Prospective Study of Cigarette Smoking and Amyotrophic Lateral Sclerosis
M. G. Weisskopf1,2 ,
M. L. McCullough3,
E. E. Calle3,
M. J. Thun3,
M. Cudkowicz4 and
A. Ascherio1,5,6
1 Department of Nutrition, Harvard School of Public Health, Boston, MA.
2 Department of Environmental Health, Harvard School of Public Health, Boston, MA.
3 Epidemiology and Surveillance Research, American Cancer Society, Atlanta, GA.
4 Neurology Clinical Trial Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
5 Department of Epidemiology, Harvard School of Public Health, Boston, MA.
6 The Channing Laboratory, Department of Medicine, Harvard Medical School and Brigham and Womens Hospital, Boston, MA.
Received for publication October 8, 2003; accepted for publication February 4, 2004.
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ABSTRACT
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Cigarette smoking has been proposed as a risk factor for amyotrophic lateral sclerosis (ALS), but because of the low incidence of ALS this association has been examined only with case-control methods. The authors prospectively assessed the relation between cigarette smoking and ALS mortality among participants in the Cancer Prevention Study II cohort of the American Cancer Society, a cohort of over 1 million people enrolled in 1982 who completed a lifestyle questionnaire including a detailed smoking history at baseline. Causes of deaths were ascertained through death certificates; ALS was not identified separately until 1989. From January 1, 1989, through 1998, 291 women and 330 men died from ALS. The relative risk of ALS among current smokers compared with never smokers was 1.67 (95% confidence interval: 1.24, 2.24; p = 0.002) in women and 0.69 (95% confidence interval: 0.49, 0.99; p = 0.04) in men. The difference in the relative risk estimates between the sexes was statistically significant (p < 0.0003). This large prospective study provides limited evidence that current cigarette smoking may be associated with increased death rates from ALS in women but not in men.
amyotrophic lateral sclerosis; mortality; motor neuron disease; prospective studies
Abbreviations:
Abbreviations: ALS, amyotrophic lateral sclerosis; CI, confidence interval; CPS II, Cancer Prevention Study II; ICD-9, International Classification of Diseases, Ninth Revision.
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INTRODUCTION
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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder of motor neurons that afflicts an estimated 30,000 Americans (1). The consequences of ALS are dramatic, as it rapidly compromises motor function. The median survival time from diagnosis with ALS is an estimated 1.53 years, and mean survival times are only minimally longer (26). Although there are familial cases of ALS, and both autosomal dominant and autosomal recessive transmissions have been documented (7), about 90 percent of cases are sporadic (8) and of unknown etiology. Several risk factors for sporadic ALS have been examined epidemiologicallyincluding aspects of diet, farm work, and exposure to metals or solventsbut evidence of associations has remained generally inconsistent, in part because analyses have been limited to case-control studies (9, 10).
Cigarette smoke contains numerous toxic chemicals including many that induce oxidative stress (1113), which has been suggested to play a role in the pathogenesis of ALS. A significant positive association between cigarette smoking and risk of ALS has been recently reported in two case-control studies (14, 15). Although no relation was found in some previous studies (1621), the null findings may have been the result of several limitations, including small sample size and biased control selection.
Data from prospective cohort studies could bring stronger evidence to the assessment of the relation between cigarette smoking and ALS. The relatively low frequency of the disease, however, means that a very large cohort would be necessary. The Cancer Prevention Study II (CPS II) cohort of the American Cancer Society, comprising over 1 million Americans (22), provided the opportunity to assess prospectively the relation between cigarette smoking and ALS mortality among men and women.
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MATERIALS AND METHODS
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Study population
The CPS II is a prospective cohort study of nearly 1.2 million US men and women, begun in 1982. Participants were recruited by American Cancer Society volunteers in 50 states, the District of Columbia, and Puerto Rico (22). Families with at least one member over the age of 45 years and other family members over the age of 30 years were invited to participate. The median age at cohort entry in 1982 was 57 years for men and 56 years for women. In total, 508,334 men and 676,288 women completed a four-page questionnaire. Because deaths from ALS before 1989 were not coded separately, we included in the study only 459,360 men and 638,849 women who were still alive as of January 1, 1989. The follow-up period extended from January 1, 1989, to December 31, 1998.
