Association between cytochrome P450 2C19 polymorphism and clinical outcomes in Chinese patients with coronary artery disease

BackgroundCytochrome P450 (CYP)2C19 is expressed in vascular endothelium and metabolizes arachidonic acid to biologically active epoxyeicosatrienoic acids, which play a key role in regulating vascular tone. The aim of this study was to investigate whether the genetic functional variant 681G > A (*2) of cytochrome CYP2C19 is associated with adverse cardiovascular outcomes in Chinese patients with coronary artery disease (CAD).MethodsBetween July 2008 and September 2009, 654 consecutive patients with CAD were enrolled in this study. All participants underwent CYP2C19 genotyping. The primary study endpoint was a composite of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke. Secondary endpoints included the components of the primary endpoint, death from any cause, and recurrent revascularization.ResultsThe baseline characteristics were well-balanced between carriers (heterozygous *1/*2, n = 291; homozygous *2/*2, n = 57) and non-carriers (n = 306) of the CYP2C19*2 variant. During the follow-up period (11.42 ± 4.23 months), the primary endpoint occurred more frequently in homozygous *2/*2 than in non-carriers (n = 306) of CYP2C19*2 variant (12.28% versus 3.27%; adjusted hazard ratio [HR] = 5.191; 95% confidence interval [CI] = 1.936–13.917; P = 0.001); however, no such increase was evident in heterozygous *1/*2 patients (4.12% versus 3.27%; adjusted HR = 1.208; 95% CI 0.517–2.822; P = 0.662).ConclusionsThe homozygous CYP2C19*2/*2 genotype is an independent determinant of adverse vascular events in Chinese patients with CAD.     

CYP2C19*2/ABCB1-C3435T polymorphism and risk of cardiovascular events in coronary artery disease patients on clopidogrel: Is clinical testing helpful?

BackgroundStudies evaluating CYP2C19*2 and ABCB1-C3435T polymorphisms have shown conflicting results. We performed this meta-analysis to evaluate role of clinical testing for these polymorphisms in CAD patients on clopidogrel.Methods19,601 patients from 14 trials were analyzed. The endpoints were major adverse cardiovascular events (MACE), cardiovascular (CV) death, stent thrombosis (ST), myocardial infarction (MI), stroke and major bleeding. Combined relative risks (RR) with 95% confidence intervals (CI) were computed for each outcome by using standard methods of meta-analysis and test parameters were computed.ResultsCYP2C19*2 polymorphism was associated with higher risk of MACE [RR: 1.28, CI: 1.06–1.54; p = 0.009], CV death [RR: 3.21, CI: 1.65–6.23; p = 0.001], MI [RR: 1.36, CI: 1.12–1.65; p = 0.002], ST [RR: 2.41, CI: 1.69–3.41; p < 0.001]. No difference was seen in major bleeding events [RR: 1.02, CI: 0.86–1.20; p = 0.83]. Subgroup analysis showed similar results for elective PCI [RR: 1.34, CI: 1.01–1.76; p = 0.03], and PCI with DES [RR: 1.53, CI: 1.029–1.269; p = 0.03]. CYP2C19*2 polymorphism has very low sensitivity (28–58%), specificity (71–73%), positive predictive value (3–10%) but good negative predictive value (92–99%). ABCB1-C3435T polymorphism analysis revealed similar MACE [RR: 1.13, CI: 0.99–1.29; p = 0.06], ST [RR: 0.88, CI: 0.52–1.47; p = 0.63] and major bleeding [RR: 1.04, CI: 0.87–1.25; p = 0.62] in both groups.ConclusionIn CAD patients on clopidogrel therapy, CYP2C19*2 polymorphism is associated with significantly increased adverse cardiovascular events. However, due to the low positive predictive value, routine genetic testing cannot be recommended at present.     

