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Smoking and Risk of Multiple Sclerosis: Evidence of Modification by NAT1 Variants

Briggs, Farren B. S.a; Acuna, Brigidb; Shen, Lingb; Ramsay, Patriciaa; Quach, Honga; Bernstein, Allanc; Bellesis, Kalliope H.b; Kockum, Ingrid S.d; Hedström, Anna K.e; Alfredsson, Larse; Olsson, Tomasd; Schaefer, Catherineb,*; Barcellos, Lisa F.a,b,*

doi: 10.1097/EDE.0000000000000089
Neurologic Disease

Background: Tobacco smoke is an established risk factor for multiple sclerosis (MS). We hypothesized that variation in genes involved in metabolism of tobacco smoke constituents may modify MS risk in smokers.

Methods: A three-stage gene-environment investigation was conducted for NAT1, NAT2, and GSTP1 variants. The discovery analysis was conducted among 1588 white MS cases and controls from the Kaiser Permanente Northern California Region HealthPlan (Kaiser). The replication analysis was carried out in 988 white MS cases and controls from Sweden.

Results: Tobacco smoke exposure at the age of 20 years was associated with greater MS risk in both data sets (in Kaiser, odds ratio [OR] = 1.51 [95% confidence interval (CI) = 1.17–1.93]; in Sweden, OR = 1.35 [1.04–1.74]). A total of 42 NAT1 variants showed evidence for interaction with tobacco smoke exposure (Pcorrected < 0.05). Genotypes for 41 NAT1 single nucleotide polymorphisms (SNPs) were studied in the replication data set. A variant (rs7388368C>A) within a dense transcription factor-binding region showed evidence for interaction (Kaiser, OR for interaction = 1.75 [95% CI = 1.19–2.56]; Sweden, OR = 1.62 [1.05–2.49]). Tobacco smoke exposure was associated with MS risk among rs7388368A carriers only; homozygote individuals had the highest risk (A/A, OR = 5.17 [95% CI = 2.17–12.33]).

Conclusions: We conducted a three-stage analysis using two population-based case-control datasets that consisted of a discovery population, a replication population, and a pooled analysis. NAT1 emerged as a genetic effect modifier of tobacco smoke exposure in MS susceptibility.

Supplemental Digital Content is available in the text.

From the aGenetic Epidemiology and Genomics Laboratory, Division of Epidemiology, School of Public Health, University of California, Berkeley, Berkeley, CA; bDivision of Research, Kaiser Permanente, Oakland, CA; cPalm Drive Hospital, Sebastopol, CA; dDepartment of Medicine, Center for Molecular Medicine, Karolinska Institute, Solna, Sweden; eInstitute of Environmental Medicine, Karolinska Institute, Solna, Sweden.

Submitted 30 May 2013; accepted 22 November 2013; posted 12 March 2014.

* Senior authors contributed equally.

The Kaiser Permanente Northern California Region Health Plan study was supported by the National Institute of Neurological Disorders and Stroke (R01 NS049510, R01 NS0495103) and the National Institute of Allergy and Infectious Diseases (R01 AI076544). Farren Briggs is a National Multiple Sclerosis Society Post-Doctoral Fellow (FG 1847A1/1).

The authors report no conflicts of interest.

Conflicts of interest: none declared.

Supplemental digital content is available through direct URL citations in the HTML and PDF versions of this article ( This content is not peer-reviewed or copy-edited; it is the sole responsibility of the author.

Correspondence: Lisa F. Barcellos, Genetic Epidemiology and Genomics Laboratory, Division of Epidemiology, School of Public Health, 324 Stanley Hall, University of California, Berkeley, CA 94720. E-mail:

© 2014 by Lippincott Williams & Wilkins, Inc