Hua Zhang

Beijing Hospital, Peping, Beijing, China

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Publications (9)24.01 Total impact

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    ABSTRACT: Cytotoxic T lymphocyte-associated antigen-4 (CTLA4), a critical negative regulator of the T-cell response, has been considered a candidate for many autoimmune diseases. Evidence from Caucasians supported a genetic predisposition of CTLA4 to myasthenia gravis (MG), but the contribution in East Asians has not been established.
    PLoS ONE 07/2014; 9(7):e101986. DOI:10.1371/journal.pone.0101986 · 3.53 Impact Factor
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    ABSTRACT: Carboxylesterase 1 hydrolyzes the majority of clopidogrel to the inactive metabolite. The aim of this study was to assess the effects of the CES1A2 A(-816)C polymorphism and other genetic and clinical factors on clopidogrel response variability. An additional aim was to investigate the relationship between genetic variations and development of stent thrombosis (ST). We recruited 162 coronary heart disease patients treated with aspirin and clopidogrel, and we genotyped them for the CES1A2 A(-816)C, CYP2C19 *2/*3, PON1 Q192R, and ABCB1 C3435T polymorphisms. Platelet reactivity was analyzed using the VASP-PRI assay. We also carried out a case-control study in which 22 patients undergoing stent implantation who had ST were matched with 86 ST-free controls. The VASP-PRI values were significantly higher in the carriers of the CES1A2 -816C allele (P=0.014) and CYP2C19 loss of function (LOF) alleles (P=0.004). Furthermore, the patients with CYP2C19 LOF alleles showed an increased risk of ST (ORadj=4.28, P=0.033). However, there was no significant association between the CES1A2 -816C allele and the development of ST. The CYP2C19 and CES1A2 genotypes alone could explain 6.1 and 3.7% of the interindividual variability in the VASP-PRI results, respectively. The value increased to 12.5% when clinical factors (e.g. BMI and triglycerides) were also considered. The PON1 Q192R and ABCB1 C3435T genetic variations produced no significant impact. The CES1A2 -816C and the CYP2C19 LOF alleles were associated with attenuated platelet reactivity to clopidogrel. CYP2C19 LOF was also predictive of ST; however, the association between the CES1A2 -816C allele and development of ST requires further study.
    Pharmacogenetics and Genomics 02/2014; DOI:10.1097/FPC.0000000000000035 · 3.45 Impact Factor
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    ABSTRACT: A genome-wide association study and 2 replication studies identified 2 single-nucleotide polymorphisms (SNP) of caspase recruitment domain-containing protein 9 (CARD9) and small nuclear RNA-activating complex polypeptide 4 (SNAPC4) at Chr 9q34.3 associated with ankylosing spondylitis (AS) in whites. We explored a possible association of SNP in CARD9 and SNAPC4 and AS in a Chinese Han population from Shandong. The study included 1150 patients with AS and 1120 healthy controls who underwent genotyping for 4 SNP of CARD9 and 2 of SNAPC4; we replicated the results in another 490 patients and 380 healthy controls of Ningxia Han Chinese during the same time. We used quantitative real-time PCR (qRT-PCR) to measure CARD9 and SNAPC4 mRNA expression in peripheral leukocytes from 44 patients and 36 controls and allele-specific mRNA expression of CARD9 and SNAPC4 in leukocytes from 130 controls. We validated that an SNP in SNAPC4, rs11145835, was significantly associated with AS in our Chinese Han population (p = 0.001) and replicated the association in samples from the Chinese Ningxia Han population (p = 0.002). Carrying the G allele of rs11145835 was associated with increased risk of AS (OR 1.34, 95% CI 1.12-1.59) and with decreased expression of CARD9 (p = 0.001) and SNAPC4 (p = 0.02) in leukocytes. SNAPC4 mRNA expression was lower in leukocytes from patients than from controls (p = 0.0002). Our study confirmed that an SNP rs11145835 in 9q34.3 that harbors CARD9 and SNAPC4 is associated with AS in a Chinese Han population, and rs11145835 in SNAPC4 is a potential causal variant.