Evaluation of the INNOVANCE PFA P2Y assay and its association with CYP2C19 genotypes

The purpose of this study was to evaluate associations between INNOVANCE PFA P2Y (PFA P2Y) test results and CYP2C19 genotypes and provide baseline data for PFA P2Y testing to establish a therapeutic monitoring strategy for clopidogrel. A total of 75 new patients with acute coronary syndrome with planned percutaneous coronary intervention were enrolled between June 2012 and September 2012. All patients received clopidogrel at an initial loading dose of 600?mg followed by a 75-mg daily maintenance dose. Blood samples were obtained on the third morning after clopidogrel loading. PFA P2Y, VerifyNow P2Y12 and VASP assays were used to determine platelet inhibition due to clopidogrel, and the Verigene CYP2C19 test was used for CYP2C19 genotyping. The genotype frequency of 75 patients was as follows: CYP2C19 *1/*1 (wild type), 28 (37.3%); *1/*2, 31 (41.3%); *1/*3, 4 (5.3%); *2/*2, 5 (6.7%); *2/*3, 5 (6.7%); *1/*17, 1 (1.3%); and *2/*17, 1 (1.3%). Classified according to CYP2C19 genotypes, there were 29 (38.7%) extensive metabolizers (EM) or ultra rapid metabolizers (UM), 35 (46.7%) intermediate metabolizers (IM), and 10 (13.3%) poor metabolizers (PM). Median (interquartile range) PFA P2Y closure times (seconds) were 119 (101–260), 300 (130–300) and 300 (300–300) in the PM, IM and EM or UM groups, respectively (p?<?0.05). Median (interquartile range) VerifyNow PRUs were 294 (213–297), 215 (165–320) and 189 (118–279); and the VASP platelet reactivity index (%) was 52.7 (33.3–91.9), 59.9 (41.4–72.8) and 38.9 (26.8–62.2) in the PM, IM and EM or UM groups, respectively (p?>?0.05). Compared with non-carriers, carriers of reduced function CYP2C19 alleles tended to have higher platelet reactivity after clopidogrel treatment. The cut-off for PM versus other groups (IM and EM or UM) was ≤141 seconds (AUC 0.704, sensitivity 70%, specificity 76.6%) on the ROC curve. A statistically significant correlation between PFA P2Y (seconds) and VerifyNow (PRU) was found (ρ?=??0.47, p?<?0.0001). In conclusion, the PFA P2Y test showed a statistically significant association with CYP2C19 metabolizer phenotypes based on CYP2C19 genotyping and effectively determined the risk groups resistant to clopidogrel therapy, including PM.     

High on-treatment platelet reactivity by ADP and increased risk of MACE in good clopidogrel metabolizers

High on-treatment platelet reactivity (HPR) by ADP, which primarily reflects the effect of thienopyridines, has been found to be an independent predictor of ischemic events in patients with acute coronary syndrome (ACS) on dual antiplatelet therapy. CYP2C19*2 is associated with HPR by ADP. The aim of our study was to evaluate if high on-clopidogrel platelet reactivity (HPR) by ADP is associated with an increased risk of major adverse coronary events (MACE) after ACS independent of CYP2C19*2 allele, i.e. whether genotyping patients for CYP2C19*2 polymorphism is sufficient to identify those to be switched to novel antiplatelets. A total of 1187 patients were included (CYP2C19 *1/*1 n?=?892; *1/*2 n?=?264; *2/*2 n?=?31); 76 MACE (CV death and non-fatal MI) were recorded in non-carriers of CYP2C19*2 (8.5%) and 39 in carriers of CYP2C19*2 (13.2%). At the landmark analysis in the first 6 months, HPR by ADP and CYP2C19*2 allele were both significantly and independently associated with MACE [HPR by ADP: HR?=?2.0 (95% CI 1.2–3.4), p?=?0.01; CYP2C19*2 allele: HR?=?2.3 (95% CI 1.3–3.9), p?=?0.003]. At the land mark analysis from 7 to 12 months, only HPR by ADP remained significantly associated with the risk of MACE [HPR by ADP: HR?=?2.7 (95% CI 1.4–5.3), p?=?0.003; CYP2C19*2: HR?=?0.8 (95% CI 0.2–1.1), p?=?ns]. CYP2C19*2 allele and HPR by ADP are both independently associated with an increased risk of MACE in the first 6 months after ACS. HPR by ADP is associated with an increased risk until 12 months of follow-up. Therefore, both phenotype and genotype are clinically relevant for the evaluation of the antiplatelet effect of clopidogrel and for the prognostic stratification of ACS patients.     

