyNow P2Y12 assay (n=1415). RESULTS: 1011 patients (47%) carried at least one CYP2C19*2 allele. The mean on-treatment platelet reactivity was significantly higher in carriers than in non-carriers (250±76 vs 231±83 P2Y12 reaction unit, p<0.001). For up to 12 months' follow-up, the composite of cardiovascular death, non-fatal myocardial infarction and stent thrombosis was significantly higher in carriers of the CYP2C19*2 allele than non-carriers (2.0% vs 0.8%, p=0.02). On landmark analysis, there was no difference in clinical outcome after 12 months between the groups. CONCLUSION: The CYP2C19*2 genetic variant may be associated with worse outcome in Korean patients treated exclusively with DES and dual-antiplatelet therapy due to a significant increase in cardiac death, myocardial infarction or stent thrombosis.

High frequencies of Y-chromosome haplogroup O2b-SRY465 lineages in Korea: a genetic perspective on the peopling of Korea.

BACKGROUND: 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. RESULTS: 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. CONCLUSIONS: 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.

Relationships between genetic polymorphisms of triggering receptor expressed on myeloid cells-1 and inflammatory bowel diseases in the Korean population.

AIMS: Triggering receptor expressed on myeloid cells-1 (TREM-1) has been shown to play a crucial role in the propagation of inflammatory responses. Recent studies have reported that TREM-1 expression is up-regulated in patients with inflammatory bowel disease (IBD). Therefore, we investigated the associations between TREM-1 genetic polymorphisms and IBD development and its phenotypes in the Korean population. MAIN METHODS: Three TREM-1 single nucleotide polymorphisms (SNPs, rs2234237, rs3789205, and rs9471535) were genotyped by Taqman technology on 202 Crohn's disease (CD), 265 ulcerative colitis (UC), 138 with intestinal Behcet's disease (BD), and 234 healthy controls and the relationships between these SNPs and IBD development and phenotypes were evaluated. KEY FINDINGS: We found that TREM-1 SNPs are significantly associated with the development of intestinal Behcet's disease (rs9471535: odds ratio [OR]=1.637, P=0.025; rs3789205: OR=1.668, P=0.019; rs2234237: OR=1.691, P=0.016), and in particular with skin involvement (rs9471535: OR=2.723, P=0.009; rs3789205: OR=2.477, P=0.017; rs2234237: OR=2.278, P=0.030) and the risk of azathioprine use (rs9471535: OR=2.722, P=0.021; rs3789205: OR=2.493, P=0.032; rs2234237: OR=2.638, P=0.026). However, TREM-1 SNPs were not significantly associated with the development of Crohn's disease or ulcerative colitis. SIGNIFICANCE: The results of our study suggest that TREM-1 SNPs may play a significant role in the development of intestinal Behcet's disease and may have modest effects on disease severity.

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.