Smoking and Parkinson's Disease: Using Parental Smoking as a Proxy to Explore Causality

Article (PDF Available)inAmerican journal of epidemiology 169(6):678-82 · February 2009with16 Reads
DOI: 10.1093/aje/kwn388 · Source: PubMed
Abstract
In epidemiologic studies and in studies of discordant twins, cigarette smoking has been consistently associated with a lower risk of Parkinson's disease, but whether this association is causal remains controversial. Alternatively, an infectious or toxic exposure in childhood or early adulthood could affect both the reward mechanisms that determine smoking behavior and the future risk of Parkinson's disease. If so, parental smoking, commonly established before the birth of the first child, would be unlikely to be related to Parkinson's disease risk. The authors assessed the association between Parkinson's disease and parental smoking during childhood in the Nurses' Health Study and the Health Professionals Follow-up Study conducted in the United States. During 26 years and 18 years of follow-up, respectively, 455 newly diagnosed Parkinson's disease cases were documented among those who provided information on parental smoking. The age-adjusted, pooled relative rate of Parkinson's disease was 0.73 (95% confidence interval: 0.53, 1.00; P-trend = 0.04) comparing participants who reported that both parents smoked with those who reported that neither did. Adjustment for caffeine and alcohol intake did not materially change the results. If the inverse association between smoking and Parkinson's disease were due to confounding by an environmental factor or were the result of reverse causation, it is unlikely that parental smoking would predict Parkinson's disease.
American Journal of Epidemiology
ª The Author 2009. Published by the Johns Hopkins Bloomberg School of Public Health.
All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org.
Vol. 169, No. 6
DOI: 10.1093/aje/kwn388
Advance Access publication January 8, 2009
Original Contribution
Smoking and Parkinson’s Disease: Using Parental Smoking as a Proxy to Explore
Causality
E
´
ilis J. O’Reilly, Honglei Chen, Hannah Gardener, Xiang Gao, Michael A. Schwarzschild, and
Alberto Ascherio
Initially submitted July 3, 2008; accepted for publication November 12, 2008.
In epidemiologic studies and in studies of discordant twins, cigarette smoking has been consistently associated
with a lower risk of Parkinson’s disease, but whether this association is causal remains controversial. Alternatively,
an infectious or toxic exposure in childhood or early adulthood could affect both the reward mechanisms that
determine smoking behavior and the future risk of Parkinson’s disease. If so, parental smoking, commonly estab-
lished before the birth of the first child, would be unlikely to be related to Parkinson’s disease risk. The authors
assessed the association between Parkinson’s disease and parental smoking during childhood in the Nurses’
Health Study and the Health Professionals Follow-up Study conducted in the United States. During 26 years and
18 years of follow-up, respectively, 455 newly diagnosed Parkinson’s disease cases were documented among
those who provided information on parental smoking. The age-adjusted, pooled relative rate of Parkinson’s disease
was 0.73 (95% confidence interval: 0.53, 1.00; P-trend ¼ 0.04) comparing participants who reported that both
parents smoked with those who reported that neither did. Adjustment for caffeine and alcohol intake did not
materially change the results. If the inverse association between smoking and Parkinson’s disease were due to
confounding by an environmental factor or were the result of reverse causation, it is unlikely that parental smoking
would predict Parkinson’s disease.
causality; Parkinson disease; smoking; tobacco smoke pollution
Despite the well-documented adverse health effects of
cigarette smoking, cigarette smokers and users of other to-
bacco products have lower rates of Parkinson’s disease than
nonsmokers/nonusers do. Rates of Parkinson’s disease de-
crease as dose of cigarettes per day and number of years of
smoking increase, and they increase as number of years
since quitting increases (1–5). In longitudinal studies, cur-
rent smokers, compared with never smokers, were found to
have one-third the risk of Parkinson’s disease (5). Among
men never smokers, use of smokeless tobacco was also as-
sociated with lower rates of Parkinson’s disease (6, 7). In an
ecologic study, country-specific variations in gender ratios
of Parkinson’s disease over time were found to be correlated
with variations in gender ratios of smoking (8).
