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The Pharmacogenomics Journal (2007) 7, 325–332& 2007 Nature Publishing Group All rights reserved 1470-269X/07 $30.00 Clozapine-induced agranulocytosis inschizophrenic Caucasians: confirming cluesfor associations with human leukocyteclass I and II antigens Clozapine-induced agranulocytosis (CA) is still among the least understoodadverse drug reactions in psychopharmacology. In particular, its genetic background is far from being clarified. Within the framework of a case– control study, we performed human leukocyte antigen (HLA) genotyping Department of Psychiatry and Psychotherapy, Charite´-University Medicine Berlin, Berlin, and haplotype analyses in 42 non-Jewish Caucasian schizophrenic patients (N ¼ 42) suffering from CA and 75 non-Jewish Caucasian schizophrenic Institute of Pharmacology, University Hospital patients treated with clozapine without developing CA. While controlling for Department of Gerontopsychiatry, Center for ¼ 0.835), testing of the alleles from both HLA-loci resulted in borderline results for Cw2 (P ¼ 0.085, odds ratio (OR) ¼ 0.36, 95% confidence interval (CI): 0.08–1.23), Cw7 (P ¼ 0.058, OR ¼ 2.0, 95% CI: 0.87–4.63) and DRB5*0201 (P ¼ 0.005, adjusted OR ¼ 22.15). For Dr M Dettling, Department of Psychiatry and haplotype analysis, we obtained significant association results with CA Psychotherapy, Charite´-University MedicineBerlin, Campus Benjamin Franklin, Eschenallee for the two-locus haplotypes HLA-Cw-B (P ¼ 0.022) and HLA-DRB5-DRB4 (P ¼ 0.050), and for the three-locus haplotype HLA-Cw-B-DRB5 (P ¼ 0.030).
The complex nature of CA implies that many genes might play a role, butcurrently, only HLA associations with CA are identified as clinically relevant.
The Pharmacogenomics Journal (2007) 7, 325–332; doi:10.1038/sj.tpj.6500423;published online 17 October 2006 Keywords: clozapine; agranulocytosis; HLA; idiosyncratic drug reactions A dysfunctional myelopoiesis resulting in agranulocytosis defined as neutrophilcount of less than 0.5 Â 109/l has been reported following the administrationof a wide pharmacological variety of drugs.1 Based on evidence for direct drug-induced toxicity and drug-generated antineutrophil antibodies in this context,it has been hypothesized that simple toxic and immunologic pathways are ingeneral important for developing agranulocytosis.2 However, in some clinicallyrelevant cases of drug-induced agranulocytosis, those clear definable pathome-chanisms are not seen.3,4 Clozapine is thought to be the most efficacious atypical antipsychotic agent in patients with treatment-resistant schizophrenia and has proven a threefold overall reduction of risk of suicidal behaviors of schizophrenic patients.5 Received 13 March 2006; revised 10 August2006; accepted 21 August 2006; published However, this benefit is reduced by an incidence of nearly 1% of patients who develop agranulocytosis.6 This incidence rate is unequally higher than the Genetics of clozapine-induced agranulocytosis estimated rates of drug-induced agranulocytosis in general, Second, in statistical terms haplotype-based methods with few cases per million population per year7 and can be viewed as an appropriate technique for reducing agranulocytosis induced by classical antipsychotics, with data dimensions, as the number of observed haplotypes is considerably smaller than the number of possible combina- The pathogenesis of clozapine-induced agranulocytosis tions of multiple loci. Third, if the risk of a disease is caused (CA) is unknown, and the discussion remains controversial by a haplotype structure itself, and not by a single allele, whether immunological, genetic or toxic mechanisms or haplotype-based analyses provide a better chance for a multistep phenomenon are responsible for this life- threatening side effect.9 The delayed onset of developing To identify patients at HLA-based risk for CA in a case– agranulocytosis after initial exposure of clozapine, which control design, we performed HLA genotyping and com- lasts at least 6–12 weeks, seems to be a strong argument pared allele frequencies in an – compared to previous reports against simple toxic or antibody mechanisms.10 However, – enlarged sample of 42 non-Jewish Caucasian schizo- the fact that CA relapse occurs with a more rapid and severe phrenic patients with CA and 75 non-Jewish Caucasian course after re-exposition to clozapine indicates at least an schizophrenic patients treated with clozapine without immunological background.11 Support for a genetically developing agranulocytosis. Furthermore, we calculated based hypothesis is provided by findings indicating CA as haplotype associations in these samples for the first time.
