title: CHRNA5-A3-B4 genetic variants alter nicotine intake and interact with tobacco use to influence body weight in Alaska Native tobacco users.
abstract: OBJECTIVE
  Gene variants in CHRNA5-A3-B4, which encode for the α5, α3 and β4 nicotinic receptor subunits, are associated with altered smoking behaviors in European Americans. Little is known about CHRNA5-A3-B4 and its association with smoking behaviors and weight in Alaska Native people, which is a population with high prevalence but low levels of tobacco consumption, extensive smokeless tobacco use and high rates of obesity. We investigated CHRNA5-A3-B4 haplotype structure and its association with nicotine intake and obesity in Alaska Native people.
  
  
  METHODS
  A cross-sectional study of 400 Alaska Native individuals, including 290 tobacco users.
  
  
  METHODS
  CHRNA5-A3-B4 genotype, body weight and tobacco consumption biomarkers such as plasma cotinine and urinary total nicotine equivalents (TNE).
  
  
  RESULTS
  Alaska Native people have a distinct CHRNA5-A3-B4 haplotype structure compared with European/African Americans. In 290 Alaska Native tobacco users the 'G' allele of rs578776, which tagged a 30 kb haplotype in CHRNA5-A3-B4, was prevalent (16%) and associated significantly with nicotine intake (20% higher plasma cotinine, P < 0.001, 16% higher TNE, P = 0.076), while rs16969968 was not associated with nicotine intake. Rs578776 acted in combination with CYP2A6, the main nicotine-metabolizing enzyme, to increase nicotine intake by 1.8-fold compared with the low-risk group (P < 0.001). Furthermore, rs2869950, a single nucleotide polymorphism 5' to CHRNB4, was associated significantly with increased body mass index (P < 0.01) in the tobacco users even after controlling for differences in nicotine intake (P < 0.01).
  
  
  CONCLUSIONS
  Genetic variants in CHRNA5-A3-B4 alter nicotine intake and body mass index in a population of Alaska Native people, who have a distinct haplotype structure, smoking behaviors and prevalence of obesity.
authors.affiliation: Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada.
authors.forename: Andy Z X
authors.initials: AZ
authors.lastname: Zhu
authors.forename: Caroline C
authors.initials: CC
authors.lastname: Renner
authors.forename: Dorothy K
authors.initials: DK
authors.lastname: Hatsukami
authors.forename: Neal L
authors.initials: NL
authors.lastname: Benowitz
authors.forename: Rachel F
authors.initials: RF
authors.lastname: Tyndale
mesh_terms: D000328:Adult; D000413:Alaska / Q000453:epidemiology; D001189:Aryl Hydrocarbon Hydroxylases / Q000097:blood; D015992:Body Mass Index; D001835:Body Weight / Q000235:genetics*; D003367:Cotinine / Q000097:blood; D003430:Cross-Sectional Studies; D065637:Cytochrome P-450 CYP2A6; D005260:Female; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009538:Nicotine / Q000737:chemistry / Q000652:urine; D020641:Polymorphism, Single Nucleotide; D011978:Receptors, Nicotinic / Q000235:genetics*; D012907:Smoking / Q000009:adverse effects* / Q000453:epidemiology; D014030:Tobacco, Smokeless / Q000009:adverse effects*
chemical_list: D001189:Aryl Hydrocarbon Hydroxylases; D003367:Cotinine; D065637:Cytochrome P-450 CYP2A6; D009419:Nerve Tissue Proteins; D009538:Nicotine; D011978:Receptors, Nicotinic; C447158:CHRNA5 protein, human; C447159:CHRNB4 protein, human; C585710:CYP2A6 protein, human
keywords: Alaska Native people; CHRNA5-A3-B4; obesity; smoking