title: A study of TH01 and IGF2-INS-TH haplotypes in relation to smoking initiation in three independent surveys.
abstract: OBJECTIVE
  Recent studies suggest an association between a microsatellite locus (TH01) located in intron 1 of the tyrosine hydroxylase gene (TH) and nicotine dependence. We aimed here to study whether both TH01 and haplotypes of the wider IGF2-INS-TH region influence initiation of regular smoking in current smokers.
  
  
  METHODS
  A total of 3637 individuals from three independent studies (two of adults and one of adolescents) were analysed in relation to the age of first regular smoking (AFRS). Haplotypes and genotypes were obtained for the polymorphisms TH01, IGF2 ApaI, INS HphI and DRD4 VNTR (48 bp)n. Association between IGF2-INS-TH haplotypes and AFRS was tested by a regression model. A genotype-based genetic model assuming additivity was followed in order to estimate the effect of individual loci.
  
  
  RESULTS
  Overall, no significant associations were found after correcting for multiple tests. However, an IGF2-INS-TH haplotype (*5) was found to be nominally associated with AFRS at younger ages in adult smokers. Analyses of individual loci points to TH01 as a possible candidate influencing initiation of regular smoking. An AFRS-lowering trend nominally associated with allele 9 in a dosage-dependent manner was identified in both adult cohorts. TH01 did not show association or trend with age of initiation (first puff) either in adolescents or in the adolescents smoking regularly at age 18.
  
  
  CONCLUSIONS
  This study adds to the genetic evaluation of the associations of TH01 with smoking predisposition. Differences between historical and prospective surveys, different biological pathways and possible functional roles of this microsatellite in smoking initiation are discussed.
authors.affiliation: Human Genetics Division, University of Southampton School of Medicine, Southampton General Hospital, Tremona Road, Southampton, UK.
authors.forename: Santiago
authors.initials: S
authors.lastname: Rodríguez
authors.forename: Shuwen
authors.initials: S
authors.lastname: Huang
authors.forename: Xiao-he
authors.initials: XH
authors.lastname: Chen
authors.forename: Tom R
authors.initials: TR
authors.lastname: Gaunt
authors.forename: Holly E
authors.initials: HE
authors.lastname: Syddall
authors.forename: Julie A
authors.initials: JA
authors.lastname: Gilg
authors.forename: George J
authors.initials: GJ
authors.lastname: Miller
authors.forename: Cyrus C
authors.initials: CC
authors.lastname: Cooper
authors.forename: Derek G
authors.initials: DG
authors.lastname: Cook
authors.forename: Peter H
authors.initials: PH
authors.lastname: Whincup
authors.forename: Ian N M
authors.initials: IN
authors.lastname: Day
mesh_terms: D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005828:Genetics, Population; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000235:genetics*; D008137:Longitudinal Studies; D018895:Microsatellite Repeats / Q000235:genetics; D012907:Smoking; D014029:Tobacco Use Disorder / Q000235:genetics*
chemical_list: D007335:Insulin-Like Growth Factor II