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CYP2D6 polymorphism pesticide exposure and Parkinson's disease.

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atal dopaminergic dysfunction in SCA2 patients independently of the presence of parkinsonian signs.
This work was supported by funding from Amersham Health and
by a grant from Italian Ministry of University and FIRB (Fondo per
gli Investimenti nella Ricerca di Base) and Ministry of Health (Neuroscience 2001/RBNED1ZK8F.006 and Biological Markers in Parkinson’s Disease 2000, Italy, A.F.).
We thank C. Di Nuzzo for excellent technical assistance in nuclear
medicine studies.
CYP2D6 Polymorphism,
Pesticide Exposure, and
Parkinson’s Disease
Alexis Elbaz, MD, PhD,1 Clotilde Levecque, MSc,2
Jacqueline Clavel, MD, PhD,3 Jean-Sébastien Vidal, MD,4
Florence Richard, MD, PhD,2
Philippe Amouyel, MD, PhD,2
Annick Alpérovitch, MD, MSc,1
Marie-Christine Chartier-Harlin, PhD,2 and
Christophe Tzourio, MD, PhD1
References
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ataxias ad infinitum? Neurology 2001;56:287–289.
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correlations in spinocerebellar ataxia 2: a study of 32 families.
Hum Mol Genet 1997;6:709 –715.
3. Geschwind DH, Perlman S, Figueroa CP, et al. The prevalence
and wide clinical spectrum of the spinocerebellar ataxia type 2
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4. Zhou YX, Wang GX, Tang BS, et al. Spinocerebellar ataxia
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(SCA2): morphometric analyses in 11 autopsies. Acta Neuropathol (Berl) 1999;97:306 –310.
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and neuropathological analysis of 53 patients from three unrelated SCA2 families. Brain 1995;118:1573–1581.
9. Filla A, De Michele G, Santoro L, et al. Spinocerebellar ataxia
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levodopa-responsive parkinsonism. Mov Disord 2002;18:425– 429.
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15. Trouillas P, Takayanagi T, Hallet M, et al. International cooperative ataxia rating scale for pharmacological assessment of the
cerebellar syndrome. J Neurol Sci 1997;145:205–211.
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stimulation in a patient with spinocerebellar ataxia type 2. Mov
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430
We performed a case–control study of Parkinson’s disease (PD) in a population characterized by a high prevalence of pesticide exposure and studied the joint effect
of pesticide exposure and CYP2D6. Although they are
based on a small group of subjects with the joint exposure, our findings are consistent with a gene–environment interaction disease model according to which (1)
pesticides have a modest effect in subjects who are not
CYP2D6 poor metabolizers, (2) pesticides’ effect is increased in poor metabolizers (approximately twofold),
and (3) poor metabolizers are not at increased PD risk in
the absence of pesticide exposure.
Ann Neurol 2004;55:430 – 434
Several studies suggest that exposure to pesticides may
be associated with Parkinson’s disease (PD) among humans.1–3 Recent laboratory and animal studies support
this hypothesis.4,5 In addition, it has been hypothesized
that this association may be stronger among genetically
susceptible individuals.2,3
The debrisoquine hydroxylase in cytochrome P450
D6 (CYP2D6) metabolizes several xenobiotics, including organophosphate pesticides, the herbicide atrazine,
and MPTP, a toxin that induces a parkinsonian syndrome and is structurally close to the herbicide Paraquat.6 – 8 CYP2D6 activity is genetically determined.
Poor metabolizers (PMs) have undetectable CYP2D6
activity and represent 5 to 10% of whites. This trait is
inherited as a recessive autosomal trait, and the most
frequent polymorphism among white PMs is a G/A
From the 1National Institute of Health and Medical Research
(INSERM) Unit 360, 2INSERM Unit 508, 3INSERM Unit 170,
4
Service de Neurologie, Hôpital Saint-Antoine, Paris, France.
Received Sep 8, 2003, and in revised form Dec 22, 2003. Accepted
for publication Dec 22, 2003.
Address correspondence to Dr Elbaz, INSERM Unit 360, Hôpital
de la Salpêtrière, 47 boulevard de l’Hôpital, 75651 Paris Cedex 13,
France. E-mail: elbaz@chups.jussieu.fr
© 2004 American Neurological Association
Published by Wiley-Liss, Inc., through Wiley Subscription Services
transition at the intron 3–exon 4 junction
(CYP2D6*4), with CYP2D6*4 homozygotes being
PMs.6
We investigated whether the relation between PD
and pesticides is modified by CYP2D6 in a case–control study conducted in a population characterized by a
high prevalence of pesticide exposure.