an idiosyncratic drug reaction,12 by a 21-fold higher rate ofthis drug adverse reaction among Finnish people comparedto other ethnic backgrounds,13 and by a case report ofconcordant manifestation of CA in monozygotic schizo- There are reports postulating human leukocyte antigen The 42 subjects with CA had a mean age of 45.29 years (HLA) class I and class II associations with adverse drug (s.d. ¼ 16.28, median ¼ 45.5 years), 54.8% were female, reactions, the best known are carbamazepine-induced the comparison group (with 75 schizophrenic patients hypersensitivity and its association with DR2 and DQ2, treated with clozapine for at least 2 years without CA) dipyrone-induced agranulocytosis and its association with had a mean age of 34.28 years (s.d. ¼ 10.83, median ¼ 34.0 A24, B7 and DQ1, penicilinamine-induced toxicity and years, t ¼ 4.16, Po0.001), 48.0% were female (w2 ¼ 0.492, the HLA association DR4, and the sulfonamide-induced P ¼ 0.483). Thus, consistent with the sampling procedure of toxic necrolysis with A29, B12 and DR7. However, most of controls and cases, we found age being associated with these studies are based on single assessments and do need the risk of CA, whereas sex showed no relation to the risk developing CA. Other clinically relevant data such as With respect to CA, three research groups performed HLA duration of treatment before CA, leukocyte and neutrophil association studies in patients suffering from CA with count before and after CA have been described in detail adequate case numbers: The first group by Lieberman and Yunis postulated that CA was associated with Evaluation of global differences in allele distributions HLA-B38, DRB1*0402, DQA1*0301 and DQB1 *0302 in 33 on the nine major histocompatibility complex (MHC) Jewish Caucasians, and with HLA DR*02, DQB1*0502 and loci tested using the clumping approach yielded signi- DQA1*0102 in 19 non-Jewish Caucasian patients.16,17 The ficant results for HLA-Cw (P ¼ 0.049) and for HLA-DRB5 second group failed to replicate these findings in a sample with mainly 103 Finnish and other European patients Subsequent testing of the alleles from both loci (Table 1) experiencing granulocytopenia and agranulocytosis during led to borderline results for Cw2 (P ¼ 0.085, odds ratio clozapine treatment.18 However, the studies of both groups (OR) ¼ 0.36, 95% confidence interval (CI): 0.08–1.23), Cw7 showed major statistical and/or methodological short- (P ¼ 0.058, OR ¼ 2.0, 95% CI: 0.87–4.63) and DRB5*0201 comings such as lack of clinical diagnosis or insufficient (P ¼ 0.005, adjusted OR (0.5 added in each cell) ¼ 22.15, information about important clinically relevant variables complete separation, 0 controls versus five cases of CA).
with respect to drug-induced agranulocytosis such as gender To evaluate deviations from Hardy–Weinberg equilibrium, and age. Our group did also fail to replicate the HLA-B38 we used Pearson’s w2-test with simulated P-value, based association with CA in 31 non-Jewish Caucasian schizo- on 10 000 replicates. No significant deviations from phrenic patients. However, we postulated that HLA Cw7 and Hardy–Weinberg equilibrium were found for any of the the class II antigens DQB*0502 and DRB3*0202 might be markers evaluated with P-values ranging from 0.325 (DRB3) genetic markers for this population at risk.19,20 To avoid statistical shortcomings with respect to HLA From the sliding-window approach, we consistently associations with rare idiosyncratic drug reaction, we used obtained significant global association results, based on single-locus and haplotype-based analyses for several asymptotic theory and on simulation, with CA, for the two- reasons. First, haplotype-based analyses are widely believed locus analyses: HLA-Cw-B (P ¼ 0.022) and HLA-DRB5-DRB4 to provide an efficient way of exploring multivariate linkage (P ¼ 0.050), and for three three-locus analyses HLA-Cw-B- disequilibrium patterns between markers, and to capture DRB5 (P ¼ 0.030). We therefore used the general linear- modeling (GLM) approach implemented in R to further Genetics of clozapine-induced agranulocytosisM Dettling et al Table 1 Allele counts and frequencies in 42 non-Jewish Caucasian schizophrenic patients suffering from clozapine-inducedagranulocytosis and subject-wise statistical comparisons Genetics of clozapine-induced agranulocytosis Abbreviations: CI, confidence interval; HLA, human leukocyte antigen; OR, odds ratio.
