title: Genome-wide association analyses suggested a novel mechanism for smoking behavior regulated by IL15.
abstract: Cigarette smoking is the leading preventable cause of death in the United States. Although smoking behavior has a significant genetic determination, the specific genes and associated mechanisms underlying the smoking behavior are largely unknown. Here, we carried out a genome-wide association study on smoking behavior in 840 Caucasians, including 417 males and 423 females, in which we examined approximately 380,000 single nucleotide polymorphisms (SNPs). We found that a cluster of nine SNPs upstream from the IL15 gene were associated with smoking status in males, with the most significant SNP, rs4956302, achieving a P-value (8.80 x 10(-8)) of genome-wide significance. Another SNP, rs17354547 that is highly conserved across multiple species achieved a P-value of 5.65 x 10(-5). These two SNPs, together with two additional SNPs (rs1402812 and rs4956396) were selected from the above nine SNPs for replication in an African-American sample containing 1251 subjects, including 412 males and 839 females. The SNP rs17354547 was replicated successfully in the male subgroup of the replication sample; it was associated with smoking quantity (SQ), the Heaviness of Smoking Index (HSI) and the Fagerstrom Test for Nicotine Dependence (FTND), with P-values of 0.031, 0.0046 and 0.019, respectively. In addition, a haplotype formed by rs17354547, rs1402812 and rs4956396 was also associated with SQ, HSI and FTND, achieving P-values of 0.039, 0.0093 and 0.0093, respectively. To further confirm our findings, we carried out an in silico replication study of the nine SNPs in a Framingham Heart Study sample containing 7623 Caucasians from 1731 families, among which, 3491 subjects were males and 4132 were females. Again, the male-specific association with smoking status was observed, for which seven of the nine SNPs achieved significant P-values (P<0.05) and two achieved marginally significant P-values (P<0.10) in males. Several of the nine SNPs, including the highly conserved one across species, rs17354547, are located at potential transcription factor binding sites, suggesting transcription regulation as a possible function for these SNPs. Through this function, the SNPs may modulate the gene expression of IL15, a key cytokine regulating immune function. As the immune system has long been recognized to influence drug addiction behavior, our association findings suggest a novel mechanism for smoking addiction involving immune modulation through the IL15 pathway.
authors.affiliation: School of Medicine, University of Missouri-Kansas City, Kansas City, MO 64108, USA.
authors.forename: Y-Z
authors.initials: YZ
authors.lastname: Liu
authors.forename: Y-F
authors.initials: YF
authors.lastname: Pei
authors.forename: Y-F
authors.initials: YF
authors.lastname: Guo
authors.forename: L
authors.initials: L
authors.lastname: Wang
authors.forename: X-G
authors.initials: XG
authors.lastname: Liu
authors.forename: H
authors.initials: H
authors.lastname: Yan
authors.forename: D-H
authors.initials: DH
authors.lastname: Xiong
authors.forename: Y-P
authors.initials: YP
authors.lastname: Zhang
authors.forename: S
authors.initials: S
authors.lastname: Levy
authors.forename: J
authors.initials: J
authors.lastname: Li
authors.forename: C K
authors.initials: CK
authors.lastname: Haddock
authors.forename: C J
authors.initials: CJ
authors.lastname: Papasian
authors.forename: Q
authors.initials: Q
authors.lastname: Xu
authors.forename: J Z
authors.initials: JZ
authors.lastname: Ma
authors.forename: T J
authors.initials: TJ
authors.lastname: Payne
authors.forename: R R
authors.initials: RR
authors.lastname: Recker
authors.forename: M D
authors.initials: MD
authors.lastname: Li
authors.forename: H-W
authors.initials: HW
authors.lastname: Deng
mesh_terms: D000328:Adult; D000368:Aged; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D019409:Interleukin-15 / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012189:Retrospective Studies; D012737:Sex Factors; D012907:Smoking / Q000235:genetics*
chemical_list: D019409:Interleukin-15