title: Smoking and risk of multiple sclerosis: evidence of modification by NAT1 variants.
abstract: 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 (P(corrected) < 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.
authors.affiliation: 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.
authors.forename: Farren B S
authors.initials: FB
authors.lastname: Briggs
authors.forename: Brigid
authors.initials: B
authors.lastname: Acuna
authors.forename: Ling
authors.initials: L
authors.lastname: Shen
authors.forename: Patricia
authors.initials: P
authors.lastname: Ramsay
authors.forename: Hong
authors.initials: H
authors.lastname: Quach
authors.forename: Allan
authors.initials: A
authors.lastname: Bernstein
authors.forename: Kalliope H
authors.initials: KH
authors.lastname: Bellesis
authors.forename: Ingrid S
authors.initials: IS
authors.lastname: Kockum
authors.forename: Anna K
authors.initials: AK
authors.lastname: Hedström
authors.forename: Lars
authors.initials: L
authors.lastname: Alfredsson
authors.forename: Tomas
authors.initials: T
authors.lastname: Olsson
authors.forename: Catherine
authors.initials: C
authors.lastname: Schaefer
authors.forename: Lisa F
authors.initials: LF
authors.lastname: Barcellos
mesh_terms: D026921:Amino Acid Transport Systems, Neutral / Q000235:genetics; D029681:Arabidopsis Proteins / Q000235:genetics; D001191:Arylamine N-Acetyltransferase / Q000235:genetics*; D002140:California / Q000453:epidemiology; D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D051549:Glutathione S-Transferase pi / Q000235:genetics; D006801:Humans; D007527:Isoenzymes / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000209:etiology* / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012307:Risk Factors; D012907:Smoking / Q000009:adverse effects*; D013548:Sweden / Q000453:epidemiology; D014028:Tobacco Smoke Pollution / Q000009:adverse effects
chemical_list: C420564:AAP1 protein, Arabidopsis; D026921:Amino Acid Transport Systems, Neutral; D029681:Arabidopsis Proteins; D007527:Isoenzymes; D014028:Tobacco Smoke Pollution; D001191:Arylamine N-Acetyltransferase; C089384:N-acetyltransferase 1; C496556:GSTP1 protein, human; D051549:Glutathione S-Transferase pi