Subjects and Methods
PD cases (n ⫽ 247) and controls (n ⫽ 676) were identified
among subjects enrolled in the French health insurance organization for farmers and related job categories (Mutualité
Sociale Agricole).9 Cases were individuals aged 18 to 75 years
old who submitted an application to benefit from complete
health care coverage for PD during an 18-month period. As
part of the study protocol, they were examined by a neurologist with experience in movement disorders. Whenever it
was impossible to directly examine the patient, the patient’s
treating neurologist was contacted to obtain clinical information. Parkinsonism was defined as the presence of at least
two cardinal signs: rest tremor, bradykinesia, rigidity, impaired postural reflexes.10,11 PD was defined as the presence
of parkinsonism after exclusion of other causes of parkinsonism.9 –11 Controls were recruited among all Mutualité Sociale
Agricole affiliates who made requests to be reimbursed for
health expenses. A maximum of three controls were matched
to each case for age, sex, and region of residency.
Pesticide exposure was assessed by occupational health
physicians using an individual expert evaluation procedure9,12,13; participants were classified as never users, users
for gardening, or professional users. To minimize the risk of
population stratification bias, we restricted our analyses to
subjects with both parents born in Europe. The figure shows
the proportion of cases and controls for whom a blood sample was obtained and pesticide exposure assessed. Because of
the matched design, our analyses are based on 190 cases and
419 matched controls (83 quadruplets, 63 triplets, 44 pairs)
(Figure).
CYP2D6*4 genotypes were determined using polymerase
chain reaction restriction fragment length polymorphism.
The research protocol was approved by the ethics committee
of Hôpital du Kremlin-Bicêtre. All subjects signed informed
consent.
We used a statistical method described in the context of
genes involved in the detoxification of environmental exposures.14,15 This method tests the hypothesis that there is no
variation in risk over the genetic factor among subjects not
exposed to the environmental factor, whereas the genetic factor may modify risk among exposed subjects. It relies on
testing the collapsibility of genotypes at different levels of the
environmental exposure by fixing constraints on the parameters of the models. The method leads to models with interaction terms but not all main effects that make sense from a
biological perspective. The resulting nested models are compared using likelihood ratio tests. Odds ratios (ORs), 95%
confidence intervals (CIs), and p values were calculated using
conditional logistic regression for matched sets. Because cigarette smoking is inversely associated with PD, all our analyses are adjusted for cigarette smoking.16
Results
Of the 190 patients, 123 were directly examined by the
study neurologist, and the treating neurologist provided clinical information for 56. No detailed clinical
information was obtained for 11 patients. However,
based on the clinical examination by the Mutualité Sociale Agricole physician, all fulfilled the criteria for parkinsonism, and none had used neuroleptics; they therefore were retained for our analyses. Fifty-six percent of
the cases and controls were men. Their mean age (standard deviation) was 67 (7) years. Mean age at PD onset was 64 (7) years. The frequencies of pesticide exposure and CYP2D6*4 are shown in Table 1.
Considering subjects who carried no CYP2D6*4 allele as the reference, we found that the OR was 1.02
(95% CI, 0.69 –1.51; p ⫽ 0.91) for carriers of one
allele, and 1.56 (95% CI, 0.67–3.65; p ⫽ 0.31) for
carriers of two alleles. Seventy-one percent of the cases
and 66% of the controls were exposed to pesticides for
gardening or professional use. Considering subjects not
exposed to pesticides as the reference, the OR was 1.41
(95% CI, 0.81–2.44; p ⫽ 0.22) for subjects exposed to
pesticides for gardening, and 1.76 (95% CI,
0.99 –3.15; p ⫽ 0.06) for subjects exposed to pesticides
for professional use; the OR for subjects exposed to
pesticides, either for gardening or professionally, was
1.55 (95% CI,1.00 –2.55; p ⫽ 0.05). The OR for ever
cigarette smoking was 0.60 (95% CI, 0.38 – 0.94; p ⫽
0.02).
Joint effects of pesticide exposure and CYP2D6*4
are shown in Table 2. It appears from models 1 and 2
with all main effects and interaction terms that there is
no relation between CYP2D6*4 and PD among unexposed subjects, whereas CYP2D6*4 homozygotes
(PMs) are at increased risk of PD among subjects exposed to pesticides. Among subjects exposed to pesticides for gardening or for professional use, PMs have
an approximately twofold risk of PD compared with
non-PMs. PMs with professional pesticide exposure
have the highest OR (4.74; 95% CI,1.29 –17.45; p ⫽
0.02). This pattern is consistent with model 3 that
does not include the genetic main effect (see Table 2).