    The Journal of Rheumatology 12/2013; 41(2). DOI:10.3899/jrheum.130519 · 3.17 Impact Factor
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    ABSTRACT: A hydrophilic interaction chromatography-tandem mass spectrometric (HILIC-MS/MS) method was developed for the direct determination of naloxone-3-glucuronide (N3G) in human plasma and urine. After a straightforward sample preparation by protein precipitation, N3G was analyzed directly without the need for hydrolysis. Chromatographic separation was performed on a HILIC column. The mobile phase was composed of acetonitrile-10mmol/L ammonium formate (86:14, v/v), with a flow rate of 0.4mL/min. The detection was performed on a triple quadrupole tandem mass spectrometer by multiple reaction monitoring (MRM) mode via positive electrospray ionisation (ESI+) source. The linear calibration range was 0.5 to 200ng/mL in plasma and 10 to 5000ng/mL in urine (r(2)>0.99). The intra- and inter-day precision (relative standard deviation, RSD) values were below 15% and the accuracies (relative error, RE) were -7.1% to 2.8% in plasma and -1.3% to 10.3% in urine at three quality control levels. In human subjects receiving 100mg tilidine and 8mg naloxone, mean AUC0-24 of N3G was 160.93±52.77ng/mLh and mean Cmax was 75.33±25.27ng/mL. In 24-h urine samples, 8.0% of the dose was excreted in the form of N3G in urine. These results demonstrated a new method suitable for in vivo pharmacokinetic studies of N3G.
    Journal of chromatography. B, Analytical technologies in the biomedical and life sciences 10/2013; 942-943C:83-87. DOI:10.1016/j.jchromb.2013.09.036 · 2.69 Impact Factor
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    ABSTRACT: KIF21B polymorphisms were found associated with susceptibility to multiple sclerosis and ankylosing spondylitis (AS) in populations of white European ancestry. We aimed to replicate the association of polymorphisms around KIF21B and AS in a Chinese Han population. This case-control study included 665 patients with AS and 1,042 healthy controls genotyped for seven single nucleotide polymorphisms (SNPs) of KIF21B-rs12118246, rs4915464, rs502658, rs10494829, rs12089839, rs6687260, and rs957957-by TaqMan genotyping assay; statistical analyses involved the use of PLINK. We also estimated the linkage disequilibrium and haplotypes of these SNPs. Two SNPs-rs502658 (allelic p = 0.0002, odds ratio [OR] 0.60, 95 % confidence interval [95 % CI] 0.47-0.76) and rs10494829 (allelic p = 0.003, OR 1.30, 95 % CI 1.12-1.52)-were significantly associated with AS in the Chinese Han population. In addition, a linear regression test showed that they have independent contribution to disease susceptibility. For both SNPs, haplotype AT was strongly associated with AS and increased the risk of the disease (p = 0.045, OR 1.183, 95 % CI 1.004-1.395), and the genotype GC reduced the risk (p = 0.011, OR 0.715, 95 % CI 0.55-0.928). This work identified a significant association of two SNPs in KIF21B and AS in the Chinese Han population. KIF21B may play an important role in the pathogenesis of AS in the Chinese population and might be a new therapeutic target for AS.
    Immunogenetics 09/2013; DOI:10.1007/s00251-013-0733-6 · 2.49 Impact Factor
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    ABSTRACT: BACKGROUND: Aspirin and clopidogrel dual antiplatelet therapy (DAT) reduce ischemic events in patients with cardiovascular disease. However, recurrent ischemic event occurrence during DAT remains a major concern. This systematic review assesses the efficacy and safety of adjunctive cilostazol to DAT in combination with DAT on reducing clinical adverse events. METHODS: We searched randomized controlled trials (RCTs) in PubMed, Embase, Cochrane library,, and Chinese Biomedical Database through July 2011. Pooled risk ratio (RR) with 95% confidence intervals (CIs) was calculated. Two independent reviewers evaluated the included studies. The extracted data were analyzed by Review Manager 5.1.2 (The Cochrane Collaboration, Oxford, UK) and GRADEprofiler 3.6 (GRADE Working Group). RESULTS: A total of 7 RCTs (4351 patients) were included in the analysis, with a follow-up period of 6 to 12 months. Pooled analysis showed that cilostazol was associated with a significant reduction in major adverse cardiac events (MACEs; pooled RR 0.69, 95% CI 0.52-0.91; P = .008) and repeat revascularization (RR 0.74, 95% CI 0.61-0.89; P = .002); however, cilostazol was not associated with a reduction in the risk of stent thrombosis (RR 1.00, 95% CI 0.41-2.45; P = 1.00). Cilostazol seems to be safe, with no significant increase in the risk of bleeding (RR 1.06, 95% CI 0.72-1.56; P = .77). The 4 outcomes were low-quality evidence for MACE, moderate-quality evidence for repeat revascularization, and high-quality evidence for bleeding and stent thrombosis. CONCLUSIONS: When compared to the currently recommended DAT, triple antiplatelet therapy with cilostazol can reduce repeat revascularization with no increase in the risk of bleeding.