Case ascertainment
Vital status of the study participants has been determined by automated linkage with the National Death Index through December 31, 1998 (23). Death certificates or codes for cause of death have been obtained for over 98 percent of known deaths. The underlying cause of death was coded from death certificates according to the International Classification of Diseases, Ninth Revision (ICD-9) (24). Prior to and through 1988, deaths from ALS were coded together with rare causes of death and, thus, cannot be identified. Deaths from ALS occurring after 1988 are defined as ICD-9 code 335.2 (motor neuron disease) as either the underlying or a contributing cause of death. We had available for review 183 death certificates originally coded with ICD-9 code 335.2 as the underlying cause of death in CPS II. Among these 183 certificates, 164 (89.6 percent) were specified as ALS (ICD-9 code 335.20), 13 (7.1 percent) were not specified beyond motor neuron disease (ICD-9 code 335.2), and for three certificates (1.6 percent) the text was illegible. Of the remaining three certificates (1.6 percent), two (1.1 percent) had a diagnosis of bulbar palsy, and one (0.6 percent) had a diagnosis of progressive muscular dystrophy. The results were similar when stratified by gender, as 86.1 percent and 94.6 percent of men (n = 108) and women (n = 75), respectively, were specified as having ALS. These results suggest that few death certificates with code 335.2 did not have a diagnosis of ALS.
Assessment of exposure
Cigarette smoking status was ascertained in 1982 by the question, "Do you now or have you ever smoked cigarettes, at least one a day for one years time?" Ever smokers were then asked questions on the average number of cigarettes smoked per day, the age when they started smoking, and the total number of years they smoked. Former smokers were also asked the age at which they quit smoking. Data on the covariates considered in the analyses were also obtained from responses to the questionnaire in 1982.
Statistical analyses
Participants contributed follow-up time from January 1, 1989, to the date of death from ALS or any other cause, or December 31, 1998, whichever came first. Age-specific mortality rates were calculated as the number of ALS deaths divided by the person-time of follow-up in each 5-year age group. Age-adjusted (in 5-year age groups) relative risks were calculated by dividing the incidence of ALS among participants in each category of smoking variable by the corresponding incidence in never smokers, using Mantel-Haenszel weights. We used Cox proportional hazards regression to estimate relative risk and 95 percent confidence intervals when adjusting for, or stratifying by, additional variables. To obtain a better age adjustment, we stratified the Cox models by age in single years. The significance of trends was assessed using the method of Breslow and Day (25), by assigning medians to each category and modeling as a continuous variable. In the comparison of never with past and current smoking, a single variable with values of 1, 2, and 3 was modeled. Interactions were entered as multiplicative terms (described in Results) in the Cox models, and their significance was ascertained on the basis of the Wald test or the likelihood ratio test. SAS version 6.12 software (SAS Institute, Inc., Cary, North Carolina) was used for all analyses.
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RESULTS
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Between 1989 and 1998, we documented 330 deaths from ALS during 4,135,897 person-years among men and 291 deaths from ALS during 6,018,646 person-years among women. ALS mortality rates were higher in men than in women in every age group and increased steadily with age up to age 7579 years in men and age 8084 years in women (figure 1).

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FIGURE 1. Amyotrophic lateral sclerosis (ALS) death rates in US men and women from the American Cancer Societys Cancer Prevention Study II cohort, 19891998.
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Selected characteristics of men and women included in the study by smoking status are shown in table 1. The level of education among men was highest among never smokers and lowest among current smokers. Among women, educational status was highest among former smokers. In both men and women, alcohol consumption was associated with cigarette smoking.
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TABLE 1. Baseline (1982) characteristics* among men and women according to smoking status, American Cancer Societys Cancer Prevention Study II
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Among men, the age-adjusted relative risk for ALS mortality was 0.69 (95 percent confidence interval (CI): 0.48, 0.98) for current smokers compared with never smokers (table 2). No gradation of risk was seen with cigarettes smoked per day, years of smoking, or age when quit smoking. Results were similar after adjustment for education and alcohol consumption, neither of which was significantly associated with risk of ALS (table 2). Risk of ALS among men was also not associated with ever smoking of cigars or pipes (relative risk = 0.94, 95 percent CI: 0.69, 1.29; not shown in table 2).