Model 3 is not rejected because of little loss in goodness of fit (model 3 vs model 1: ␹2 ⫽ 3.316, 6 degrees
of freedom, p ⫽ 0.77; model 3 vs model 2: ␹2 ⫽
1.745, 3 degrees of freedom, p ⫽ 0.63) and is more
parsimonious than models 1 and 2. According to
model 3, subjects not exposed to pesticides are not at
increased PD risk independently of their genotype
(OR, 1.00), non-PMs exposed to pesticides have a
modest increase in risk (OR, 1.50), and PMs exposed
to pesticides have the highest increase in risk (OR,
3.28). The OR for interaction between pesticide exposure and CYP2D6*4 is 2.20 (95% CI, 0.85–5.76; p ⫽
0.10); the interaction was of a similar magnitude in
men and women. The p value for trend in ORs was
Elbaz et al: CYP2D6, Pesticides, and PD
431
Fig. Definition of the matched sample of cases and controls for the analyses. The overall sample consisted of 247 cases and 676 controls, distributed as 194 quadruplets, 41 triplets, and 12 pairs. Plus signs denote that the corresponding data were obtained. The
figure shows the number of cases and controls in unmatched and matched samples (1) when subjects for whom pesticide exposure
was assessed were included (right side of the figure), (2) when subjects for whom we obtained a blood sample were included (middle of the figure), and (3) when subjects for whom we obtained both a blood sample and exposure data were included (left part of
the figure, present study). A blood sample (for DNA extraction) and an evaluation of pesticide exposure both were obtained for
83% of the cases and 77% of the controls (left part of the figure, unmatched sample); five cases and five controls were excluded
because at least one of their parents was born outside Europe. Conditional on pesticide exposure, there was no difference in blood
sampling rate between cases and controls. By virtue of the matched design, the unmatched sample reduced to 190 cases and 419
matched controls (10 cases who had no matched controls and 97 controls who had no matched cases were excluded).
Table 1. The Frequency of the CYP2D6*4 Allele and of Pesticide Exposure in Parkinson’s Disease Cases and Controls
Exposure to Pesticides
No. of
CYP2D6*4
Alleles
0 allele
1 allele
2 alleles
(PMs)
Total
None
Gardening Use
Totala
Professional Use
Cases
% (n)
Controls
% (n)
Cases
% (n)
Controls
% (n)
Cases
% (n)
Controls
% (n)
Cases
% (n)
Controls
% (n)
61.8 (34)
36.4 (20)
1.8 (1)
66.4 (93)
30.0 (42)
3.6 (5)
64.1 (25)
28.2 (11)
7.7 (3)
59.6 (53)
34.8 (31)
5.6 (5)
65.6 (63)
28.1 (27)
6.3 (6)
70.5 (134)
26.3 (50)
3.2 (6)
64.2 (122)
30.5 (58)
5.3 (10)
66.8 (280)
29.4 (123)
3.8 (16)
100.0 (55)
100.0 (140)
100.0 (39)
100.0 (89)
100.0 (96)
100.0 (190)
100.0 (190)
100.0 (419)
The CYP2D6*4 polymorphism was in Hardy–Weinberg equilibrium among controls ( p ⫽ 0.63). The frequency of the polymorphic allele was
21% in cases and 18% in controls.
a
PM ⫽ poor metabolizer.
432
Annals of Neurology
Vol 55
No 3
March 2004
Table 2. The Relation between CYP2D6*4, Pesticide Exposure, and Parkinson’s Disease
Exposure to Pesticides
None
Model
Gardening Use
Professional Use
OR (95% CI)
p
OR (95% CI)
p
OR (95% CI)
p
Model 1 (⫺2 log likelihood ⫽ 406.288)
0 CYP2D6*4 allele
1 CYP2D6*4 allele
2 CYP2D6*4 alleles (PMs)
1.00
1.39 (0.70–2.76)
0.41 (0.04–3.99)
—
0.35
0.44
1.73 (0.86–3.48)
1.17 (0.49–2.77)
2.75 (0.55–13.74)
0.12
0.72
0.22
1.85 (0.96–3.55)
1.83 (0.84–3.95)
4.74 (1.29–17.45)
0.06
0.13
0.02
Model 2 (⫺2 log likelihood ⫽ 407.859)
0 or 1 CYP2D6*4 allele
2 CYP2D6*4 alleles (PMs)
1.00
0.35 (0.04–3.46)
—
0.37
1.34 (0.76–2.35)
2.45 (0.50–11.98)
0.31
0.27
1.65 (0.91–2.98)
4.18 (1.17–14.96)
0.10
0.03
Model 3 (⫺2 log likelihood ⫽ 409.604)
0 or 1 CYP2D6*4 allele
2 CYP2D6*4 alleles (PMs)
1.00
1.00
—
—
1.50 (0.92–2.43) 0.10
3.28 (1.16–9.27) 0.02
Model 4 (⫺2 log likelihood ⫽ 412.298)
0 or 1 CYP2D6*4 allele
2 CYP2D6*4 alleles (PMs)
1.00
1.00
—
—
1.00
2.39 (0.92–6.24)
—
0.07
ORs (95% CI) and p values were calculated using conditional logistic regression for matched sets, while adjusting for ever cigarette smoking.