Effect of CYP2D6*10 and APOE Polymorphisms on the Efficacy of Donepezil in Patients With Alzheimer’s Disease

BackgroundThe aim of this study was to evaluate the effect of CYP2D6*10 and APOE polymorphisms on both steady-state plasma concentrations (Cp) and clinical response of donepezil in patients with mild-to-moderate Alzheimer’s disease (AD).MethodsA total of 110 Chinese AD patients participated in this study. Patients were treated with 5 to 10 mg of donepezil daily for 6 months. The genotypes of CYP2D6*10 and APOE were analyzed by polymerase chain reaction–restriction fragment length polymorphism. The steady-state Cp of donepezil was measured by high-performance liquid chromatography–tandem mass spectrometric assay method. The cognition of patients was evaluated at baseline and at 6-month follow-up by Mini-Mental Status Examination and Alzheimer Disease Assessment Scale-Cognitive subscale.ResultsAt 6-month follow-up, 56 of 96 patients (58.3%) were evaluated as responders and 40 patients (41.7%) as nonresponders to donepezil treatment. A significantly higher frequency of patients with genotypes CYP2D6*1/*10 and *10/*10 were found in responders than in nonresponders (P < 0.05). Besides, patients with CYP2D6*1/*10 and *10/*10 genotypes had higher Cp of donepezil and improved cognition scores than those with CYP2D6*1/*1 genotype (P < 0.05). However, the frequency of APOE ε4 carriers and noncarriers showed no difference between the 2 groups (P > 0.05).ConclusionsAD patients with mutant allele (*10) in CYP2D6 gene may respond better to donepezil than those with wild allele (*1). We did not find the relationship between APOE ε4 status and the efficacy of donepezil in our study.     

Cytochrome P450 2C19 loss-of-function polymorphism is a major determinant of clopidogrel responsiveness in healthy subjects

The capacity of clopidogrel to inhibit ADP-induced platelet aggregation shows wide intersubject variability. To determine whether frequent functional variants of genes coding for candidate cytochrome P450 (CYP) isoenzymes involved in clopidogrel metabolic activation (CYP2C19*2, CYP2B6*5, CYP1A2*1F, and CYP3A5*3 variants) influence the platelet responsiveness to clopidogrel, we conducted a prospective pharmacogenetic study in 28 healthy white male volunteers treated for 7 days with clopidogrel 75 mg/d. We observed that pharmacodynamic response to clopidogrel was significantly associated with the CYP2C19 genotype. Twenty of the subjects were wild-type CYP2C19 (*1/*1) homozygotes, while the other 8 subjects were heterozygous for the loss-of-function polymorphism CYP2C19*2 (*1/*2). Baseline platelet activity was not influenced by the CYP2C19 genotype. In contrast, platelet aggregation in the presence of 10 muM ADP decreased gradually during treatment with clopidogrel 75 mg once daily in *1/*1 subjects, reaching 48.9% +/- 14.9% on day 7 (P < .001 vs baseline), whereas it did not change in *1/*2 subjects (71.8% +/- 14.6% on day 7, P = .22 vs baseline, and P < .003 vs *1/*1 subjects). Similar results were found with VASP phosphorylation. The CYP2C19*2 loss-of-function allele is associated with a marked decrease in platelet responsiveness to clopidogrel in young healthy male volunteers and may therefore be an important genetic contributor to clopidogrel resistance in the clinical setting.     

CYP 450 2C19 polymorphisms in Indian patients with coronary artery disease

Background

Dual antiplatelet therapy is the cornerstone in the management of acute coronary syndromes (ACS) and prevention of stent thrombosis (ST). Genetic polymorphisms in CYP2C19 gene involved in hepatic activation of clopidogrel leads to clopidogrel non-responsiveness and may influence clinical outcomes. These polymorphisms in CYP2C19 gene and their impact on clinical outcome in coronary artery disease (CAD) have not been studied in Indian population.

Methods

We studied 110 consecutive patients (mean age 55.7 ± 10.7 years; 90% male) taking clopidogrel with angiographically proven CAD for various genetic polymorphisms in CYP2C19 gene. Relationship between loss of function mutation and clinical presentation with recurrent ACS including ST was analyzed.

Results

Out of 110 patients, 26 (23.64%) had normal genotype, 52 (47.23%) had loss of function mutation *2 and 39 (35.45%) had a gain of function mutation *17, 7 (6.36%) patients were undefined metabolizers (*2/*17) which were excluded from analyses. Final analyses included 103 patients, with 45 (40.90%) having loss of function. Overall 51 patients had ACS, with 27 developing recurrence while on clopidogrel. The prevalence of loss of function mutation was no different between the group with recurrences and those without recurrences (55.6% vs. 50%, p = 0.7). Two patients developed ST while on clopidogrel; both had loss of function mutation.

