Smoking and risk of amyotrophic lateral sclerosis: a pooled analysis of 5 prospective cohorts

Abstract

Background: Cigarette smoking has been proposed as a risk factor for amyotrophic lateral sclerosis (ALS), but epidemiological studies supporting this hypothesis have been small and mostly retrospective.

Objective: To prospectively examine the relation between smoking and ALS in 5 well-established large cohorts.

Design: Five prospective cohorts with study-specific follow-up ranging from 7 to 28 years.

Setting: Academic research.

Patients: Participants in the Nurses' Health Study, the Health Professionals Follow-up Study, the Cancer Prevention Study II Nutrition Cohort, the Multiethnic Cohort, and the National Institutes of Health-AARP (formerly known as the American Association of Retired Persons) Diet and Health Study.

Main outcome measures: Amyotrophic lateral sclerosis deaths identified through the National Death Index. In the Nurses' Health Study and the Health Professionals Follow-up Study, confirmed nonfatal incident ALS was also included.

Results: A total of 832 participants with ALS were documented among 562,804 men and 556,276 women. Smokers had a higher risk of ALS than never smokers, with age- and sex-adjusted relative risks of 1.44 (95% confidence interval, 1.23-1.68; P < .001) for former smokers and 1.42 (95% confidence interval, 1.07-1.88; P = .02) for current smokers. Although the risk of ALS was positively associated with pack-years smoked (P < .001), duration of smoking (9% increase for each 10 years of smoking, P = .006), and the number of cigarettes smoked per day (10% increase for each increment of 10 cigarettes smoked per day, P < .001), these associations did not persist when never smokers were excluded. However, among ever smokers, the risk of ALS increased as age at smoking initiation decreased (P = .03).

Conclusions: Results of this large longitudinal study support the hypothesis that cigarette smoking increases the risk of ALS. The potential importance of age at smoking initiation and the lack of a dose response deserve further investigation.

Fig. 1

Amyotrophic lateral sclerosis (ALS) rates in US men and women from the Nurses’ Health Study (NHS), the Health Professionals Follow-up Study(HPFS), the Cancer Prevention Study II Nutrition Cohort (CPS-II Nutrition Cohort), and the Multiethnic Cohort (MEC) and the NIH-American Association of Retired Persons Diet and Health Study (AARP-DH).

Figure 2

Study-specific and pooled multivariable relative risk and 95% confidence interval of amyotrophic lateral sclerosis with increment of each 10-cigarettes smoked per day. The black square and horizontal lines correspond to the study-specific multivariable relative risk and 95% confidence interval, respectively. The area of the black square reflects the study weight (inverse of the variance). The diamond represents the pooled multivariable relative risk and 95% confidence interval. The solid vertical line indicates a relative risk of 1.0. No statistical heterogeneity was found among the risk estimates across individual studies (p for heterogeneity =0.43). Pooled RR =1.10 (95% CI, 1.05–1.16, p<0.0001).

Figure 3

Study-specific and pooled multivariable relative risk and 95% confidence interval of amyotrophic lateral sclerosis (ALS) with increment of each 10-years smoked. The black square and horizontal lines correspond to the study-specific multivariable relative risk and 95% confidence interval, respectively. The area of the black square reflects the study weight (inverse of the variance). The diamond represents the pooled multivariable relative risk and 95% confidence interval. The solid vertical line indicates a relative risk of 1.0. No statistical heterogeneity was found among the risk estimates across individual studies (p for heterogeneity =0.18). Pooled RR = 1.09 (95% CI 1.03–1.16, p=0.006.

Figure 4

Pooled multivariate relative risk and 95% confidence interval of amyotrophic lateral sclerosis for age at smoking initiation. No statistical heterogeneity was found across individual studies (p for heterogeneity>0.5). Relative risks and 95% confidence intervals were 1.61 (1.08–2.39) for initiating smoking before age 16; 1.35 (1.05–1.73) for 16-<20 years; 1.39 (1.06–1.80) for 20-<30 years; and 0.87 (0.54–1.39) for 30+ years. Age and sex adjusted p for trend across ever smokers=0.028; multivariate adjusted p=0.05. Excludes AARP-DH as data were not available.