Models were compared using likelihood ratios which approximate a ␹2 distribution; the number of degrees of freedom is the difference in the
number of unfixed parameters between the models. Model 1 includes all main effects and interaction terms. Model 2 includes all main effects
and interaction terms after collapsing carriers of one CYP2D6*4 allele and noncarriers in a single category. Model 3 includes the main effect
for pesticide exposure (gardening or professional use) and the interaction between pesticide exposure and CYP2D6*4, but no main effect for
CYP2D6*4. Model 4 includes the interaction between pesticide exposure (gardening or professional use) and CYP2D6*4, but no main effects
for CYP2D6*4 and pesticide exposure. Model 3 is the most likely and parsimonious model.
OR ⫽ odds ratio; CI ⫽ confidence interval; PM ⫽ poor metabolizer.
0.03. The OR for ever cigarette smoking was 0.58
(95% CI, 0.37– 0.91; p ⫽ 0.02). We then compared
model 4 without any main effect (non-PMs exposed to
pesticides are not at increased PD risk, see Table 2) to
model 3, and we rejected this simpler model (␹2 ⫽
2.694; 1 degree of freedom; p ⫽ 0.10).
Discussion
In this case–control study of PD in a population characterized by a high prevalence of pesticide exposure
with individual exposure assessment, we found evidence in favor of an interaction between CYP2D6 and
pesticides. Our data are consistent with a detoxification
mechanism according to which pesticides have a modest effect in non-PMs and their effect is increased (approximately twofold) in PMs, whereas PMs are not at
increased PD risk in the absence of pesticide exposure.17
The frequency of homozygotes for the *4 allele observed in this study among controls was similar to that
observed in a study of 589 healthy white subjects
(3.7%).18 In a meta-analysis of 11 case–control studies
performed in white populations (totaling 1,133 cases
and 1,950 controls), the frequencies of the *4 allele
(20% in cases, 18% in controls) were similar to those
observed in this study; this meta-analysis showed that
CYP2D6 PM individuals had a modest increase in PD
risk (OR,1.47; 95% CI,1.18 –1.96).19 However, individual studies on the relation between PD and
CYP2D6 have been inconsistent. Given the low frequency of PMs, they had limited power to detect an
association of this size. In addition, if the underlying
mechanism involves an interaction with pesticides, they
were unlikely to detect an overall association with
CYP2D6 and unable to study its effect among subjects
reporting pesticide exposure, because they included a
small proportion of exposed subjects.1,19
Our study was designed to include many subjects
exposed to pesticides, to be able to compare the effect
of pesticide exposure in carriers and noncarriers of genetic polymorphisms implicated in detoxification pathways. However, note that, because of the low frequency of the genotype of interest among whites, our
findings are based on a small group of subjects who
were both PMs and exposed to pesticides, leading to
low power, and that the interaction effect was of modest size. Further confirmation of these findings is
needed. In addition, we were not able to obtain genetic
and environmental data for all the study participants,
and our analyses are based on a subset of the overall
sample; however, because there was no difference in
blood sampling rate between cases and controls conditional on pesticide exposure, the assessment of interac-
Elbaz et al: CYP2D6, Pesticides, and PD
433
tions was not subject to a major selection bias in this
study.20
Our findings are consistent with a priori hypotheses
about the relation between CYP2D6 and PD. Both
among subjects exposed to pesticides for gardening and
for professional use, the risk of PD was increased twofold among PMs in comparison with non-PMs. This
estimate of the interaction effect may be useful for future studies. Because of the low frequency of PMs, we
were not able to study the interaction between
CYP2D6 and specific pesticides. Larger studies and
laboratory data may help to elucidate which pesticides
are metabolized through this pathway and have an effect on the risk of PD.
This study was supported by the National Institute of Health and
Medical Research, the Institut Pasteur of Lille, and Agricultural Social Mutual Insurance, and was funded by the French Ministry of
the Environment (EN 96-DIO, EN98-30, C.T.). C.L. is supported
by the Ministry of Research and Technology.
We thank all the Mutualité Sociale Agricole physicians who interviewed the participants and the Mutualité Sociale Agricole employees who helped with the coordination of the study. Drs D. Gervais
and L. Benslamia participated in the examination of PD patients. C.
Cordelier and Drs C. Amiel, F. Brunner, and J.-P. Galanaud helped
with the assessment of exposure to pesticides. Dr S. Zenagui participated in the coordination of the study. We thank X. Hermant and
V. Mouroux for their technical assistance.
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