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TABLE 2. Baseline age- and multivariate-adjusted relative risk of amyotrophic lateral sclerosis by smoking category among men, American Cancer Societys Cancer Prevention Study II, 19891998
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Among women, current cigarette smoking was associated with an increased risk of death from ALS (table 3). The age-adjusted relative risk for current smokers compared with never smokers was 1.66 (95 percent CI: 1.24, 2.22). The estimate was virtually unchanged with adjustment for education and alcohol consumption. As among men, neither education nor alcohol consumption was associated with ALS. No clear gradation of risk was seen with cigarettes smoked per day in analyses restricted to current smokers, nor with age when quit smoking in analyses restricted to former smokers (table 3). There was a suggestion of decreasing risk with increasing duration of smoking or cigarettes smoked per day among current smokers. The association between current cigarette smoking and death from ALS differed significantly between men and women (p for interaction = 0.0003).
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TABLE 3. Baseline age-adjusted relative risk of amyotrophic lateral sclerosis by smoking category among women, American Cancer Societys Cancer Prevention Study II, 19891998
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Our results for both men and women were not appreciably affected by further adjustment for occupation type (white or blue collar or housewife); coffee consumption; or history of diabetes, heart disease, hypertension, or stroke as reported in the baseline questionnaire. Because of the possibility that some CPS II participants who were included in our analysis (alive in 1989) may have had ALS when they responded to the baseline questionnaire in 1982 despite the exclusion of the first 6 years of follow-up, we repeated the analyses excluding the 44,218 men and 65,836 women who reported a major illness at baseline. These analyses included 211 deaths and 242 deaths attributed to ALS among men and women, respectively. The results were not materially different from the results with the entire cohort. Comorbidities might lead to some underascertainment of ALS on death certificates. Because comorbidities would be more likely at older ages, we repeated the analyses with follow-up only until the age of 75 years. These analyses included 165 deaths and 172 deaths attributed to ALS among men and women, respectively. Compared with never smokers, the relative risks for former and current smoking men were 0.88 (95 percent CI: 0.62, 1.26) and 0.85 (95 percent CI: 0.57, 1.26), respectively. The comparable relative risks for former and current smoking women were 1.08 (95 percent CI: 0.72, 1.61) and 1.79 (95 percent CI: 1.26, 2.54), respectively.
Because of the different results obtained in men and women, we explored whether, among women, the association between smoking and ALS was modified by factors related to hormonal levels, such as menopausal status, use of oral contraceptives, or postmenopausal hormones. In separate analyses, we found significantly stronger positive associations among premenopausal women or women with a history of use of oral contraceptives. In contrast, use of postmenopausal hormones did not appear to modify the association between smoking and risk of ALS. None of these analyses was based on an a priori hypothesis, however, and the results should thus be interpreted cautiously.
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DISCUSSION
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In this large prospective study, we found a positive association between current cigarette smoking and increased death rate from ALS in women but not in men. The increased risk in women was seen only in current smokers. There was no evidence of a dose-response relation.
The influence of cigarette smoking on the risk of ALS has been previously examined only in case-control studies (1421, 26). In many of these studies, no association was seen (1621, 26), but methodological considerations limit the interpretation of these studies. Most investigations had small sample sizes (less than 100 cases) (16, 17, 19, 21) and used controls that are likely to have smoking habits similar to those of the cases, such as friends (16, 21), spouses (20), or controls matched on lifestyle (17) or socioeconomic status (21). In one study (26), determination of smoking status was based on medical records, which are generally incomplete with respect to smoking histories. In others, the reported control selection methods (18) and details of smoking exposure (1820, 26) were minimal.
More recently, two case-control studies have attempted to address some of these methodological issues and have found increased risk of ALS among cigarette smokers (14, 15). In a population-based case-control study in western Washington State, with 161 cases and 321 controls selected through random digit dialing and Medicare lists, Nelson et al. (15) found an odds ratio of 3.7 (95 percent CI: 1.6, 8.4) among men and of 3.2 (95 percent CI: 1.3, 8.0) among women when comparing current smokers with never smokers. That study also found significant increases in risk of ALS with increasing pack-years of smoking and duration of smoking. A second population-based case-control study in New England, with 109 cases and 256 controls selected through random digit dialing, found an odds ratio of 1.7 (95 percent CI: 1.0, 2.8) for ever smokers compared with never smokers (14). This study, however, did not find dose-response relations by pack-years or years smoked. Only Nelson et al. (15) and Kondo and Tsubaki (20) reported results separately for men and women, although all previous studies included both sexes. Nelson et al. (15) found an increased risk of ALS among both male and female current smokers, but past smoking was associated with increased ALS risk only among women. There were two substudies in the report by Kondo and Tsubaki (20). The first involved cases identified from mortality records (n = 458 for men, with 216 controls; n = 254 for women, with 421 controls) and found relative risks for smokers of 0.95 among men and 0.92 among women. The second involved hospitalized ALS cases (104 men, 54 women) and single matched controls. In this substudy, the relative risk for smokers among men was 1.05, while the relative risk among women was undefined because none of the controls smoked (1.9 percent of the cases reported smoking).