Conclusion

CYP2C19 gene polymorphisms are common in Indian population. Loss of function mutation status did not affect the clinical outcomes. A larger study also considering P2Y12 receptor polymorphisms together with platelet activity testing, may be required to establish the role of CYP2C19 gene polymorphisms in clinical practice.     

Platelet aggregation at discharge: A useful tool in acute coronary syndromes?

IntroductionInhibition of platelet aggregation appears two hours after the first dose of clopidogrel, becomes significant after the second dose, and progresses to a steady-state value of 55% by day seven. Low response to clopidogrel has been associated with increased risk of stent thrombosis and ischemic events, particularly in the context of stable heart disease treated by percutaneous coronary intervention.ObjectiveTo stratify medium-term prognosis of an acute coronary syndrome (ACS) population by platelet aggregation.MethodsWe performed a prospective longitudinal study of 70 patients admitted for an ACS between May and August 2009. Platelet function was assessed by ADP-induced platelet aggregation using a commercially available kit (Multiplate^® analyzer) at discharge. The primary endpoint was a combined outcome of mortality, non-fatal myocardial infarction, or unstable angina, with a median follow-up of 136.0 (79.0–188.0) days.ResultsThe median value of platelet aggregation was 16.0 U (11.0–22.5 U) with a maximum of 41.0 U and a minimum of 4.0 U (normal value according to the manufacturer: 53–122 U). After ROC curve analysis with respect to the combined endpoint (AUC 0.72), we concluded that a value of 18.5 U conferred a sensitivity of 75.0% and a specificity of 68% to that result. We therefore created two groups based on that level: group A – platelet aggregation <18.5 U, n = 44; and group B – platelet aggregation ≥18.5 U, n = 26. The groups were similar with respect to demographic data (age 60.5 [49.0–65.0] vs. 62.0 [49.0–65.0] years, p = 0.21), previous cardiovascular history, and admission diagnosis. There were no associations between left ventricular ejection fraction, GRACE risk score, or length of hospital stay and platelet aggregation. The groups were also similar with respect to antiplatelet, anticoagulant, proton pump inhibitor (63.6 vs. 46.2%, p = 0.15) and statin therapy. The variability in platelets and hemoglobin was also similar between groups. Combined event-free survival was higher in group A (96.0 vs. 76.7%, log-rank p < 0.01). Platelet aggregation higher than 18.5 U was an independent predictor of the combined event (HR 6.75, 95% CI 1.38–32.90, p = 0.02).ConclusionIn our ACS population platelet aggregation at discharge was a predictor of medium-term prognosis.     

Next-Generation Sequencing of CYP2C19 in Stent Thrombosis: Implications for Clopidogrel Pharmacogenomics

Purpose

Describe CYP2C19 sequencing results in the largest series of clopidogrel-treated cases with stent thrombosis (ST), the closest clinical phenotype to clopidogrel resistance. Evaluate the impact of CYP2C19 genetic variation detected by next-generation sequencing (NGS) with comprehensive annotation and functional studies.

Methods

Seventy ST cases on clopidogrel identified from the PLATO trial (n =?58) and Mayo Clinic biorepository (n =?12) were matched 1:1 with controls for age, race, sex, diabetes mellitus, presentation, and stent type. NGS was performed to cover the entire CYP2C19 gene. Assessment of exonic variants involved measuring in vitro protein expression levels. Intronic variants were evaluated for potential splicing motif variations.

Results

Poor metabolizers (n =?4) and rare CYP2C19*8, CYP2C19*15, and CYP2C19*11 alleles were identified only in ST cases. CYP2C19*17 heterozygote carriers were observed more frequently in cases (n =?29) than controls (n =?18). Functional studies of CYP2C19 exonic variants (n =?11) revealed 3 cases and only 1 control carrying a deleterious variant as determined by in vitro protein expression studies. Greater intronic variation unique to ST cases (n =?169) compared with controls (n =?84) was observed with predictions revealing 13 allele candidates that may lead to a potential disruption of splicing and a loss-of-function effect of CYP2C19 in ST cases.

Conclusion

NGS detected CYP2C19 poor metabolizers and paradoxically greater number of so-called rapid metabolizers in ST cases. Rare deleterious exonic variation occurs in 4%, and potentially disruptive intronic alleles occur in 16% of ST cases. Additional studies are required to evaluate the role of these variants in platelet aggregation and clopidogrel metabolism.