Allele counts and frequencies are shown, however, P-values and OR refer to subject-wise analysis; for allele counts below 5 no further statistical analysis were performed.
Note: HLA-B data are presented for reasons of comprehensiveness, although no significant association was detected with the clump approach.
aw2-tests or Fisher’s exact tests were performed, dependent on cell counts.
bOR, calculated from the count data, and Fisher’s exact CIs or mid-P exact CIs are shown.
c‘0’ means that no antigen was expressed.
elucidate, which specific haplotypes were associated with concerns about generalization of our study results. However, CA, while controlling for age and sex.
only ORs not adjusted for covariates could be calculated, In the analysis of HLA-Cw-B haplotypes, Cw7-related which implicates that adjusting at least for age and sex was alleles (Cw7-B18, P ¼ 0.035 and Cw7-B39, P ¼ 0.024) were essential when analyzing the relationship of HLA haplo- significantly associated with CA (Table 2) in a dominant types with CA in unmatched cases and controls.
model, while controlling for age (Po0.0001) and sex The pathomechanism of CA discussed is controversial, in (P ¼ 0.835). Additive models (data not shown) led to particular, with respect to the degree of genetic mechanisms essentially the same results. The DRB5-DRB4 analysis involved. Studies of the HLA alleles located in the short arm revealed a significant association for the group of pooled of chromosome 6, region 6p21, however, have always been alleles with a frequency below the threshold of 0.02, but not useful in understanding immune responses and transplanta- for the more common alleles. Further assessment showed tion, and it is well known that HLA alleles and haplotypes that the DRB5*0201–DRB4*000 haplotype caused this are associated with several immune- and non-immune- mediated diseases as well as with adverse drug reactions For the three-locus haplotypes, significant associa- to xenobiotics. Thus, the HLA system seems to represent a tions with CA were found for HLA-Cw7-B18-DRB5*000 promising target assessing an immunogenetic background (P ¼ 0.004), HLA-Cw7-B39-DRB5*000 (P ¼ 0.005) and HLA- of this life-threatening side effect.
Cw7-B44-DRB5*000 (P ¼ 0.018; Table 2).
In our study, HLA class I and II antigens Cw7, B38 and B39 and DRB5 seem to represent promising targets indicatingmechanisms of CA not investigated so far. Interestingly, each of these targets is involved in different immunologic-based etiologies of rare and/or virus-induced diseases.
To our knowledge, for the first time haplotype analyses of Recently, it has been shown that the proportion of natural HLA class I and II antigens were performed in an – compared killer (NK) cells coexpressing CD16 and CD158b þ is to previous reports – enlarged sample of 42 schizophrenic influenced by zygosity for the HLA-Cw7 (NK1 ligand) individuals suffering from CA. Ordered according to haplotype. As NK cells are involved in protection from virus their physical position HLA-A-Cw, HLA-Cw-B, HLA-B- infection, a reduced size of a ligand-specific NK subset in DRB1, HLA-BRB1-DQB and HLA-DQB-DPB were evaluated.
types might help to explain a increased susceptibility to We yielded the following results for Caucasian schizophre- virus-induced diseases.23 It has also been suggested that nic patients with CA compared to Caucasian schizophrenic the transplacental passage of maternal HNA-1a, HPA-3b and controls and controlled for age and sex: (1) two Cw7-related HLA alloantibodies specific for HLA-A3 and HLA-B38 anti- significant two-locus haplotype associations (Cw7-B18 and gens caused neutropenia and thrombocytopenia in a Cw7-B39); (2) another two-locus haplotype, DRB5*0201- neonate.24 And it is also well known that the DR15 DRB4*000, was also significantly associated with CA; (3) haplotype shows the strongest genetic association with multiple sclerosis in Caucasians possibly contributing to its HLA-Cw7-B39-DRB5*000 and HLA-Cw7-B44-DRB5*000 also pathophysiology by antigen presentation.25 displayed a significant association.