Whether the observed inverse associations between
smoking and Parkinson’s disease are causal remains con-
troversial; the association could be explained by a still-
unknown third factor that increases the risk of Parkinson’s
disease and also causes an aversion to smoking. This factor
is unlikely to be genetic because, in monozygotic and di-
zygotic twin studies, which control tightly for genetics and
shared environment, smoking remains associated with
Parkinson’s disease (9, 10). However, confounding by an
environmental factor cannot be eliminated by twin studies.
For example, a person could be exposed to a toxic chem-
ical or an infectious agent that causes subclinical damage
to the dopaminergic system, which is involved in novelty
seeking and addiction, and this exposure could reduce his
or her desire to smoke while independently increasing the
risk of Parkinson’s disease. This apparently intractable
confounding could be circumvented by examining the re-
lation between parental smoking and risk of Parkinson’s
disease because the hypothetical toxic chemical or infec-
tious agent is less likely to affect parents’ smoking behav-
ior, which is typically established before the birth of the
first child (11). Children of smokers are exposed to
Correspondence to E
´
ilis J. O’Reilly, Departments of Epidemiology and Nutrition, Harvard School of Public Health, 677 Huntington Avenue,
Boston, MA 02215 (e-mail: eoreilly@hsph.harvard.edu).
678 Am J Epidemiol 2009;169:678–682
environmental smoke and are more likely to become
smokers themselves, so if smoking is truly protective, they
would be expected to have a lower risk of Parkinson’s
disease than children of parents who do not smoke. On
the other hand, if the association between smoking and
Parkinson’s disease were due to exposure to a toxic chem-
ical or an infectious agent, no relation would be expected
between parental smoking, which was established prior to
the offspring being exposed, and Parkinson’s disease risk.
We examined the association between parental smoking
and Parkinson’s disease rates in the Nurses Health Study
and Health Professionals Follow-up Study in the United
States.
MATERIALS AND METHODS
Study population
The Nurses’ Health Study enrolled 121,701 female nurses
aged 35–55 years who returned a mailed questionnaire in
1976 regarding lifestyle and medical history (12). The
Health Professionals Follow-up Study enrolled 51,529
males aged 40–75 years who returned a similar question-
naire in 1986 (13). Participants of both cohorts have re-
ceived follow-up questionnaires biennially to record newly
diagnosed illnesses and to update lifestyle and dietary
information.
Case ascertainment
Health Professionals Follow-up Study and Nurses’
Health Study participants were first asked about a lifetime
diagnosis of Parkinson’s disease on the 1988 and 1994
questionnaires, respectively, and on every follow-up ques-
tionnaire thereafter. Confirmation of self-reported Parkinson’s
disease has been described elsewhere (14). Briefly, permis-
sion to contact the treating neurologist was sought from
participants who reported a new diagnosis of Parkinson’s
disease. Neurologists (or internists if the neurologists did
not respond) were then asked to complete a questionnaire
to provide their judgment on the certainty of the diagnosis,
the date on which symptoms were first noticed, and the
date of diagnosis; copies of medical records were also
sought. Confirmed cases of Parkinson’s disease included
those for which 1) the level of certainty of the diagnosis
reported by the treating neurologist or internist was definite
or probable, 2) the medical record indicated a final diag-
nosis of Parkinson’s disease by a neurologist, or 3) there
was evidence at a neurologic examination of at least 2 of
the 3 cardinal signs of Parkinson’s disease (rest tremor,
rigidity, or bradykinesia) in the absence of features sug-
gesting other diagnoses. A movement disorder specialist,
blinded to exposure status, reviewed the medical records.
Overall, the diagnosis was confirmed by the treating neu-
rologist in 84.6% and by the treating internist in 9.7%
Table 1. Age-adjusted Baseline Risk Factors for Parkinson’s Disease by Parental Smoking Status in the Nurses’
Health Study (1976) and the Health Professionals Follow-up Study (1986), United States
Parental Smoking Status
Nurses’ Health Study
Health Professionals
Follow-up Study
Neither
Parent
1
Parent
Both
Parents
Neither
Parent
1
Parent
Both
Parents
Total no.