    Journal of Cardiovascular Pharmacology and Therapeutics 12/2012; 18(3). DOI:10.1177/1074248412468944 · 3.07 Impact Factor
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    ABSTRACT: PURPOSE: To assess the influence of the P450 oxidoreductase *28 SNP (POR*28) on tacrolimus pharmacokinetics in the Chinese population. METHODS: Seventy-one healthy Chinese volunteers enrolled in the study received an oral dose of 2 mg of tacrolimus after providing written informed consent. CYP3A5*3 was genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and POR*28 was genotyped by PCR-direct sequencing. Tacrolimus whole blood concentrations were determined by ultra performance liquid chromatography-tandem mass spectrometry and the pharmacokinetics analyses was evaluated by nonparametric methods. RESULTS: The frequencies of CYP3A5*3 and POR*28 allele were 73.3 % and 29.6 %, respectively. No significant differences existed in tacrolimus pharmacokinetics between the POR*28 CC homozygotes (n = 32) and the POR*28 T allele (n = 39) in all subjects. The mean tacrolimus AUC(0-24), AUC(0-∞) and C(max) for the POR*28 CC (n = 14) homozygotes in CYP3A5 expressers (CYP3A5*1/*1 or *1/*3 genotype) were 71.5 ± 38.9 h ng/mL, 94.3 ± 58.3 h ng/mL and 17.6 ± 9.8 ng/mL, which were much higher than the POR*28 CT heterozygotes (n = 17) of 46.7 ± 24.9 h ng/mL, 57.4 ± 33.9 h ng/mL and 11.2 ± 6.4 ng/mL (P < 0.05, respectively). We did not observe any significant differences in tacrolimus pharmacokinetics between the POR*28 CC homozygotes (n = 18) and POR*28 T carriers (n = 22) in CYP3A5 nonexpressers (CYP3A5*3/*3 carriers). CONCLUSIONS: The POR*28 CT genotype presented a significantly lower level of tacrolimus exposure (AUC, C(max)) compared with the POR*28 CC genotype in CYP3A5-expressing subjects. It suggested that the POR*28 genetic polymorphism might also be responsible for the marked interindividual variability of tacrolimus besides the CYP3A5*3 genetic polymorphism.
    European Journal of Clinical Pharmacology 10/2012; 69(4). DOI:10.1007/s00228-012-1432-1 · 2.70 Impact Factor
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    ABSTRACT: The aim of this study was to establish population pharmacokinetic models of tacrolimus in healthy Chinese volunteers. A total of 956 tacrolimus whole blood concentrations from 73 healthy volunteers were determined using ultraperformance liquid chromatography mass spectrometry/mass spectrometry. Population pharmacokinetic analyses were performed using NONMEM. The final population pharmacokinetic models were validated with bootstrap and visual predictive check. A number of covariates were analyzed, including CYP3A5 and ABCB1 polymorphism, demographic characteristics and hematological and biological indices. The structural model was a two-compartment model with first-order absorption, and a lag time was fitted to the data. The typical population values of tacrolimus for the pharmacokinetic parameters of apparent clearance (CL/F), apparent distribution volume of the central compartment (V(2)/F), intercompartmental clearance (Q/F), apparent distribution volume of the peripheral compartment (V(3)/F), absorption rate (ka) and lag time (ALAG) were 27.7 l/h, 37.5 liters, 34.4 l/h, 357 liters, 0.795 h(-1) and 0.226 h, respectively. The interindividual variabilities of these parameters were 63.3, 62.0, 50.8, 52.3, 32.9 and 4.45%, respectively, and the intraindividual variability of observed concentrations was 14.9%. The covariates that were retained in the final models were CYP3A5 genotype on CL/F, and body surface area and red blood count on V(3)/F. Population pharmacokinetic models of tacrolimus were developed in healthy volunteers. These results could provide a reference for individualized tacrolimus therapy in the clinical setting.
    Pharmacology 11/2011; 88(5-6):288-94. DOI:10.1159/000331856 · 1.58 Impact Factor
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    ABSTRACT: The cause of myasthenia gravis (MG) is unknown, but it is widely believed to be an autoimmune disease occurring in genetically susceptible individuals. The human leukocyte antigen (HLA) region is considered to be the most important genetic region for MG susceptibility genes. To investigate the association between HLA-DRB1 and myasthenia gravis (MG) in a northern Han Chinese population, a polymerase chain reaction with sequence-specific oligonucleotide probe hybridization method was used to determine the HLA-DRB1 genotypes of 91 patients with MG and 171 healthy individuals. We found that the HLA-DRB1(*)09 allele was significantly more prevalent among patients with MG than among healthy controls, especially those who experienced early onset of the disease (≤40 years), those who were seronegative for acetylcholine receptor antibody, and those with ocular MG. The prevalence of the HLA-DRB1(*)08 allele was significantly lower among patients with MG than among controls. These results indicate that HLA-DRB1(*)09 might be positively associated and DRB1(*)08 negatively associated with MG in the northern Han Chinese population.
    Journal of Clinical Neuroscience 09/2011; 18(11):1524-7. DOI:10.1016/j.jocn.2011.05.002 · 1.32 Impact Factor