     

Single polymorphism nucleotide rs1333049 on chromosome 9p21 is associated with carotid plaques but not with common carotid intima-media thickness in older adults. A combined analysis of the Three-City and the EVA studies

ObjectivesTo address the relationship of rs1333049, the 9p21 variant showing the strongest association with coronary heart disease (CHD), with carotid plaques and plaque-free common carotid artery intima-media thickness (CCA-IMT) in older adults from 2 French population-based cohorts.MethodsWe genotyped for rs1333049, 4097 CHD-free participants including 3191 aged 65–86 years from the Three-City (3C) Study and 906 aged 59–71 years from the Vascular Aging Study (EVA). Plaque-free mean CCA-IMT and the presence of carotid plaques were assessed.ResultsIn multivariate analysis, each C allele copy of rs1333049 was associated with baseline carotid plaques (odds ratio (OR) = 1.24; 95% confidence interval (CI) = 1.13–1.36; p < 0.001) but not with baseline CCA-IMT (p = 0.19). Among the EVA participants, the C allele was associated with 4-year plaques progression (p = 0.04) but not with CCA-IMT progression.ConclusionThe chromosome 9p21 locus might influence CHD risk through carotid plaques development.     

The impact of the CYP2C9 and VKORC1 polymorphisms on acenocoumarol dose requirements in a Romanian population

AimTo investigate the genotype–phenotype correlation in Romanian patients treated with acenocoumarol.Material and methodsWe studied 301 consecutive patients who required treatment with acenocoumarol, admitted within the Municipal Hospital of Cluj-Napoca and the Heart Institute “Niculae St?nciou” in Cluj-Napoca over a 3-year period. For each patient we recorded clinical parameters which could interfere with the achievement of stable therapeutic international normalized ratio (INR). We performed genetic analysis which consisted of genotyping the CYP2C9 gene and the VKORC1 gene. Patients were divided in three groups according to the acenocoumarol dose needed to reach a stable INR: the low dose group (≤ 7 mg/week), the medium dose group (> 7 mg and < 28 mg/week) and the high acenocoumarol dose group (> 28 mg/week).ResultsWe found that patients' age was significantly different between groups (p < 0.001). No differences existed between groups regarding the pathologies which required anticoagulation therapy or the concomitant treatment. The following parameters increased the odds of receiving a low dose of acenocoumarol: patient's age over 65 years (OR, 3.2; p = 0.01; 95%CI: 1.24–8.25), the presence of the CYP2C9*3 allele (OR, 3.4; p = 0.006; 95%CI: 1.41–8.34), and the GA or AA genotype of c.-1639G>A polymorphism of VKORC1 (OR, 6.5; p = 0.01; 95%CI: 1.38–30.5; respectively OR, 11.6; p = 0.003; 95%CI: 2.26–59.58). A high acenocoumarol dose was less likely to be administered to an elderly patient (OR, 0.24; p = 0.001; 95%CI: 0.1–0.56) or to a patient with the GA or AA genotype (OR, 0.2; p < 0.001; 95CI%: 0.09–0.45; respectively OR, 0.05; p = 0.006; 95%CI: 0.007–0.43).ConclusionThe stable therapeutic dose of acenocoumarol is dependent of patient's age, the presence of the CYP2C9*3 allele and the c.-1639G>A polymorphism of VKORC1.     

Polymorphisms of MDR1, CYP2C19 and P2Y12 genes in Indian population: Effects on clopidogrel response

Aims/objectiveInfluence of genetic variations on the response of clopidogrel, an antiplatelet drug is implicated. In the present study, the prevalence of single nucleotide polymorphisms of MDR1 (C3435T), CYP2C19 [CYP2C19*2 CYP2C19*3, CYP2C19*17] and P2Y₁₂ (i-T744C) in Indian population and their effects on clopidogrel response was analyzed.Methods and resultsTo analyze the prevalence of polymorphisms, 102 healthy individuals were recruited. Clopidogrel response was assessed by ADP induced platelet aggregation in clopidogrel naïve acute myocardial infarction (AMI) patients (n = 26) screened from 100 AMI cases, before loading dose of 300 mg, at 24 h before next dose and 6 days after on 75 mg per day and platelet aggregation inhibition (PAI) was calculated between these time intervals. Genotyping was carried out by PCR-based restriction enzyme digestion method for C3435T of MDR1 and i-T744C of P2Y₁₂, by multiplex PCR for CYP2C19*2 (G681A) and CYP2C19*3 (G636A) and by nested PCR for CYP2C19*17 (C806T). The effect of the above mentioned genetic variations on PAI was analyzed. Variant allele of CYP2C19*3 was not observed while the prevalence of 3435T of MDR1 (0.524), CYP2C19*2 (681A, 0.352); i-744C of P2Y₁₂ (0.088), as well as wild type allele CYP2C19*17 (C806, 0.897) associated with decrease clopidogrel response were observed. Trend toward poor response to clopidogrel was observed at 24 h with the variant genotypes of CYP2C19*2 and i-T744C of P2Y₁₂ as compared to wild type.ConclusionThe present study did show a trend toward impaired response of clopidogrel to inhibit platelet aggregation with variant genotypes of CYP2C19*2 and iT744C of P2Y₁₂ compared to respective wild type genotype at 24 h.     