(no. of cases)
30,182 (104) 45,562 (154) 17,177 (29) 11,907 (81) 13,633 (66) 5,128 (21)
Mean (range)
age, years
44 (30–63) 44 (30–57) 39 (30–60) 53 (39–77) 53 (39–77) 47 (39–77)
Caffeine intake,
g/day
365 397 407 214 243 248
Alcohol intake,
g/day
5.4 6.4 8.3 9.6 11.8 14.1
Smoking, %
Never 54.0 43.0 31.4 58.8 47.0 42.7
<10 pack-years 17.6 19.2 18.5 10.7 10.8 10.6
10–24 pack-years 16.0 20.2 24.6 17.2 21.2 21.7
25–44 pack-years 8.8 12.5 18.0 9.6 14.9 17.5
45 pack-years 2.5 3.7 6.2 3.7 6.1 7.5
Predicted relative
rate based
on pack-years
a
Reference 0.95 0.89 Reference 0.90 0.87
a
Predicted relative rates of Parkinson’s disease for parental smoking were calculated as an average of the relative
rates for pack-years published in the study by Herna
´
n et al. (2) weighted by the distribution of smoking history at
baseline within each level of parental smoking. (Compared with never smoking, the published relative rates for 1–9,
10–24, 25–44, and 45 pack-years were 1.0, 0.8, 0.4, and 0.4 in the Nurses’ Health Study and 0.6, 0.5, 0.5, and 0.3 in
the Health Professionals Follow-up Study, respectively.)
Smoking and Parkinson’s Disease 679
Am J Epidemiol 2009;169:678–682
of the cases and by review of the medical records in the
remainder.
Exposure assessment
In both cohorts (women in 1982 and men in 2004), par-
ticipants reported whether their parents (neither, mother
only, father only, both) smoked while living with them dur-
ing childhood. To gain statistical power, the categories
‘mother only’ and ‘father only’ were collapsed to ‘one
parent smoked.
Statistical methods
Participants contributed person-time of follow-up from
the date of return of the baseline questionnaire to the date
of Parkinson’s disease diagnosis, death from any cause, or
end of follow-up (June 2002 for the Nurses Health Study
and January 2004 for the Health Professionals Follow-up
Study). Mantel-Haenzel age-adjusted incidence relative
rates and 95% confidence intervals were obtained relative
to the incidence rates for those whose parents did not smoke.
To adjust for other risk factors for Parkinson’s disease, we
used Cox proportional hazards analysis. A Wald test deter-
mined whether the relative rate from each study was hetero-
geneous. A pooled relative rate was calculated by weighting
the study-specific log relative rate by the inverse of their
variances using a random-effects model (15). All reported
P values are 2-sided.
RESULTS
During 26 years of follow-up in the Nurses’ Health Study,
328 newly diagnosed Parkinson’s disease cases were docu-
mented. The 1982 questionnaire was completed by 110,163
eligible women; of these, 92,921 gave information on pa-
rental smoking (287 cases). During 18 years of follow-up in
the Health Professionals Follow-up Study, 384 newly diag-
nosed Parkinson’s disease cases were documented. The
Table 2. Parental Smoking Status and Risk of Parkinson’s Disease in the Nurses’ Health Study
(1976–2002) and the Health Professionals Follow-up Study (1986–2004), United States
Parental Smoking
Status
No. of
Person-Years
No. of
Cases
Age-adjusted
RR
95% CI
P for
Heterogeneity
Health Professionals Follow-up Study
Neither parent smoked 208,563 81 Reference
At least 1 parent smoked 328,860 87 0.73 0.54, 0.99
1 Parent smoked 238,655 66 0.72 0.52, 0.99
Both parents smoked 90,205 21 0.80 0.49, 1.30
Total 537,423 168
Nurses’ Health Study
Neither parent smoked 755,123 104 Reference
At least 1 parent smoked 1,569,776 183 0.94 0.74, 1.20
1 Parent smoked 1,137,480 154 1.01 0.79, 1.30
Both parents smoked 432,296 29 0.68 0.45, 1.03
Total 2,324,899 287
Pooled Analysis
Neither parent smoked 963,686 185 Reference
At least 1 parent smoked 1,898,636 270 0.85 0.67, 1.07 0.2
1 Parent smoked 1,376,135 220 0.87 0.64, 1.20 0.1
Both parents smoked 522,501 50 0.73 0.53, 1.00 0.6
Total 2,862,322 455
P for trend 0.04 0.6
Abbreviations: CI, confidence interval; RR, relative rate.