As reported previously, we also found CA being signifi- Probably, owing to the small numbers of specific HLA cantly associated with the HLA-Cw-7 allele in a smaller alleles, significant associations with CA showed large 95% subgroup of non-Jewish Caucasian schizophrenic patients CIs for ORs, including ‘1’. Obviously, this limitation raises with an OR of 4.2 in heterozygotes and OR of 8.4 in Genetics of clozapine-induced agranulocytosisM Dettling et al Table 2 Two- and three-locus haplotype associations in 42 non-Jewish Caucasian schizophrenic patients suffering from clozapine-induced agranulocytosis Abbreviations: CI, confidence interval; HLA, human leukocyte antigen; OR, odds ratio.
Base defines the ‘reference’ haplotype. Rare haplotypes are collapsed into a single category, if their frequency was estimated below the 5(2/N) criterion. In cases ofsignificant results suggesting to fall within the ‘rare’ category, we allowed a minimal haplotype frequency of 0.015.
aORs were calculated with the haplo.cc-function, without adjusting for covariates.
bMeans that no controls with this haplotype were available.
*Means several rare alleles at one locus.
P-values were accepted as significant when they were p0.05.
homozygotes. Additionally, HLA class II allele coded susceptibility had been reported significantly associated patients.16,17 Thus, some but not all of these findings are with HLADQB-0502, DRB1-0101 and DRB3-0202.19,20 Other supported by our haplotype analyses in a larger sample with groups reported associations of CA with HLA-B38, DRB1- 42 schizophrenic patients suffering from CA.
0402, DRB4-0101, DQB1-0201 and DQB1-0302 haplo- Although our marker density is far away from mapping types in Jewish and HLA-DR-02, DRB1-1601, DRB5-02 and density currently used in fine mapping studies of linkage Genetics of clozapine-induced agranulocytosis disequilibrium structures within the MHC,26 it covers an of clozapine treatment had not developed any hemato- important range of classic clinically relevant immunologic areas of the MHC. As our goal was to analyze genetic riskfactors for CA within the MHC, we performed an association study, combining class I and class II loci, taking into account Polymerase chain reaction (PCR)-based techniques were that both play different roles in immunologic responses of used to identify specific alleles. DNA was isolated by vertebrate organisms based on a different genetic history.27 standard chloroform/phenol extraction from venous leuko- Interestingly, it seems that both parts of the MHC might cytes. HLA class I was genotyped by allele-specific PCR contribute to a risk for developing CA. However, probably using prepipetted 96-well cyclerplates (Protrans, Ketsch, not as a common haplotype, spanning from MHC-I over Germany). HLA class II was genotyped with an INNO-LiPA MHC-III to MHC-II loci, but as different and independent rSSO-kit (Medipro, Ketsch, Germany). PCR and hybri- genetic risk factors. As we had no indication for stratifica- dization conditions were applied as recommended by the tion, interaction effects with sex were not further analyzed; manufacturers. HLA class II genotypes were addressed additionally, sample size limitations did not encourage using InnoLipa identification software V4.0 (Innogenetics, Focusing on the role of HLA for CA does not mean to For all subjects, we obtained genotype data for HLA class I disregard other hypothesized immunogenetic pathways.
loci: HLA-A, -Cw and -B and class II loci DRB5, DRB4, DRB3, Structures such as the Fcg receptors and its polymorphisms have also been tested for association with CA; however,data indicating Fcg receptor-related pathways playing a major role in the development of CA have not been The statistical analyses were carried out using the SPSS 12.0 reported.22 We are aware that also non-immunological (Chicago, IL, USA) and the statistical software package R31 but genetically based hypotheses exist, but aberrations in for Windows. A nominal significance level of 0.05 was enzymatic pathways, which result in toxic reactive meta- bolites and/or abnormal high concentrations of the main For evaluation of global differences in single-allele metabolites of clozapine or focusing on defective oxidative distributions, we performed analyses using simulation mechanisms of CA, have not been convincingly supported methods as implemented in ‘clump’ software.32 This approach uses Monte Carlo techniques to randomly gen- Genetic background might play a crucial role in the erate new cell counts for contingency tables under the null induction of drug reactions such as CA. However, we are far hypothesis, while keeping the margins of the table fixed.
from the purpose to appreciate the patients’ genotype-based Generally, it represents an efficient strategy to screen for risk for this severe side effect as the complex nature of interesting association in areas, where a priori knowledge is adverse drug reactions implies that many genes might play a sparse. It thereby allows reducing the number of necessary role. Currently, only HLA associations with CA are identified statistical tests for associations by applying simulation methods developed for genetic case–control studies withsparse tables. It yields unbiased estimates of significance forHLA loci, interesting polymorphisms can then be further analyzed by conventional tests for single-allele association.