IL6, IL10 and TGFB1 gene polymorphisms in coeliac disease: differences between DQ2 positive and negative patients

Predisposition to coeliac disease (CD) might be partially due to an individual pattern of hyper-inflammatory biased immune response. One of these patterns of intense response may be linked to the haplotype carrying HLA-DQ2 alleles and TNF −308A allele. However, 10 % of CD patients do not express the DQ2 heterodimer and these do not usually carry the TNF −308A allele. A similar response might be achieved by genes codifying other cytokines.ObjectivesTo study biallelic polymorphisms in genes codifying for TNFα, IL10, IL6 and TGFβ1 in DQ2 negative CD patients and to compare the results with DQ2 positive patients and healthy controls, in order to establish whether any of these polymorphisms have a role in CD susceptibility.MethodsTNF −308 (G > A), IL-6 −174 (G > C) and TGFB1 codon 10 (+ 869, T > C) and codon 25 (+ 915, G > C) polymorphisms and IL-10 haplotype of polymorphisms in positions −1082 (G > A), −819 (C > T) and −592 (C > A) were typed by a SSP-PCR technique.ResultsThe distribution of allele frequencies for TNF −308 is different between DQ2 positive CD patients and controls and the same occurs for haplotype frequencies of the IL10 promoter (−1082, −819, −592): The frequencies of the TNF −308A allele (p = 0.027), TNF −308A carriers (p = 0.031) and of IL10GCC haplotype are increased (p = 0.013) in DQ2 positive CD patients. However, the IL6 −174 allele G is more frequent in DQ2 negative patients than in healthy controls (p = 0.018), DQ2 negative controls (p = 0,018), and DQ2 positive patients (p = 0.008).ConclusionsDQ2 negative CD patients show an increased frequency of genotypes associated to IL6 high production. These were mainly allele G homozygous for the IL6 gene (−174) polymorphism. The IL6 −174GG genotype (homozygous) may be an additional risk marker for CD in DQ2 negative patients, representing an alternative susceptibility factor for CD when TNF −308A is negative.     

Influence of the CYP2J2 Gene Polymorphisms on Chronic Obstructive Pulmonary Disease Risk in the Chinese Han Population

IntroductionCytochrome P450 (CYP) 2J2 is a major enzyme that controls epoxyeicosatrienoic acids biosynthesis, which may play a role in chronic obstructive pulmonary disease (COPD) development. In this study, we aimed to assess the influence of CYP2J2 polymorphisms with COPD susceptibility.Material and methodsA case–control study enrolled 313 COPD cases and 508 controls was to investigate the association between CYP2J2 polymorphisms and COPD risk. Agena MassARRAY platform was used to genotype CYP2J2 polymorphisms. Odds ratios (OR) and 95% confidence intervals (CI) were calculated to evaluate the association between CYP2J2 polymorphisms and COPD risk.ResultsWe observed rs11207535 (homozygote: OR = 0.08, 95%CI = 0.01–0.96, p = 0.047; recessive: OR = 0.08, 95%CI = 0.01–0.94, p = 0.044), rs10889159 (homozygote: OR = 0.08, 95%CI = 0.01–0.92, p = 0.043; recessive: OR = 0.08, 95%CI = 0.01–0.90, p = 0.040) and rs1155002 (heterozygote: OR = 1.63, 95%CI = 1.13–2.36, p = 0.009; dominant: OR = 1.64, 95%CI = 1.15–2.35, p = 0.006; additive: OR = 1.45, 95%CI = 1.09–1.92, p = 0.011) were significantly associated with COPD risk. Allelic tests showed T allele of rs2280274 was related to a decreased risk of COPD and T allele of rs1155002 was associated with an increased COPD risk. Stratified analyses indicated the effects of CYP2J2 polymorphisms and COPD risk were dependent on gender and smoking status (p < 0.05). Additionally, two haplotypes (A_rs11207535C_rs10889159T_rs1155002 and A_rs11207535C_rs10889159C_rs1155002) significantly decreased COPD risk.ConclusionIt suggested CYP2J2 polymorphisms were associated with COPD susceptibility in the Chinese Han population.     