Parental
Smoking
Smoking
C
Parkinson’s Disease
Figure 1. Paradigm I: The inverse relation between smoking and
Parkinson’s disease is not causal. The observed association is due to
confounding. C represents one or more factors causally related to
both Parkinson’s disease and smoking status that, given it exists,
would confound the association between smoking and Parkinson’s
disease. Under this paradigm, parental smoking would not be
associated with Parkinson’s disease risk because there is no open
path between parental smoking and Parkinson’s disease. Such a
path could be provided by an influence of parental smoking on
caffeine intake under the assumption that caffeine is causally related
to Parkinson’s disease (not shown in figure) (5, 14). Because
adjustment for caffeine intake did not attenuate the relation between
parental smoking and Parkinson’s disease, such an explanation is
unlikely.
680 O’Reilly et al.
Am J Epidemiol 2009;169:678–682
2004 questionnaire was completed by 34,884 eligible men;
of these, 30,668 gave information on parental smoking (168
cases). The average age at diagnosis of Parkinson’s disease
was 68.8 years (range: 46.6–87.8) for the men and 69.3
(range: 46.3–81.3) for the women.
As expected, participants’ baseline smoking status was
predicted by parental smoking. Ever smokers constituted
69% of the women and 57% of the men whose parents were
both smokers but only 46% of the women (P < 0.0001) and
41% of the men (P < 0.0001) whose parents were both
nonsmokers. We calculated expected relative rates of
Parkinson’s disease for each level of parental smoking
status as the averages of published study-specific relative
rates for pack-years (2) weighted by the distribution of
pack-years of smoking at baseline within each category of
parental smoking. We conservatively predicted a reduction
in risk of Parkinson’s disease of 11% for men and 13% for
women who reported that both parents smoked compared
with those who reported that neither parent smoked. Daily
caffeine and alcohol intake was higher among those whose
parents smoked (Table 1).
Among both men and women, the risk of Parkinson’s
disease was lower for individuals who reported that both
parents were smokers than for those who reported that nei-
ther parent smoked (Table 2). In a pooled analysis, those
reporting that both parents were smokers had a 27% lower
risk of Parkinson’s disease than those reporting that neither
parent smoked (relative rate ¼ 0.73, 95% confidence inter-
val: 0.53, 1.00; P-trend ¼ 0.04) (Table 2). We further ad-
justed the pooled data for caffeine and alcohol intake at
baseline and found that the effect estimate did not materially
change but, as expected, that confidence intervals were
wider (pooled relative rate ¼ 0.76, 95% confidence interval:
0.55, 1.05).
We then restricted the multivariable pooled analysis to
never smokers at baseline. There was no association be-
tween parental smoking and Parkinson’s disease, as would
be expected if the effect of parental smoking is primarily
mediated through smoking by the offspring.
DISCUSSION
In this pooled analysis of 2 large cohorts, risk of
Parkinson’s disease was 27% lower for individuals whose
parents smoked than for individuals whose parents were
nonsmokers. An inverse association between smoking and
Parkinson’s disease has been found in numerous epidemio-
logic studies, but consensus is lacking as to whether the
relation is causal, due to confounding, or a result of reverse
causation. If the desire to initiate or continue smoking and
Parkinson’s disease were both independently affected by
a third factor, then parental smoking should not be related
to Parkinson’s disease risk. This causal structure is illus-
trated with directed acyclic graphs (Figure 1) (16, 17).