For each locus, 10 000 replicates were analyzed.
We subsequently analyzed those alleles that were The study design was described in detail elsewhere.20 In potentially associated to CA individually as phenotypes by conclusion, we performed a case–control study, where Pearson’s w2-tests, or by Fisher’s exact test, when an expected subjects with CA were traced and approached by means cell value was less than 5 and we excluded those single of the German CA surveillance system. Controls were alleles with an overall allele frequency below 5. Genotype- clozapine-treated in-patients, selected from the Department specific risks were estimated as OR using standard cross- of Psychiatry, Charite´-University Medicine Berlin between product ratio; CIs were calculated as mid-P intervals or The study was approved by the Ethical board of the Additionally, to avoid unrecognized associations (equiva- lent to type II errors) owing to the process of allele The study sample consisted of n ¼ 42 subjects with and 75 combination, we analyzed those single alleles that were subjects without CA, who served as controls. All subjects found in more than 20 subjects for an association to CA.
of both groups met Diagnostic and Statistical Manual of This restriction to more frequent alleles was based on two the American Psychiatric Association (DSM-IV) criteria for reasons: (1) risks that do not apply frequently are only of schizophrenia, paranoid type (DSM-IV, 1994) and originated questionable practical or theoretical value in rare occur- rences such as CA and (2) estimates based on very small The 42 subjects with CA received no other treatment apart numbers are probably more sensitive to chance.
from clozapine before onset of agranulocytosis, whereas Power calculations with realistic assumptions in our comparison subjects even after a minimum 2-year period sample revealed that the probability to detect a single-allelic Genetics of clozapine-induced agranulocytosisM Dettling et al association with an OR of at least 2 was 0.84 (Genetic Power Calculator, http://statgen.iop.kcl.ac.uk/gpc/). As not allalleles at each locus were tested, tests could be regarded as This study was supported by Grant 01 EC 9406 from the German essentially independent from each another.
Federal Ministry of Education and Research. We thank all participat- Deviations from Hardy–Weinberg equilibrium within ing patients and supporting doctors.
each group were evaluated with the R package ‘Genetics’,version 1.0.3. Tests were based on simulation with 10 000 1 Be´nichou C, Solal-Celigny P. Standardization of definitions and criteria The sliding-window approach included in the R package for causality assessment of adverse drug reactions. Drug-induced blood ‘haplo.stats’ was used for detecting two- and three-locus cytopenias: report of an international consensus meeting. Nouv Rev Fr (sub)-haplotype associations. Haplotypes frequencies were estimated by the expectation-maximization (EM) algorithm, 2 Vincent PC. Drug-induced aplastic anaemia and agranulocytosis. Drugs associations between statistically inferred haplotypes and 3 Liu ZC, Uetrecht JP. Metabolism of ticlopidine by activated neutrophils: CA were analyzed using the score method by Schaid.33,34 implications for ticlopidine-induced agranulocytosis. Drug Metab Dispos The ‘haplo.score’ method assigns the probability for each haplotype pair in each individual and from there 4 Gardner I, Popovic M, Zahid N, Uetrecht JP. A comparison of the covalent binding of clozapine, procainamide, and vesnarinone to models the individual’s phenotype as a function of human neutrophils in vitro and rat tissues in vitro and in vivo. Chem the inferred haplotype pair. Accounting for haplotype ambiguity is carried out through weighting by their 5 Hennen J, Baldessarini RJ. Suicidal risk during treatment with clozapine: a meta-analysis. Schizophr Res 2005; 73: 139–145.
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Doi:10.1016/j.theochem.2005.06.032

Journal of Molecular Structure: THEOCHEM 731 (2005) 73–81Prediction of antifungal activity by support vector machine approachShi-Wei Chena, Ze-Rong Lib,*, Xiang-Yuan Lia,**aCollege of Chemical Engineering, Sichuan University, Chengdu 610064, People’s Republic of ChinabCollege of Chemistry, Sichuan University, Chengdu 610065, People’s Republic of ChinaReceived 13 December 2004; revis

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