Reduced clot permeability and susceptibility to lysis in patients with acute coronary syndrome: effects of inflammation and oxidative stress

BackgroundStable angina is associated with unfavorable fibrin structure/function. It is not known how acute coronary syndromes (ACS) affect fibrin architecture.ObjectiveWe investigated fibrin clot properties and their determinants in ACS patients.Patients and methodsClot permeability, turbidity and fibrinolysis were assessed in 40 patients with ACS versus 40 controls with stable angina matched for age, sex, and risk factors.ResultsPatients with ACS had lower clot permeability (p = 0.001), faster fibrin polymerization (p = 0.008), and prolonged fibrinolysis time (p < 0.0001) than controls. C-reactive protein (CRP) and 8-epi-prostaglandin F_2α, a marker of oxidative stress, were the only independent predictors of clot permeability (R² = ?0.74; p < 0.0001 and R² = ?0.65; p < 0.0001, respectively) and fibrinolysis time in ACS patients (R² = 0.60; p < 0.0001 and R² = 0.59; p = 0.0002, respectively). In angina patients, fibrinogen and CRP predicted permeability (R² = ?0.71; p < 0.0001 and R² = ?0.62; p < 0.0001), and D-dimer predicted lysis time (R² = 0.54; p = 0.0005). In regression analysis models incorporating all patients, the only independent predictor of all clot variables was being an ACS patient (R² 0.51 to 0.85; p < 0.001).ConclusionsThis first study of clot properties in patients during an ACS demonstrated that compared with stable angina patients, their clots are composed of dense networks that are more resistant to lysis and these features are correlated with raised CRP and oxidative stress.     

Adiponectin G276T gene polymorphism is associated with cardiovascular disease in Japanese patients with type 2 diabetes

ObjectiveAdiponectin has anti-atherogenic properties and reduced serum adiponectin levels are associated with cardiovascular disease (CVD). In this study, we examined the relationship between CVD and adiponectin (ADIPOQ) gene G276T polymorphism that is associated with serum adiponectin level in a large cohort of type 2 diabetic patients.Research design and methodsWe enrolled 2637 Japanese type 2 diabetic subjects (males, 61.1%; age, 54.9 ± 7.9 years old), determined their genotypes regarding ADIPOQ G276T polymorphisms, and evaluated the association between this polymorphism and the prevalence of CVD (myocardial infarction and/or cerebral infarction).ResultsThe prevalence of CVD tended to be higher as the number of G alleles increased [GG (9.5%), GT (6.8%), TT (5.6%), p value for trend = 0.0059] and was significantly higher in the subjects with GG genotype compared to those with GT or TT genotype (9.5% vs. 6.6%, p = 0.0060). Multiple logistic regression analyses revealed that the number of G alleles (Odds ratio (OR) = 1.49 with 95%CI 1.09–2.05, p = 0.0125) and GG genotype (OR = 1.66 with 95%CI 1.13–2.43, p = 0.0098) were significantly associated with CVD even after adjustment for conventional risk factors. Interestingly, the presence of obesity further and significantly increased the risk of CVD in the subjects with GG genotype (OR = 1.67 with 95%CI 1.14–2.44, p = 0.0090) but not in the subjects with TT or GT genotype (OR = 1.17 with 95%CI 0.73–1.89, NS).ConclusionsIt is likely that the G allele of the ADIPOQ G276T polymorphism is a susceptibility allele for CVD in Japanese type 2 diabetic patients, especially when they accompany obesity.     

