Dong Jik Shin

Relation of Genetic Polymorphisms in the Cytochrome P450 Gene With Clopidogrel Resistance After Drug-Eluting Stent Implantation in Koreans

Clopidogrel is a prodrug that has to be converted to an active metabolite by hepatic cytochrome P450 (CYP) isoenzymes to inhibit platelet aggregation. Individual variability of platelet inhibition by clopidogrel suggests a possibility for genetic factors having a significant influence on clopidogrel responsiveness. In this study, we sought to determine the relation of genetic polymorphisms of CYP genes to clopidogrel resistance in Koreans. Four hundred fifty patients who underwent successful percutaneous coronary intervention with drug-eluting stents were randomly assigned to treatment with dual antiplatelet regimen (aspirin plus clopidogrel) or triple antiplatelet regimen (aspirin plus clopidogrel plus cilostazol). Clopidogrel resistance using VerifyNow P2Y12 assay and genetic analysis were performed in 387 patients. Clopidogrel resistance was found in 112 patients (28.9%). In the clopidogrel-responsive group, there was a significantly higher proportion of cilostazol use. Because cilostazol showed a significant influence on clopidogrel resistance, we examined the association of single-nucleotide polymorphisms and clopidogrel resistance in the dual and triple antiplatelet therapy groups, respectively. In all subjects, the CYP2C19*3A allele was significantly more prevalent in the clopidogrel-resistant group compared with the clopidogrel-responsive group. Multiple logistic regression analysis demonstrated that CYP2C19*3 is an independent predictor of clopidogrel resistance. In conclusion, CYP2C19*3 single-nucleotide polymorphisms is an independent risk factor of clopidogrel resistance in Korean subjects with coronary artery disease.

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 12u2005months 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.

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 Crohns 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.

Adiponectin and progression of arterial stiffness in hypertensive patients

BACKGROUNDnRecent 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.nnnMETHODSnOne 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.nnnRESULTSnMean 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.nnnCONCLUSIONSnPlasma 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 of signal transducer and activator of transcription 4 genetic variants with extra-intestinal manifestations in inflammatory bowel disease

AIMSnThe STAT4 gene encodes a transcription factor which plays an important role in the development of inflammation of many immune-mediated diseases. We investigated the relationship between STAT4 single nucleotide polymorphisms (SNPs) and susceptibility to ulcerative colitis (UC) and Crohns disease (CD) and disease phenotypes in the Korean population.nnnMAIN METHODSnWe performed a case-control association study in individuals with UC (N=246), CD (N=182), and healthy controls (N=229).nnnKEY FINDINGSnWe genotyped 8 STAT4 SNPs (rs11889341, rs7574865, rs8179673, rs6752770, rs925847, rs10168266, rs10181656, and rs11685878) in the STAT4 gene in patients and controls. SNP rs925847 in the STAT4 gene was significantly associated with susceptibility to UC (P=0.025; OR=0.63) in dominant genotype analysis, though none of these SNPs were associated with CD susceptibility. Moreover, a significant association was identified between SNP rs11889341 and joint involvement (P=0.040; OR=3.79), and between SNP rs925847 and eye involvement (P=0.030; OR=2.42) in UC patients. For CD, rs925847 genetic variant was associated with joint (P=0.029; OR=3.93) and perianal lesions (P=0.033; OR=2.27).nnnSIGNIFICANCEnOur data demonstrated that the STAT4 genetic variants could predispose an individual to IBD and its extra-intestinal ailments in Koreans, suggesting the common pathogenesis of IBD (especially, extra-intestinal manifestations) and other autoimmune diseases.

Association of Plasma Retinol-Binding Protein 4, Adiponectin, and High Molecular Weight Adiponectin with Insulin Resistance in Non-Diabetic Hypertensive Patients

Purpose 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. Results 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). Conclusion RBP4 was not associated with IR or metabolic indices and the predictive value for IR was minimal in hypertensives. HMW adiponectin didnt have a superior predictive value for IR compared to adiponectin. Therefore, we can suggest that RBP4 and HMW adiponectin dont have more additive information than adiponectin in non-diabetic hypertensives.

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

AIMSnTriggering 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.nnnMAIN METHODSnThree TREM-1 single nucleotide polymorphisms (SNPs, rs2234237, rs3789205, and rs9471535) were genotyped by Taqman technology on 202 Crohns disease (CD), 265 ulcerative colitis (UC), 138 with intestinal Behcets disease (BD), and 234 healthy controls and the relationships between these SNPs and IBD development and phenotypes were evaluated.nnnKEY FINDINGSnWe found that TREM-1 SNPs are significantly associated with the development of intestinal Behcets 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 Crohns disease or ulcerative colitis.nnnSIGNIFICANCEnThe results of our study suggest that TREM-1 SNPs may play a significant role in the development of intestinal Behcets disease and may have modest effects on disease severity.

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

AIMSnTo 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.nnnMETHODS AND RESULTSnWe 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.nnnCONCLUSIONnWe 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.

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

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 Crohns disease (CD) or ulcerative colitis (UC) in the Korean population.

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.