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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
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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
Letter to Branches For instant updates: http//:www.cwu.org email: info@cwu.org 150 The Broadway, Wimbledon, London, SW19 1RX Tel: 020 8971 7200 Fax: 020 8971 7300 General Secretary: Billy Hayes (www.billyhayes.co.uk) No. 527/09 To: All Branches Dear Colleagues Swine Flu - HPA Advice on Exclusion from Workplaces and Schools This LTB is being issued further to LTB 394/09 dated 5 May 2