Under the paradigm of reverse causation, where subclinical
disease influences smoking behavior, parental smoking would
also not predict Parkinsons disease in offspring (Figure 2).
Were smoking truly protective against Parkinson’s disease,
and parental smoking predicted smoking, then parental
smoking would be expected to be inversely associated with
Parkinson’s disease, as we found (Figure 3).
Parental
Smokin
g
SmokingParkinson’s Disease
Figure 2. Paradigm II: Parkinson’s disease prevents smoking. The
observed association is due to reverse causation. Because there is no
open path between parental smoking and Parkinson’s disease, no
association would be expected.
Parental
Smoking
Smoking
C
Parkinson’s Disease
Figure 3. Paradigm III: The inverse relation between smoking and
Parkinson’s disease is causal. C represents one or more factors
causally related to Parkinson’s disease and smoking status that,
given it exists, could confound the association between smoking
and Parkinson’s disease. The effect of parental smoking on
Parkinson’s disease is probably mediated through its effects on indi-
viduals’ smoking status because there are no alternative open paths
between parental smoking and Parkinson’s disease even in the pres-
ence of C; the association, as illustrated, is causal.
Parental
Smoking
Smoking
C
Parkinson’s Disease
Figure 4. Paradigm IV: Parental smoking and Parkinson’s disease
are confounded. C represents a factor causally related to both paren-
tal smoking and Parkinson’s disease. An assumption underlying the
conclusion that smoking could be causally related to Parkinson’s dis-
ease is the nonexistence of C.
Parental
Smoking
Smoking
C
U
Parkinson’s Disease
Figure 5. Paradigm V: Parental smoking is associated with an in-
dependent cause of Parkinson’s disease. C represents a factor that is
causally related to Parkinson’s disease and is associated with paren-
tal smoking, although not causally. U represents a predictor of both
parental smoking and C. Under this paradigm, the inverse association
between parental smoking and Parkinson’s disease would not be a re-
sult of a causal relation between smoking and Parkinson’s disease.
Smoking and Parkinson’s Disease 681
Am J Epidemiol 2009;169:678–682
An inverse association between parental smoking and
Parkinson’s disease could exist under other scenarios. The
possibility cannot be ruled out, for example, that an expo-
sure such as a toxic or infectious agent in a family could
affect parental smoking behavior as well as the future risk of
Parkinson’s disease for both parents and children (Figure 4).
Alternatively, a toxic or infectious agent may bemore common
in a household where there is parental smoking (Figure 5).
Such an exposure would have to be transgenerational, affect-
ing both parent and child in early life, and to be present in all of
the settings in which the association between smoking and
Parkinson’s disease has been found.
Our analysis provides a novel approach to assessing
causality, and, when taken with the results of previous
longitudinal (1–5) and ecologic (8) studies, suggests a caus-
al interpretation of the relation between smoking and
Parkinson’s disease over confounding or reverse causation.
However, causality cannot be proven until a mechanism is
elucidated (18).
Our interest in smoking and Parkinson’s disease is etio-
logic. Smoking is hugely damaging to health; any benefit
derived from a reduction in risk of Parkinson’s disease is
outweighed by the increased risks of cancer and cardiovas-
cular disease. This, however, should not be an impediment
to evaluating tobacco components for possible neuroprotec-
tive effects.
ACKNOWLEDGMENTS
Author affiliations: Department of Epidemiology, Har-
vard School of Public Health, Boston, Massachusetts (E
´
ilis
J. O’Reilly, Alberto Ascherio); Department of Nutrition,
Harvard School of Public Health, Boston, Massachusetts
(E
´
ilis J. O’Reilly, Xiang Gao, Alberto Ascherio); Epidemi-
ology Branch, National Institute of Environmental Health
Sciences, Research Triangle Park, North Carolina (Honglei
Chen); Department of Neurology, Miller School of Medi-
cine, University of Miami, Miami, Florida (Hannah Gar-
dener); Department of Neurology, Massachusetts General
Hospital, Boston, Massachusetts (Michael A. Schwarzs-
child); and Channing Laboratory, Department of Medicine,
Brigham and Women’s Hospital and Harvard Medical
School, Boston, Massachusetts (Alberto Ascherio).