Our study has several limitations. Follow-up of the CPS II cohort was limited to mortality and did not directly measure ALS incidence. The median survival with ALS is short (1.53 years) (26), so mortality should be a reasonable surrogate for incidence. Further, death certificate data have been estimated to accurately identify 7090 percent of ALS or motor neuron disease cases (2730). Thus, a small number of ALS deaths will have been attributed to other causes in CPS II. However, this would not materially bias the relative risk estimates unless the misclassification of the cause of death was strongly related to cigarette smoking. The general validity of our ALS assessment is supported by our finding of an increasing risk of ALS mortality with age in both men and women except at the oldest ages when the risk decreases again, which is in good agreement with results from previous US studies with respect to both the rate and the trend over age (3133). In addition, the age-specific rates in our study predict a cumulative ALS mortality (assuming no competing risks) between the ages of 55 and 74 years of 1.48 per thousand in men and of 0.94 per thousand in women, which are similar to those found in incidence studies. For example, in a study in Washington State (34), the predicted cumulative incidence per thousand over the same age period assuming no competing risks (our calculation) would be 1.66 in men and 1.35 in women. Further, the fact that results did not materially change by excluding deaths after the age of 75 years, which are probably more prone to misclassification, suggests that diagnostic errors are unlikely to fully explain our results. An additional limitation is that smoking status was determined in 1982 only. Cessation of smoking during follow-up could bias the risk estimates for current smokers toward the null. While this would not account for the opposite results observed in men and women, it would also make our results more similar to those of Nelson et al. (15), who found an increased risk of ALS among women who were former smokers but not among men who were former smokers. Finally, CPS II participants are, on average, more educated and affluent than the US population as a whole (35). Although these differences may influence comparisons of absolute rates between the CPS II and US populations, they should not affect internal validity.
If the relation between smoking and ALS is causal, it is unclear why smoking would increase risk in women but not in men. There was some suggestion in our data of possible effect modification by menopausal status or oral contraceptive use but, because of the small number of cases in these subanalyses, this result should be interpreted cautiously. It remains possible that the positive association in women is due to chance or residual confounding rather than to a causal relation with smoking.
Cigarette smoking might influence the risk of ALS by either a direct neurotoxic effect on motor neurons or increasing oxidative stress. Cigarette smoke contains lead and other heavy metals (11), and body burdens of many of these compounds are significantly higher in smokers than in nonsmokers (11, 36, 37). Although the results have been questioned to some extent (9), there are several case-control studies that have shown a positive association between heavy metal and other chemical exposures and the development of ALS (10, 38). In a recent large case-control study, exposure to agricultural chemicals was found to be significantly associated with a higher incidence of ALS (39). Before restrictions on organochlorine pesticide use, cigarette smoke was found to be a significant source of exposure to dichlorodiphenyltrichloroethane (DDT) and related compounds (40). Although the concentrations of individual organochlorine pesticides in tobacco have declined dramatically since the early 1970s, cigarette smoke may remain a source of exposure to other agricultural chemicals that could directly injure motor neurons. Cigarette smoke may also influence the development of ALS by inducing oxidative stress. There are many oxidant compounds in cigarette smoke (12), and cigarette smokers have been found to have higher blood levels of products of lipid peroxidation (13). In addition, cigarette smoke has been found to inhibit vascular endothelial growth factor in hypoxic conditions in vitro and in vivo (41). Low circulating vascular endothelial growth factor levels, as found in individuals homozygous for a mutation in the gene promotor, have been recently found to be associated with higher risk of ALS (42).
In summary, we found an increased risk of ALS mortality among female smokers but not among male smokers. The possibility of effect modification, not only by hormones and oral contraceptive use but also by other factors that might relate to the absence of effect among the men in our cohort, should be explored.
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NOTES
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Reprint requests to Dr. Marc G. Weisskopf, Department of Environmental Health, Occupational Health Program, Harvard School of Public Health, Landmark Center, 3rd Floor, P.O. Box 15697, Boston, MA 02215 (e-mail: mweissko{at}hsph.harvard.edu). 
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