BACKGROUND AND AIMS: Gene variants in CHRNA5-A3-B4, which encode for the alpha5, alpha3 and beta4 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. DESIGN, SETTING, PARTICIPANTS: A cross sectional study of 400 Alaska-Native individuals including 290 tobacco users. MEASUREMENTS: CHRNA5-A3-B4 genotype, body weight, and tobacco consumption biomarkers such as plasma cotinine and urinary total nicotine equivalents (TNE). FINDINGS: 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 30kb haplotype in CHRNA5-A3-B4, was prevalent (16%) and significantly associated 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 significantly associated 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.
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