The study was supported by a National Institutes of
Health/National Institute of Neurological Diseases and
Stroke grant (to A. A.) to study Parkinson’s disease in the
Health Professionals Follow-up Study and Nurses Health
Study cohorts and by the intramural program of the National
Institutes of Health, the National Institute of Environmental
Health Sciences (to H. C.).
Conflict of interest: none declared.
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    • "It would be necessary to confirm the results in larger, independent samples of PD patients, composed of smokers and non-smokers. Another limitation concerns to the fact that parental smoking is related to PD risk [36]. It would have been preferable to take this variable into account when exploring the relationship between a genetic variant that influences smoking behavior (which is likely genetically and socially inherited, to some extent from parents) and PD risk. "
    [Show abstract] [Hide abstract] ABSTRACT: BACKGROUND: Smoking is a well documented environmental factor that reduces susceptibility to Parkinson's disease (PD). Several genetic variants within the nicotinic cholinergic receptor gene cluster, CHRNA5-CHRNA3-CHRNB4 have been reported to be associated with nicotine dependence (ND), and this association has been validated in multiple studies. OBJECTIVES: Due to the inverse correlation between smoking and PD susceptibility, we investigated whether ND-related genetic variants are associated with age at onset (AAO) of PD among smokers. METHODS: We performed a genetic association study in a sample of 677 Italian PD patients, ages 34-76. 438 had never smoked (NS), and 239 were current or past smokers (ever-smokers, ES). Three independent SNPs within the CHRNA5-CHRNA3-CHRNB4 gene cluster (rs588765, rs16969968, rs578776) were analyzed for association with AAO. RESULTS: We demonstrated an interaction between the rs588765 SNP and smoking status (NS vs. ES) that was nominally significant in its effect on PD AAO (p = 0.04). The rs588765 ND risk allele 'C' was associated with delayed AAO among ES (even when smoking intensity variables are accounted for), but had no significant effect among NS. In the ES group, a dominant model of inheritance was observed: carriers of the 'CC' genotype presented delayed AAO compared to carriers of the 'CT' or 'TT' genotypes. CONCLUSION: Our preliminary results suggest that the ND risk variant, rs588765, has a protective effect in PD, and is associated with later AAO, but only when the individual was previously exposed to nicotine. This may be explained by modulating the neuroprotective effect of chronic nicotine exposure against striatal dopaminergic damage. Further validation studies in additional populations are required.
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    • "It also becomes clear that this association is present as long as 20 years before the disease starts [13]. Researchers develop alternative study designs, including assessment of passive [15] and parental smoking [16]. In addition, studies show that the activity of monoamine oxidase B, which metabolizes MPTP into MPP+, is reduced in smokers " brains [17], and that two cigarette smoke compounds, nicotine and hydroquinone, inhibit the aggregation of alpha-synuclein [18]. "
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  • [Show abstract] [Hide abstract] ABSTRACT: The Nurses' Health Study was designed as a prospective follow-up study to examine relations between contraception and breast cancer. With follow-up questionnaires mailed every 2 years, investigators have added extensive details of lifestyle practices. The study, currently in its 20th year, has maintained high follow-up with > 90% of participants responding to each of the follow-up cycles since 1988. The relations between use of hormones, diet, exercise, and other lifestyle practices have been related to the development of a wide range of chronic illnesses among women. This review describes the methods used to follow up the study participants and summarizes the major findings that have been described over the first 20 years of the study. We highlight additional areas added to the study in recent years to address emerging issues in women's health. Special emphasis is placed on the recent findings from the study, including relations between weight gain and heart disease, diabetes, and mortality, the lack of relation between calcium and osteoporotic fractures, and the positive relation between postmenopausal use of hormones and risk of breast cancer.
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