Proinflammatory HLA-DRB1*01-haplotype predisposes to ST-elevation myocardial infarction

BackgroundMajor histocompatibility complex (MHC) gene region harbours haplotypes that associate with coronary artery disease (CAD). Their role in ST-elevation infarction (STEMI) or on the inflammatory level is not known.MethodsFour candidate MHC markers were analyzed by real-time quantitative PCR and constructed into haplotypes from patients with STEMI (n = 162), matched controls with no CAD (n = 319) and general population sample (n = 149). High sensitivity C-reactive protein (hsCRP) was assessed in a follow-up visit from patients (n = 86) and at inclusion from other study subjects.ResultsThe haplotype with one copy of HLA-DRB1*01, C4A, C4B but no HLA-B*35 doubled the risk of STEMI (OR = 2.15, 95%CI = 1.11–4.15, p = 0.020 for patients vs. controls, and OR = 2.26, 95%CI = 0.97–5.24, p = 0.052 for patients vs. population sample). The association between patients and controls persisted in multivariate analyses. The frequency of the haplotype was 5.86% (n = 19/324) in patients, 2.82% (n = 18/638) in controls and 2.68% (n = 8/298) in population sample. None of the individual MHC markers alone showed significant association with STEMI.In multivariate analyses, the haplotype carriers had higher hsCRP levels in patients (median 3.37 mg/L in carriers vs. 1.14 mg/L in non-carriers, p = 0.019) and in controls (median 2.90 mg/L vs. 1.21 mg/L, p = 0.009, respectively).ConclusionThe MHC haplotype associates with STEMI and elevated baseline hsCRP levels. The results are in concordance with previous data on non-STEMI patients, implying that a HLA-DRB1*01 – related haplotype increases the risk of CAD, possibly though increased inflammation.     

Investigation of SLC2A1 26177A/G gene polymorphism via high resolution melting curve analysis in Malaysian patients with diabetic retinopathy

PurposeIn this study, we aimed to investigate the possible association between SLC2A1 26177A/G polymorphism and diabetic retinopathy (DR) in Malaysian patients with type 2 diabetes.MethodsGenomic DNA was extracted from 211 Malaysian type 2 diabetic patients (100 without retinopathy [DNR], 111 with retinopathy) and 165 healthy controls. A high resolution melting assay developed in this study was used to detect SLC2A1 26177A/G polymorphism followed by statistical analysis.ResultsA statistically significant difference in 26177 G minor allele frequency between healthy controls (19.7 %) and total patient group (26.1 %) (p < 0.05, Odd ratio = 1.437, 95% Confidence interval = 1.015–2.035) as well as between healthy controls (19.7 %) and DNR patients (27.5%) (p < 0.05, Odd ratio = 1.546, 95% Confidence interval = 1.024–2.336) was shown in this study. However, when compared between DR and DNR patients, there was no significant difference (p > 0.05).ConclusionsThis is the first study which shows that SLC2A1 26177G allele is associated with type 2 diabetes in Malaysian population but not with DR.     

细胞色素P450 2C19*2基因多态性联合钙通道阻滞剂与冠状动脉支架内血栓形成的相关性

目的:探讨经皮冠状动脉介入术(PCI)后接受氯吡格雷治疗的患者中,细胞色素P450 2C19(CYP2C19)*2基因多态性(681A)与支架内血栓形成的相关性,以及服用钙通道阻滞剂(CCBs)与支架内血栓形成的相关性。方法:检测1 738例冠心病PCI术后患者的CYP2C19基因多态性,并将这些患者分为CCBs组和非CCBs组,采用比浊法检测二磷酸腺苷(ADP)途径诱导的血小板最大聚集率(MPAR),比较两组患者MPAR及支架内血栓形成率的差异。结果:19例(2.4%)CYP2C19*2基因型的患者(包括CYP2C19*2/*2或*1/*2)和7例(0.75%)基因型为CYP2C19*1/*1的患者发生了明确的支架内血栓形成;CYP2C19*2基因型患者支架内血栓形成的发生率明显高于CYP2C19野生型纯合子患者(CYP2C19*1/*1)(风险比为4.26,95%可信区间为1.28～9.22,P<0.05);基因型为CYP2C19*1/*1的患者发生支架内血栓形成的风险最低,而基因型为CYP2C19*2/*2的患者支架内血栓形成的风险最高(风险比为0.568,95%可信区间为0.308～2.070,P<0.01);CCBs组和非CCBs组MPAR及支架内血栓形成率差异无统计学意义。结论:PCI术后接受氯吡格雷治疗的冠心病患者中,CYP2C19*2基因型患者支架内血栓形成的风险增加,而服用CCBs不会导致氯吡格雷抗血小板聚集作用减弱以及支架内血栓形成事件增加。