title: Serotonin transporter and receptor genes significantly impact nicotine dependence through genetic interactions in both European American and African American smokers.
abstract: BACKGROUND
  Pharmacologic studies implicate a significant role of genes encoding the serotonin transporter (SLC6A4) and the 5-HT3AB subunits HTR3A and HTR3B in nicotine dependence (ND). However, whether they are involved in ND remains largely unknown.
  
  
  METHODS
  Here, we examined the impact of variations in the three genes on ND in 1366 individuals from 402 African American (AA) and 671 individuals from 200 European American (EA) families. The ND of each smoker was assessed with smoking quantity (SQ), heaviness of smoking index (HSI), and Fagerström test for nicotine dependence (FTND).
  
  
  RESULTS
  Association analysis revealed marginal association of rs10160548 in HTR3A with SQ and HSI in AA, 5-HTTLPR in SLC6A4 with FTND in EA, and rs11606194 in HTR3B with SQ and FTND in the pooled sample. Haplotype-based association analysis revealed a few major haplotypes in HTR3A that were significantly associated with ND in the AA, EA, and pooled samples. However, none of these associations remained significant after correcting for multiple testing except for a haplotype G-C-C-T-A-T formed by SNPs rs1150226, rs1062613, rs33940208, rs1985242, rs2276302, and rs10160548 in HTR3A for the AA sample. Considering biological functions of the three genes, we examined interactive effects of variants in the three genes, which revealed significant interactions among rs1062613 and rs10160548 in HTR3A, rs1176744 in HTR3B, and 5-HTTLPR and rs1042173 in SLC6A4 in affecting ND in the three samples.
  
  
  CONCLUSIONS
  We conclude that SLC6A4, HTR3A and HTR3B play a significant role in ND through genetic interactions.
authors.affiliation: Shanxi Key Laboratory of Environmental Veterinary Science, Shanxi Agricultural University, Shanxi, China.
authors.forename: Zhongli
authors.initials: Z
authors.lastname: Yang
authors.forename: Chamindi
authors.initials: C
authors.lastname: Seneviratne
authors.forename: Shaolin
authors.initials: S
authors.lastname: Wang
authors.forename: Jennie Z
authors.initials: JZ
authors.lastname: Ma
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Payne
authors.forename: Jundong
authors.initials: J
authors.lastname: Wang
authors.forename: Ming D
authors.initials: MD
authors.lastname: Li
mesh_terms: D000328:Adult; D001741:Black or African American / Q000208:ethnology / Q000235:genetics*; D004843:Epistasis, Genetic / Q000235:genetics; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D044406:Receptors, Serotonin, 5-HT3 / Q000235:genetics*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics*; D014029:Tobacco Use Disorder / Q000175:diagnosis / Q000208:ethnology / Q000235:genetics*; D044465:White People / Q000208:ethnology / Q000235:genetics*
chemical_list: C509409:HTR3A protein, human; C509410:HTR3B protein, human; D044406:Receptors, Serotonin, 5-HT3; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins